PukeOnAPlate

Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Rahan. Episode Eighty. By Roger Lecureux, drawn by Andre Cheret. The Valley of Torments. What a strange trap. Curious about everything, the son of Crao observed the butterfly trapped in the spider's web. Alerted, it rushed towards its prey. When the hoarse and powerful roar of a lion sounded not far from there. You also hunt, “long mane”! Oh! As cries of terror arose, he rushed off. And. Page Two. Attacking an old woman is easier than catching a "Two-horned", aye, "long mane"! Ra-ha-ha! Rahan's combat clamor drowned out the roars of the beast, which left its victim to face. Accustomed to these confrontations since his early childhood, the son of Crao knew how to dodge and feint. You are not lively enough, "Long mane"! Page Three. He had jumped on the back of the lion, which reared up, plowing the air with its formidable claws Ra-ha-ha! The ivory blade sparkled in the sun, plunging into the beast's throat and reappearing in scarlet. Cutting the vein, or "Life-flow," Rahan only struck once. Ra-ha-ha! His long cry had another accent, that of victory. Page Four. Her body lacerated, the old woman was dying in the grass. Tall and yellow grass such as Rahan had never seen before. You. You are. The first Hunter that I. Have seen from. Since all the. Mine perished in the valley of torments. Ten times ten seasons ago! You are. Brave, but. You cannot do anything anymore. For the old Cereha. Take me. Me to the cave where I have. Still, lived! It is. That I would like. Leave for the territory of shadows! Moved, the son of fierce ages granted this wish. He reached the cave when two eagles burst out. Back, “Hooked Beaks”! Do not be afraid! I collected them. There are from moons and moons ago. They are. They were my only companions! The birds of prey did not in fact attack. Page Five. And they contented themselves with observing Rahan. How could an old woman like you survive so many seasons alone in this land!? Oh! I forgot the taste a long time ago. Of meat. But herbs. Magical herbs, spared me the sufferings of hunger! Eating herbs!? A slab of slate was placed on top of cold ashes. On this plate a whitish thing had hardened. Since it is on this slate, maybe it is good to eat!? Rahan nibbled on the thing, which crumbled beneath his teeth. It was bland, but it seemed nourishing to him. Never venture into it. The Valley of torments, my son! You would experience thirst and hunger there. Which gnaws at the insides! Every moment of the day and night, you would know. Fear you would be. Threat of death is lurking everywhere! Page Six. Exhausted by this warning, the old woman panted. She found the strength to hold out a bag of skin. My son, take it! Take! Thanks to these magic grains. The, the hunters could. Could. Could. Argh! Cereha! Cereha had just died without revealing her secret. Rahan was respectfully covering her with the strange yellow weeds when a rustling alerted him. An immense troop of men, women and children was advancing through the savannah, heading towards the valley that Cereha cursed so much! Oh! It was not a clan. There were ten, a hundred clans. It was a horde! Sometimes, in these fierce times, "Those-who-walk-upright" thus gathered their forces to conquer new territories. Impressed, Rahan watched the human wave approach. Page Seven. It was then that the eagles attacked him! You think Rahan stole Cereha's life? You want to avenge her! It cost him to strike these birds of prey that demonstrated their loyalty to the dead woman. Protecting his face, he backed away from the pecks. Enough “Hooked Beaks”! Enough! Without even realizing it he found himself at the very edge of the rock. To parry a new assault he jumped back. And that was the fall! Escaping from the skin bag, the “Magic” grains swirled like yellow snowflakes. Inanimate at the bottom of the ravine, he did not hear the screams of the scouts of the horde who were rushing towards him. He was spying on the horde! If he is not dead, Urak will break his bones! Page Eight. Rahan, who was recovering his spirits, did not have time to ward off the attack of the colossus. This hunter had the strength of a great "Four Hands" and remained indifferent to the blows that the son of Crao threw at him! Ha-ha! Urak will finish you! He was suffocated under the embrace, his vision became blurry. The monster man will crush Rahan! Rahan must be cunning! Argh! Ha-ha-ha! No hunter, no matter how strong, can stand up to Urak! Rahan was crushed at the feet of the triumphant colossus. Page Nine. But it was only a feint! Oh!? You will learn that cunning can make strength fail, Urak! The son of fierce ages had unbalanced his opponent and paralyzed him with an implacable hold. Argh! Aie! Aie! Admiring clamors arose. Rahan could break your leg and make you a useless hunter! But Crao taught him generosity! Stand up Urak! Rahan forgives you! Bitter and vexed, the colossus joined his people. Where are you from brothers? Where are you going? We came together to discover the “Territory of Happiness”! The spirits told the great wizard Wahuk that we will find it beyond this valley! No, brothers! Do not risk yourself in the valley of torments! It is cursed! Page Ten. Thirst and hunger, cold and heat, fear and death await you! Rahan recounted the ordeals of Cereha to the clan. An rumble arose and Rahan understood that he could not convince them. But if all these dangers are real, why risk the fate of the entire horde!? But the sorcerer Wahuk, was indigent. This crazy woman was lying! The horde only believes the spirits who have promised it. Beyond the valley, the territory of happiness! Why not send a small group of scouts to reconnoiter? The spirits would undoubtedly see no harm in it! The irony of these last words escaped Wahuk. Approvals were heard from all sides. “Hair of Fire” speaks reason. Yes. Better to sacrifice a few of us than the whole horde! The horde will wait here for the scouts to return before venturing into the valley! Page Eleven. The horde split into five groups. Hunters, women, children, chiefs, and sorcerers. They will choose their scouts! While these groups consulted, Rahan once again entrusted his destiny to his weapon. Rahan will leave this territory without knowing the secret of the “Magic Grains”! The chiefs designate Daok the most valiant of them! Wahuk, who is trusted by the spirits, will represent the sorcerers! The women's assembly chose the courageous Inoo! And we, your sons, have chosen the bold Song! No one can represent the hunters better than Urak! Rahan will accompany these scouts! With a little resigned sigh, Rahan pointed at his knife, which pointed in the exact direction of the Valley of Torments! Suddenly screams broke out. The “Two-teeth”! The “Two-teeth”! A few mammoths were passing in the distance, towards which the hunters were already rushing. Page Twelve. The son of Crao appreciated the courage of these men who, a moment later, faced the monsters. Rahan will have to reckon with Song's temerity! Clinging to his fleece, the young Song had climbed onto a mammoth, that he was stabbing with his short spear! Die "Two-tooth!" Song wants it! Rahan saw no more. Breaking the circle of hunters a large Mammoth charged the frightened women. The one who had been designated to be part of the Clan-of-the-sacrifices had just tripped and hit a rock. No! No! Unconscious, she was right in the path of the mammoth! Her fate depended on Rahan's speed. Page thirteen. Ra-ha-ha! It was only a respite. Other mammoths rushed into the ravine! This way Inoo! Strain! Song will pay for his bravery with his life! The “Two-tooth” that Song was riding collapsed, dragging the child with it! Yes. And Rahan will join the territory of shadows without having discovered the secret of Cereha! Rahan felt the mysterious grains which had scattered around this stump when he fell. They arrive! We are lost! Igloo and the son of Crao saw the enormous brown wave of monsters rolling towards their precarious refuge. Nothing could save them! Page Fourteen. And then there was a miracle! The mammoth had collapsed in front of the stump and the others, by avoiding this obstacle, spared Rahan and his young companion! The “Two-tooths” are moving away! We are saved! But song is not saved yet! Stuck under the mammoth he had killed, the reckless child screamed. Courage Song! Courage! Ra-ha-ha! But the efforts of the son of Crao were in vain. If Urak hadn't rushed to the rescue. Under the traction of the two men the huge head rose, freeing Song. Thanks, thanks. I thought I was joining the territory of shadows! We would have missed you, little scout! Rahan and the colossus exchanged a long look and smiled at each other. Together they had saved the child, and erased the memory of their confrontation! Page Fifteen. Saluted by the entire horde, the “Clan of Sacrifices” entered the Valley of Torments the same day. It was made up of Inoo, Song, Urak, the sorcerer Wahuk, and Chief Daok. And the son of Crao. Never forget that I am the boss! If you want to eat, you will have to obey me! These words irritated Rahan. Rahan never had a boss, Daok! But he will not bother your clan. He will live on his own! He will hunt for himself! So be it. In the days that followed, in fact, Rahan lived on the fringes of the scouts. And sometimes macabre discoveries were made. “No one returns from the valley of torments” said old Cereha! Why leave Rahan aside Doak!? He. Shut up, Inoo! Decisions can only be made by Daok, and Me! Daok and Wahuk imposed all the chores on the other three. Page Sixteen. One morning, cries of fear alerted Rahan. Urak, who was returning from a watering hole, had a terrifying monster on his tail! Your spears! Your spears, quickly! What are you waiting for to help Urak!? Thinking only of their own safety, Daok and Wuhak hid in the rocks. Leave it to Rahan, let go! Over there, the colossus had just narrowly avoided the animal. The horned monster saw the man, who from the top of a rock, was throwing stones at him. Derisory projectiles, which aggravated him. Attack “Three-horns”! Rahan awaits you! The tricerotops did not attack, it approached heavily. And Rahan, firmly gripping his weapon, let himself fall on the monster! Ra-ha-ha! Page Seventeen. The son of the ferocious ages had relied on his weight to puncture the neck of the "Three Horns." It did not happen. The spear broke without even cutting the leathery skin! Run away, Rahan! Flee! No weapon can break the skin of this monster! You can't do anything against him! Yes! There is still an old trick left. It can Succeed! The triceratops stared with its little eyes at the man who, leaning against the rock, was teasing him again. He charged! Inoo and Song returned to camp screaming in horror. The monster was only twenty steps away from Rahan who still did not move! Oh! Rahan! Rahan! Ra-ha-ha! It is only when the frightening armored head obscured the sky that. Page Eighteen. The son of Crao dived sideways! The “Three horns” were smashed. The leather shield and back of his skull shattered. He could not resist the granite! The “Three-horned One” is dead, but others could come! We must break camp! That day, the son of Crao definitely won the esteem of Urak, Inoo and young Song. Chief Daok and sorcerer Wahuk, at last reluctantly accepted him into the “Clan of Sacrifices”. They plunged further into the valley of torment. They only allowed themselves rest at night. Rahan, then, enchanted his companions with a thousand stories, a thousand revels. How wonderful it is to know so much! But Daok and Wahuk's bitterness grew every day. “He” will soon have more authority than us! You have to find the opportunity to get rid of him! Page Nineteen. They were still moving forward but, one morning, there was discouragement. Is this the land of happiness that the spirits promised you, Wahuk!? The valley debouched onto an immensity of desert, on which an unbearable sun blazed! The territory exists! We will discover it behind this desert! So, before risking it we need water, lots of water! Rahan will find a source! Leaping into the foliage, the son of the wild ages was remembering the warning of the old Cereha. No one returns from the valley of torments! The cold, the heat. The thirst! While he scanned the surroundings, another danger threatened him. Daok! Daok who found the long-awaited opportunity! You have humiliated me too often Rahan! It is time for you to join the "Territory of Shadows" Page Twenty. The trickster was going to release his arrow. When. No, Daok! If you killed Rahan, Song and Urak would never forgive you! I will not tell them what you were going to do, because we have to stay united to reach the territory of happiness! But never do it again! Ignoring the danger he had faced, the son of fierce ages reappeared a long time later. The containers he had made from large bamboos were filled with water. We may not find another source for days and days! May the sun not strike us down first! The desert stretched as far as the eye could see, a hell of heat and light. Ah! If we could take a little of this shadow with us! Take away some shade? This is a wonderful idea, Inoo! Rahan knows what to do! Page Twenty-One We are going to build a hut. That walks! Cut bamboos and vines! Setting an example, Rahan was already reaping large palm fronds. The sun was still burning the sky when they entered the desert. But the shelter imagined by Rahan protected them from the relentless rays. A new ordeal began. The food brought at departure was exhausted. And, as the days went by, the water reserve diminished. “Thirst, hunger, death,” as Cereha predicted. One morning, however, in the gray of dawn. The “Long horns!” Do not move! As silent as a shadow, the son of Crao managed to approach the herd. Rahan does not like killing "Longhorns." But he has to! Page Twenty-Two. As soon as they smelled danger, the antelopes ran away. But. Ra-ha-ha! A little later. Extraordinary! I have never seen a hunter catch a “Long Horn" while running! You will get there one day, Song! This meat will keep us going for a while longer. As long as you save water! The precious water was, this night, to provoke a drama. Rahan was startled awake by cries of rage. Over there, near the overturned containers, Urak was manhandling Daok! I surprised Daok! He. He was stealing water! By wanting to prevent it, I have. I knocked them over. The colossus, overwhelmed, clawed at the sand into which pumped the spilled water! Page Twenty-Three. Without the water, it would be wiser to turn back! And Daok-the-selfish deserves that we abandon him in the desert! Turn back!? Never! The territory of happiness is now very close! The spirits have said it! Once again, Wahuk, the sorcerer, was able to convince the “Clan of Sacrifices.” And the odyssey continued. The “Walking Hut” was like a raft on an ocean of dunes, sailing under the light of the sun. The nights alone brought a little coolness. Then, Rahan meditated while observing the sky, which was a mystery to him. Why do they always shine in the same place? He began to think that other men under other skies were contemplating the same stars, and that gave him back his confidence. We will live! We will find the horde again! Page Twenty-Four. One morning, a howl erupted behind a nearby dune. Argh! Song! It was Song who shouted! The son of Crao rushed forward. But it was too late! The child had just been stung by a large black scorpion! You will never strike again, “Tail-of-death”! An instant later. Song, you are going to die, are you not? No Inoo, not yet! Quickly light a fire! As for you, little one, you will have to grit your teeth! The child did not flinch when Rahan cut his heel, and pressed on the wound to extract the deadly venom. You are brave like a true hunter, Song! Page Twenty-Five. He also remained stoic when the glowing embers made his flesh sizzle! This wound will heal very quickly. You are not joining the territory of shadows, Song! You saved me from the "Two-teeth"! You saved Urak from the "Three-Horned Monster"! You saved Song! Without you, our clan would already be decimated! It will be in a moment, Inoo! Look! The son of Crao had turned pale. It was impossible to escape the new danger that presented itself! As if springing from the sand, scorpions arrived from everywhere! Countless like the leaves of a tree, they slowly approached. The “tails-that-kill” are surrounding us! We are lost! The horrible black sheet of scorpions was indeed spreading around the “walking hut”. Impassable! The “Clan of Sacrifices” did not seem to be able to escape the frightening peril. The scorpions were approaching! Approaching! Page Twenty-Six. No! No! We still have a chance to ward off the "Tails-that-kill!" Rahan threw himself on the pillars of the "Walking Hut," dislocating it. A moment later he spread the bamboos, vines and palm fronds in a circle. The “tails that kill” fear fire! As soon as the flames rose, in fact, the mass of scorpions froze. But this ring of fire would quickly go out. What would happen then? The “Tails-that-Kill” are abandoning us! The black stream of scorpions was retreating towards the dunes from which they had sprung! And the path was clear! But the ordeal of the “Sacrifices” was not over! Without water and food, they were now without shelter! And the sun remained implacable. Page Twenty-Seven. That was why they screamed with joy when a green forest finally appeared on the horizon. The spirits told me so! The territory of happiness is there! Wahuk-the-sorcerer soon had a new song to sing. They now faced an inextricable jungle! We will find water and game here! But the dangers remain just as great! Rahan had barely finished these words when he and his companions fell into a ravine hidden by the bushes! Huge snakes immediately attacked them! Although not venomous, these reptiles were formidable! Ra-ha-ha! You will not strangle Rahan, "Boak!" Freeing themselves first, Rahan and Urak went to the aid of the others. The strength of the colossus was marvelous! Argh! Page Twenty-Eight. We have to get out of this Ravine as quickly as possible! Other snakes were arriving, ever more numerous and the wall of the ravine was almost vertical! Look, Rahan is abandoning us! I knew he was a coward! With the agility of a “Four-hands,” the son of Crao had scaled the wall, and disappeared. But he reappeared a moment later. Hold on to these vines! Rahan will help you get out of the "Boaks" lair! A little later. Rahan could have abandoned you in the ravine, Daok! Do you still think he is "Cowardly"? Hum. Bravo, Rahan! Bravo! The Clan of sacrifices continued their exhausting march. Water and game no longer posed a problem. Page Twenty-Nine. But this jungle was infested with wild animals. How many times did Rahan have to intervene to save his companions? No one knows. Ra-ha-ha! His devotion to the small clan did not outweigh the hatred that Daok and Wahuk bore him. He is great, he is very useful to us! But one day we will not need him anymore! So. To cross this green hell, it was sometimes necessary to enter swamps, the kingdom of caimans. Back, “Skin of Wood”! We are not coming to steal your territory! On the contrary, we would like to flee it! Urak's force completed Rahan's address. Could not the colossus, with his hands alone, dislocate the jaw of a saurian! Page Thirty. The yellow-leaf season was approaching when they discovered the high mountains. The territory of happiness is behind these mountains! We are saved! Let us hope for that Wahuk! Inoo and Song are at the end of their strength! The fantastic trek into unknown territory had been going on for too long. All were exhausted. In the ravine in which they entered, shortly after, an icy wind blew which added to their torments. Harassed and chilled, they took refuge in the first cave that came along. Rest, Rahan will light a fire. A little later. If wild animals want to compete with us for the cave, this fire will keep them away! Oh! Worn down with fatigue, everyone else was sound asleep. Page Thirty-One. If Rahan falls asleep too, the fire will go out! And what will happen if a danger shows up? Oh! Rahan has an idea! He remembered a distant memory. That of a spider alerted by the vibrations of its web! In the ravine he discovered enough vines to weave a coarse net at the entrance to the cave. Shortly after, with one of these vines tied to his wrist, he fell into a deep sleep. The fire was still glowing when a shock woke him. The “Web” was moving! Something wanted to enter the cave! Page Thirty-Two. Rahan scattered wood to rekindle the fire. And. The “Balouas!” Breaking the "Web," a couple of grizzly bears burst in. Ra-ha-ha! Neither his cry nor the growls of the bears woke the others! He would fight alone! Oh! He did not have time to cut the line which hindered his movements. A paw whipped the vine, throwing him to the ground. He had let the firebrand escape and, in the returning darkness, he glimpsed the grizzly bears rushing towards him. Ra-ha-ha! It was not Rahan's battle cry that startled Urak awake. But the burn from the torch that had rolled under his thigh! Page Thirty-Three. Stunned, the colossus saw the son of Crao struggling with the two bears. That. What. Oh! Hold on Rahan! I am coming! I am coming! With the intervention of Urak the confrontation took place. A new trick. Rahan was able to deliver a devastating blow. Ra-ha-ha! He was going to help Urak. But it was unnecessary. The second grizzly's bones cracked under the colossus' grip. Crack! The others finally woke up. Oh! What. What happened? If Rahan had not been awake, these Bears would have torn us to pieces while we slept! Two more long days the "Clan of sacrifices" marches in this defile, crossing the mountain range. Page Thirty-Four. And it was, after so much torment, the overwhelming, the desperate discovery. Is this the territory of happiness that you promised the horde, Wahuk!? The gully opened onto an endless ocean! For two seasons we have faced death. For nothing! Not for nothing, Inoo. If we survive, our experience will serve the horde! They will not venture out in search of a territory that only exists in the mind of Wahuk! The wizard said nothing, but. The horde must never know that my predictions were wrong! These must die! All of them! The same ordeals awaited the clan of sacrifices on the way back. They had to go back through the mountain and the marshes. Page Thirty-Five. The green-leaf season returned when they had re crossed the desert. But how can you find your way back, Rahan!? Rahan is guided by the stars, Song! He knows under what star leads us to the horde. Every night, this star shows him the direction to take! Song was astounded. This revelation defeated the sinister project of Wuhak and Daok. Since he knows the language of the stars, only he can bring us back to the horde! We cannot kill him first! The heat was less oppressive and the crossing of the desert looked less difficult returning than going there. Rahan had imagined a way to carry water and food in abundance. Pretexting on their title, the chief and the sorcerer were reluctant to attend to the travoi. If you do not do your part. Page Thirty-Six. We will abandon you here and the “Hooked-Beaks” will take care of you! A flock of vultures had been escorting the “Clan of the Sacrifices” since daylight. And pull, hard! We will arrive faster! The raptors were on the lookout for failure. Faced with this threat, Daok and Wahuk complied reluctantly! One night, the son of Crao exclaimed, pointing to the starry sky. We will soon find the horde! She is in that direction! Daok and Wuhak were astounded. And indeed, at dawn. We are back in the “Valley of Torments”! The horde is without doubt somewhere behind these mountains! But all the dangers are not yet over! Inoo and Daok will scout with Rahan! Page Thirty-Seven. Shortly after, the three scouts climbed towards a summit. Rahan did not notice Chief Daok's looks of hatred. They were walking along a deep precipice when. Look! Over there! It is the horde! It is time to end this, Rahan! We do not need you anymore, "Hair of Fire"! Nor you either, Inoo! This brutal and vicious attack was unpredicted, unexpected. But the son of Crao, in an instinctive reflex, was able to grab a projection and the wrist of his companion. I was tired of putting up with your authority, Rahan! You will die! Suspended in the void, Rahan and Inoo could not escape the rock that Daok-the-deceiver was going to throw! Page Thirty-Eight. Argh! But Daok's laughter became a howl of terror. He, in turn, had just been pushed into the void by. Wahuk-the-sorcerer! And you will soon find it again at the bottom of the abyss! All I have to do now is eliminate Song and Urak! Ha-ha-ha! The sorcerer disappeared. Rahan felt as if the nerves in his wrists were going to rupture! Hold on to Rahan's legs, Inoo! With both hands, Rahan might be able to. However. This. This. It is horrible! Rahan has lost his balance on the edge of a precipice! He dragged Inoo and Daok into his fall! They. They are dead! The lie did not fool the child. Rahan is more agile than a two-horned-mountain-goat! He could not have fallen! You lie Wahuk! You Lie! Page Thirty-Nine. You dare to insult Wahuk-the-sorcerer! Your Blasphemy deserves immediate death! The sorcerer did not have time to throw his assegai. Urak lifted him off the ground! Why did you follow Rahan and the others, fiend? We want the truth, Wahuk! You hear? The truth! The son of fierce ages now held on with both hands, his strength deserting him. Without me you could still save yourself! I am going to let go of you, Rahan! I will never forget, in the land of the shadows, everything you did for us! Determined to sacrifice herself, Inoo was going to let go! No, Inoo! Do not do that! Look! The child and the colossus who had just appeared were about to throw down a solid line! Page Forty. An instant later. Daok wanted to kill us. And he was in turn thrown into the abyss by Wahuk! We did not know, Inoo. Wahuk confessed everything to us. Song pointed to the flock of vultures which, over there, were fighting over the sorcerer's flesh! I. I. I did not want to kill him! But I. I had to squeeze a little too hard. The colossus, overwhelmed, looked at his powerful hands with a sort of disgust. Wahuk was not a good wizard, Urak. He always lied to us and wanted us dead! We will tell the horde! Shortly after, in front of the rediscovered horde, Inoo recounted the odyssey of the "Sacrifices", denouncing the perfidiousness of Wahuk, and exalting the self-sacrifice of Rahan. It is thanks to Rahan that we came back! It is thanks to "Fire Hair" that we know that beyond the valley of torment, the "territory of happiness" does not exist! Page Forty-One. Insensitive to this praise, the son of Crao observed the cliff from which he had fallen months before with the bag of "Magic Grains." At the foot of this cliff tall yellow grass had grown, like he had seen near the cave of the old Cereha. He remembered the charge of the mammoths. The paws of the "Two-tooths" have buried the "Magic-grains"! And this yellow grass grew, giving other grains! If a grain produces a cluster of seeds, all these grains could cover an entire plain with yellow grass! He had shucked the ear between his fingers. He wiped out some winnings. When he blew gently, only a white powder remained on the rock. A magic powder? Is this the secret that Cereha did not have time to reveal to Rahan? Page Forty-One. He tasted cautiously on his tongue the powder that had become like a paste. The same taste as the “Thing” that Cooked on the Cereha fire! Rahan wants to know! He climbed onto the cliff, at the foot of which a carpet of yellow grass rippled in the breeze. Moved, he approached the cave. The “Hooked-Beaks” had to search for another home! No, the faithful eagles were still there! But they did not flinch when the son of fierce ages respectfully saluted the skeleton of old Cereha. Rahan is not coming to violate your secret, Cereha, since you wanted to confide it to him! In the darkness, he discovered armfuls of "yellow herbs", jars of water, and containers filled with white powder. And balls of dough, hardened by time. Rahan understands! The powder of the “Magic Grains” with water forms this paste which, when cooked well, can feed “Those-who-walk-upright!” Page Forty-Three. You had a wonderful secret, Cereha! As you wished, Rahan will reveal it to all his brothers! Thanks to you, when the game is rare, they will no longer know hunger! Rahan, in fact, revealed to the horde the secret of the “Magic Grains.” Who knows, Inoo? Perhaps the horde will no longer have to look elsewhere for the “Territory of Happiness!? In enthusiasm, they mowed the "Yellow Herbs", they pounded the ears of the "Magic Grains", and they kneaded their white powder. But when the dough cakes began to cook, a religious silence ensued. What shall we call this food, Rahan? I do not know. Was the secret of wheat discovered in the night of wild ages, by the old hermit Cereha? No one will ever know. The son of Crao, forgetting all the bad memories of the valley of torments, turned and remembered with delight to what men, thousands of centuries later, would call "Bread"!

doi:10.3390/brainsci10110868. The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices. Oliver Cameron Reddy and Ysbrand D van der Werf. Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam. Brain Science, 2020, volume 10, page 868. Abstract: The glymphatic system is a “pseudo-lymphatic” perivascular network distributed throughout the brain, responsible for replenishing as well as cleansing the brain. Glymphatic clearance is the macroscopic process of convective fluid transport in which harmful interstitial metabolic waste products are removed from the brain intima. This paper addresses the glymphatic system, its dysfunction and the major consequences of impaired clearance in order to link neurodegeneration and glymphatic activity with lifestyle choices. Glymphatic clearance can be manipulated by sleep deprivation, cisterna magna puncture, acetazolamide or genetic deletion of AQP4 channels, but how lifestyle choices affect this brain-wide clearance system remains to be resolved. This paper will synthesize existing literature on glymphatic clearance, sleep, Alzheimer’s disease and lifestyle choices, in order to harness the power of this mass transport system, promote healthy brain ageing and possibly prevent neurodegenerative processes. This paper concludes that: 1. Glymphatic clearance plays a major role in Alzheimer’s pathology. 2. The vast majority of waste clearance occurs during sleep. 3. Dementias are associated with sleep disruption, alongside an age-related decline in AQP4 polarization and, 4. Lifestyle choices such as sleep position, alcohol intake, exercise, omega-3 consumption, intermittent fasting and chronic stress all modulate glymphatic clearance. Lifestyle choices could therefore alter Alzheimer’s disease risk through improved glymphatic clearance, and could be used as a preventative lifestyle intervention for both healthy brain ageing and Alzheimer’s disease. Keywords: glymphatic system, protein aggregates, Alzheimer’s disease, amyloid-beta, sleep, disease prevention. Section 1. Introduction. Discovered in 2012, the glymphatic system, which stands for glial-dependent lymphatic transport, has been categorized as a macroscopic waste clearance system. Due to the similarities in function, the glymphatic system has been described as the central nervous system’s analogue to the lymphatic system. The transportation of the central nervous system’s interstitial fluid (ISF) has long been thought to move via diffusion, but recently ISF was observed moving at a much faster rate than that possible through diffusion. This suggests the involvement of a mass transport system. This glial cell-dependent paravascular network removes soluble proteins and metabolites from the central nervous system, but in addition supplies the brain with glucose, lipids and neuromodulators, utilizing paravascular tunnels formed by astroglial cells. Since this is a relatively new discovery, the amount of scientific literature surrounding the glymphatic system is rapidly increasing, and therefore its definition is continuously being renewed. This has caused controversy surrounding both the directionality and the anatomical space in which this system resides. For instance, the movement of ISF along paravascular spaces of veins remains disputed, and some claim that a distinct route exists for this clearance pathway. These discrepancies can, however, be partially explained by the limited amount of literature and methodological differences between studies. The glymphatic system is constantly filtering toxins from the brain, but during wakefulness, this system is mainly disengaged. During natural sleep, levels of norepinephrine decline, leading to an expansion of the brain’s extracellular space, which results in decreased resistance to fluid flow. This is reflected by improved cerebrospinal fluid (CSF) infiltration along the perivascular spaces, and therefore increased interstitial solute clearance. The increase in clearance happens specifically during non-rapid eye movement sleep (N), also known as quiescent sleep. The third N stage, N3 or slow-wave sleep, is categorized by slow oscillatory brain waves, that create a flux of CSF within the interstitial cavities, leading to an increase in glymphatic clearance. The role of sleep in glymphatic clearance has been conclusively demonstrated, and since the vast majority of clearance occurs during sleep, the glymphatic system can simply not be investigated without examining the basic aspects of sleep. Impaired glymphatic clearance has been linked to neurodegenerative diseases. Alzheimer’s disease is a chronic neurodegenerative disease and the most common dementia, typically beginning with disorientation and then proceeding to a gradual deterioration of memory, language and physical independence, among others. Amyloid-beta and tau protein aggregations are heavily associated with Alzheimer’s disease, creating plaques and neurofibrillary tangles in the brain that lead to brain degradation. Glymphatic clearance moves tau proteins and amyloid-beta aggregates out of the brain. This suggests that the glymphatic system is involved in modulating, or possibly protective against, Alzheimer’s disease. This paper will focus on Alzheimer’s disease, since it is the most frequent dementia, but will hopefully remain applicable to other neurodegenerative diseases, since several dementias are thought to be caused by protein aggregation. The need for an intervention is gaining urgency. Benveniste and colleagues recently used MRI scans in combination with contrast agents to monitor CSF flow through the brain in real time, yet a method for manipulating glymphatic activity in humans still remains to be developed. Regulating glymphatic clearance could increase waste removal of aggregates in diseases associated with protein deposition, slowing or even reversing neurodegeneration. Sleep is a primary driver of glymphatic clearance. However, research on a wealth of other lifestyle choices such as sleep quality, quantity, physical exercise, changes in body posture, omega 3, chronic stress, intermittent fasting and low doses of alcohol has begun to emerge. Despite these advances, scholars in this field have not yet adequately harnessed the power of lifestyle-regulated glymphatic clearance. Lifestyle choices remain to be evaluated and compared. No guides or literature reviews exist on how to use preventative measures to bolster glymphatic activity. With the incidence of neurodegenerative disease increasing and evidence of the glymphatic systems’ involvement growing, there is an urgent need to capitalize on the uses of this mass transport system. Lifestyle changes decelerating disease progression could be an important discovery, opening a therapeutic avenue and the potential for improvements in quality of life. In order to infer the causal relationships of lifestyle choices in reducing brain ageing and Alzheimer’s disease, this paper will first investigate why glymphatic clearance primarily occurs during sleep, and which underlying mechanisms drive glymphatic clearance. Next, this paper will inspect the implications of a dysfunctional glymphatic pathway and establish the relationship between glymphatic clearance and neurodegenerative disease. Finally, this paper will investigate how lifestyle choices affect this mass transport system and how they can be used as a protective and preventive measure in the context of aging and Alzheimer’s disease. Section 2. Materials and Methods. This literature review synthesizes research on the glymphatic system, neurodegenerative disease and various lifestyle choices. By critically analyzing this literature, we aim to work towards a preventive guide for Alzheimer’s disease, and hopefully also other neurodegenerative diseases. We have gathered papers from the scientific database “PubMed”, as well as additional sources from the reference lists of some of the papers found through the database searches. Using the keywords “glymphatic” and “system”, the search yielded 389 results. Of these 389 papers, those including lifestyle choices and those related to Alzheimer’s disease were selected, based on title, abstract and applicability to the research question. A PRISMA flow chart documents the precise selection process and assessment of eligibility, see Figure 1 in the original text. Section 3. Results. 3 point 1. The Glymphatic System of the Brain. 3 point 1 point 1. Fluid Movement in the Brain. The brain consists of four aqueous compartments: CSF, ISF, intracellular fluid and blood, all separated by two main barriers regulating their ionic and biochemical composition: the blood–brain barrier and the blood, CSF barrier, see Figure 2. The blood–brain barrier is located throughout the brain along the vasculature. Tight junctions on endothelial cells block the movement of macromolecules but allow fluids and solutes to diffuse into the brain from the perivascular space between endothelial cells and astrocytic endfeet. The blood–CSF barrier, on the other hand, has fenestrated endothelial cells allowing macromolecules into the interstitial space. This barrier is located within the choroid plexus of the two lateral, the third and the fourth ventricles. Its epithelial cells have an abundance of tight junctions in order to regulate CSF composition. These do allow the movement of macromolecules and principally transport Sodium, Potassium, Chlorine and Bicarbonate ions through primary active transport using a Sodium, Potassium ATPase. The constant production of CSF by the choroid plexus drives the flow direction of CSF through the brain. Collectively, this results in a CSF production of around 500 milliliters each day, flowing from the lateral ventricles to the third and then fourth ventricle, entering the subarachnoid space, bathing the brain. It exits predominantly through the perineural spaces of the cranial nerves along the internal carotid artery, or into the olfactory-nasal submucosa pathway, ultimately draining into deep cervical lymph nodes. Figure 2. The four fluid compartments of the brain, separated by the blood–brain barrier or the blood–CSF barrier. The blood–brain barrier is situated wherever the vasculature reaches. The blood–CSF barrier is situated only in the choroid plexus and allows the passage of macromolecules. 3 point 1 point 2. Paravascular Spaces. Within the interstitial spaces of the brain, CSF travels towards perivascular and perineural spaces, and in doing so clears solutes from the neuropil into meninges. These then exit the brain and drain into cervical lymphatic vessels and are ultimately degraded in the liver. CSF enters the brain via para-arterial channels and exchanges with ISF, which in turn is cleared by paravenous pathways, depicted in Figure 3. CSF from the subarachnoid spaces enters the Virchow–Robin spaces along para-arterial channels and exchanges with ISF, contrary to the classical model of CSF secretion and absorption. CSF enters the brain exclusively via periarterial spaces and ISF drains exclusively into perivenous spaces. The CSF influx is balanced by the perivenous eflux of ISF ridding the neuropil of proteinaceous metabolites. Patients suffering from central oedema show a significant decrease in CSF entering perivascular spaces, suggesting that a CSF movement is driven not only by a pressure difference, but also by pulsations of arterial smooth muscle. Figure 3. This figure depicts the circulation of cerebrospinal fluid, CSF, and its interchange with interstitial fluid, ISF, CSF entering the perivascular space of penetrating arteries, then through convective flow clearing waste products into the perivenous spaces, ultimately leaving the brain through paravenous efflux routes. 3 point 1 point 3. Fluid Movement within the Interstitial Space. Once deeper within the brain, CSF movement is facilitated by aquaporin 4, AQP4, water channels on the endfeet of astrocytes, which ensheathe the blood vasculature. CSF then enters the parenchyma and mixes with the ISF, where both continuously interchange. The separation here has been proven by AQP4 knockout mice, which have significantly less CSF to ISF exchange than wild type mice, suggesting that AQP4 channels are responsible for CSF, ISF exchange, but the influx of CSF into the periarterial spaces was not affected. Although convection occurs within the perivascular spaces, within the extracellular space, diffusion is responsible for the movement of ISF. Overlapping astrocytic endfeet which completely ensheathe the cerebral microvasculature inhibit the access of molecules with larger molecular weight from entering the interstitium. 3 point 2. Sleeping the Brain Clean. “Innocent sleep. Sleep that soothes away all our worries. Sleep that puts each day to rest. Sleep that relieves the weary labourer and heals hurt minds. Sleep, the main course in life’s feast, and the most nourishing.” William Shakespeare, Macbeth. In 1606, William Shakespeare was already aware that sleep has vital and specific roles: to repair both the body and mind. Four hundred years later, sleep still largely remains an enigma and is one of the last physiological processes with a lack of scientific consensus. What we do know is that sleep is a quiescent behavioral state, associated with reduced responsiveness to weak stimuli and rapid reversibility in response to strong stimuli, and is required for memory formation, brain plasticity and immune function, among others. Sleep comes in two metabolic and electrophysiological varieties, namely rapid eye movement sleep (R) and non-rapid eye movement sleep (N). In order to correctly classify these stages, this paper will use the American Academy of Sleep Medicine, AASM, scoring, classifying sleep stages as N1, N2, N3 and R sleep, replacing the previous Rechtschaffen and Kales 1968 scoring of sleep stages: NREM 1, 2, 3, 4 and REM sleep. Regardless of the classification, the N sleep stages are not considered distinct entities, rather gradual transitions in wave form densities detected by electroencephalography. 3 point 2 point 1. The Glymphatic System and Sleep. The glymphatic system is constantly filtering toxins from the brain, but during wakefulness, this system remains mainly disengaged. Although sleep is often associated with rest, glymphatic activity is dramatically boosted during sleep. Photoimaging of in vivo mice demonstrated a 90 percent reduction in glymphatic clearance during wakefulness, and twice the amount of protein clearance from the brain intima during sleep. Sleep-induced enhancement of glymphatic function appears to arise from the expansion of the ISF space. In a human in vivo study, blood oxygen level-dependent functional magnetic resonance imaging (Bold fMRI) was used in combination with electroencephalograph and CSF measurements in order to detect in which sleep state most brain activity occurred. They found that during wakefulness, CSF flow had a small-amplitude rhythm, peaking at around 0.25 Hertz, one cycle per four seconds, whereas during sleep, large oscillations occurred every 20 seconds, peaking at around 0.05 Hertz, or one cycle per twenty seconds, resulting in a significantly greater inflow of CSF than during the day. As well as cleansing the brain, the replenishing role of the glymphatic system was observed. Glymphatic-induced reoxygenation of the brain occurs during large pulsations of CSF. The pulsating fashion in which these sleep oscillations occur suggests that the majority of glymphatic activity occurs during N3 sleep. During this stage of sleep, slow oscillatory brain waves were shown to increase the amount of CSF within the interstitial cavities, leading to an 80 to 90 percent increase in glymphatic clearance relative to the waking state, and demonstrate the importance of slow-wave sleep. 3 point 2 point 2. Slow-Wave Sleep. Glymphatic clearance mainly occurs in slow-wave sleep, which is synonymous with the N3 sleep stage. It is characterized by high-voltage synchronized electroencephalograph waveforms: delta oscillations and slow oscillations. Slow-wave sleep has numerous functions including learning, memory and metabolite clearance. In young adults, slow-wave sleep makes up between 10 and 25 percent of total sleep time, but this kind of sleep is not evenly distributed throughout the night, mostly occurring in the first half, with more R sleep occurring in the second half. These slow waves usually lie between 0.5 and 4.5 hertz on electroencephalography and have been linked to sleep pressure, occurring in abundance early in the night and then decreasing. The phenomenon of large bundles of neurons coordinating their electrical activity, rhythmically and repetitively depolarizing, is termed slow oscillatory neuronal activity. These pulsations range from 20 to 30 seconds and reflect important physiological restoration of the brain and blood oxygenation, precisely matching the time, rhythm and electrical activity of the N3 stage, confirming that this waste clearance system is primarily active during slow-wave sleep. 3 point 2 point 3. Sleep and Alzheimer’s Disease. The most common dementia and a chronic age-related neurodegenerative disease, Alzheimer’s is associated with a deterioration of memory, language and the ability to self-care, among others. The complex cascade of neurotransmitters and hormones involved in sleep regulation of the brainstem and hypothalamus is the same as that responsible for Alzheimer’s disease. Sleep abnormalities such as insomnia and sleep apnoea are highly prevalent in patients with neurodegenerative disease, often predating the onset of cognitive or neurological impairment. Although this finding suggests that sleep contributes to the onset of Alzheimer’s disease, the direction of causality is not clear. Sleep disorders may be connected to Alzheimer’s disease itself or associated factors such as pain, depression or drug therapy. Major sleep disturbances include insomnia, sleep apnoea syndrome (SAS) and circadian rhythm sleep disorder. Sleep disturbances occur early in disease progression, with minor cases already demonstrating impaired sleep. Alzheimer’s patients have a shorter total sleep time, increased awakening and worse sleep efficiency compared to controls; specifically, slow-wave sleep was found to be impaired. In Alzheimer’s disease, sleep-related issues appear to be associated with the suprachiasmatic nucleus, which regulates the circadian rhythm and naturally deteriorates with age. Sleep disturbances are present in 25 to 35 percent of Alzheimer’s patients, often resulting in impaired slow-wave sleep, a shorter total sleep time and sleep fragmentation. Despite this, however, only one third of Alzheimer’s patients suffer from clinically diagnosed sleep disturbances, placing some question over the causal interrelationship of sleep and neurodegenerative disease. Although only associations have been made so far, there are genetic links emerging between sleep and Alzheimer’s disease. One of the major genetic risk factors for Alzheimer’s disease is apolipoprotein E, APOE, of which reduced function is associated with sleep apnoea, the progression of sleep disturbances, cognitive performance and sleep deterioration. APOE therefore provides a genetic link between sleep and neurodegenerative disease, adding to the validity of this relationship. We therefore suggest that sleep and sleep impairments likely play a compelling role in neurodegenerative disease in particular in regard to waste removal from the central nervous system. It remains to be demonstrated whether other mechanisms aside from sleep universally impair this process. 3 point 2 point 4. Sleep and Toxic Waste Products in Animals. Using position emission tomography (PET) scans and the tracer F-florbetaben, amyloid-beta levels in 20 mice were assessed during normal sleep and sleep deprivation; a one night comparison showed that there was a significant increase in amyloid-beta levels in the hippocampus and the thalamus in 19 out of 20 mice, demonstrating in vivo evidence of the effects of sleep deprivation on recognized neurodegenerative processes. This relationship could be bidirectional, since amyloid-beta has also been linked to decreasing sleep quality. This can be attributed to the increase in interstitial space volume during sleep. There is a doubling of amyloid-beta clearance in the sleep state, and conversely sleep deprivation shows a reduction in the clearance of CSF metabolites. This indicates the usefulness of sleep monitoring as a non-invasive prognostic marker for neurodegenerative disease. The accumulation of amyloid-beta peptides within the brain parenchyma can lead to neuroinflammation and cognitive decline. 3 point 2 point 5. Slow-Wave Sleep and Age. Sleep varies greatly across our lifespan, starting as polyphasic sleep during early life, becoming monophasic during childhood, then slowly decreasing in duration until the age of 60, when the amount of sleep either remains constant or increases. During this time span, many micro and macro changes occur, the largest of which is the amount of slow-wave sleep, peaking during puberty and then declining with age. The origin of the decrease in slow-wave sleep is still unknown, but a suggested mechanism is the neuronal loss occurring with age, as ageing is often accompanied by a significant loss in cortical grey matter, most of which occurs in the prefrontal cortex, where slow oscillations originate, according to the global hypothesis. Alzheimer’s disease is often regarded as accelerated ageing. The gradual deterioration of slow-wave sleep over time is a possible explanation and would therefore result in less glymphatic clearance and an increased risk of neurodegeneration. 3 point 2 point 6. Governors of Sleep. Although the timing and structure of sleep are controlled by both circadian rhythm and homeostatic processes, slow-wave sleep, R sleep, cortisol and melatonin levels are not affected by circadian rhythm and are mainly driven by homeostatic forces. For example, the amount of slow-wave sleep increases with the number of waking hours. Alongside these slow-wave oscillations, the neuromodulator norepinephrine has been found to regulate glymphatic clearance. 3 point 2 point 7. The Chief Modulator: Norepinephrine. The level of arousal also plays an important role in the movement of CSF and ISF. As we sleep, the central levels of norepinephrine decline, due to lowering locus coeruleus-derived noradrenergic tone, leading to the expansion of the extracellular space, decreasing resistance and therefore increasing CSF influx and ISF efflux. Natural sleep is therefore associated with improved tracer penetration along the periarterial spaces and increased interstitial solute clearance, such as amyloid-beta. These findings were recreated in anesthetized mice, with the volume fraction of the interstitial space during wakefulness being 13 to 15 percent and 22 to 24 percent during both sleep and anaesthesia, again suggesting that sleep eases convective fluid flow. Additionally, norepinephrine receptor antagonists induced glymphatic clearance, suggesting norepinephrine release during the daytime could be suppressing clearance, by decreasing the amount of interstitial space. This blockade of adrenergic signaling expanded the ISF volume, accelerated glymphatic clearance and was associated with slow-wave electroencephalograph activity. Norepinephrine also suppresses choroid plexus CSF production. These expansions and increases in CSF production decrease resistance and increase perfusion, leading to a further boost in the removal of metabolic waste products from the brain. These findings indicate glymphatic clearance increase, its specificity to sleep and the link to levels of CSF flow, which can be modulated in a clinical setting. 3 point 2 point 8. Heartbeat or Breathing Rate. During wakefulness, CSF exhibits a small-amplitude rhythm synchronized to the respiratory signal, whereas during sleep, within the N3 stage, large oscillations occur every 20 seconds, driven by ventricular movement, resulting in significantly greater inflow of CSF. The physical forces propelling CSF in glymphatic clearance are intracranial pulsations. Intracranial pulsations have an established relationship with oscillations of blood pressure, which coincide with heart rate. As well as heart rate, lower-frequency events of respiration, such as vasomotion, were also demonstrated to contribute to glymphatic pulsations. As opposed to systemic arterial pulsations dissipating at an arteriolar and venous level, in the brain, the rigid skull promotes propagation of arterial pulsations, which are still measurable in the microvasculature and venous outflow. Even acute decreases in arterial pulsations impair glymphatic clearance. Paradoxically, the N3 sleep stage which has the highest levels of CSF influx and amyloid-beta removal also has the lowest rates of arterial pulsations, suggesting that other factors are at play. Only recently, lower-frequency intracranial pressure oscillations produced by respiration were shown to complement cardiac pulsations, which could alternatively drive clearance. Ultrafast magnetic resonance imaging demonstrated that forced inspiration was a main driver of CSF flow in both the lateral ventricles and the subarachnoid space. A combination of both heartbeat and respiratory rate appears to drive these pulsations. 3 point 3. Impaired Glymphatic Clearance. 3 point 3 point 1. Alzheimer’s Disease and Glymphatic Clearance. All prevalent neurodegenerative diseases are characterized by the accumulation of aggregated proteins. Accumulations of amyloid-beta plaques and neurofibrillary tangles of hyperphosphorylated tau are implicated in the cognitive decline in Alzheimer’s disease. Perivascular drainage pathways function as a sink for interstitial amyloid-beta and perivascular spaces are also associated with amyloid deposition and Alzheimer’s pathology. Additionally, an abnormal perivascular space has been linked to impaired glymphatic clearance. Amyloid-beta plays a role in synaptic regulation and neuronal survival. Interstitial bulk flow and amyloid-beta accumulation both occur in the perivascular space, but the predominant site of amyloid-beta accumulation is the cerebral arteries. Alongside this, abnormal enlargement of the perivascular space is a frequently observed difference between Alzheimer’s patients and healthy controls. Since glymphatic clearance is responsible for the movement of tau and amyloid-beta aggregates out of the brain, glymphatic clearance is of utmost importance to neurodegenerative disease, but remains understudied. 3 point 3 point 2. Alzheimer’s, Endfeet and AQP4. Glymphatic clearance is impaired in a rodent animal model of Alzheimer’s disease, due to changes in the number of AQP4 water channels responsible for the movement of CSF and ISF, expressed on astrocytic endfeet. AQP4 is usually on the endfeet of astrocytes rather than the soma, with abnormal AQP4 localization associated with perturbed glymphatic clearance. Since AQP4 polarity is crucial for CSF inflow and the clearance of amyloid-beta, the loss of AQP4 polarization in the brain contributes to the impairment of glymphatic function. In the brain, AQP4 mainly exists in two isoforms: a long isoform, AQP4-M1, and a short isoform, AQP4-M23, which both form hetero-tetramers in the plasma membrane of astrocytic endfeet. Furthermore, mouse models using AQP4 deletion showed a decreased clearance of amyloid-beta, confirming their involvement in neurodegeneration. 3 point 3 point 3. Glymphatic Clearance and Age. Glymphatic clearance seems to clear toxic aggregates efficiently until the end of the reproductive lifespan, then the system seems to fail. In old mice, a decrease in AQP4 expression, mis-localization of AQP4 away from the astroglial endfeet and reduced pulsations of the arterial wall led to a 40 percent reduction in amyloid-beta clearance from the brain, depicted in Figure 4. Glymphatic activity in old mice was observed to be reduced by 80 to 90 percent. This could explain the increase in frequency of amyloid-beta in aged brains. Amyloid-beta accumulation is increased due to impaired glymphatic clearance, but high levels of amyloid-beta in the interstitial space also impair fluid movement, creating a positive feedback loop, further reducing amyloid-beta deposition. This means patients with Alzheimer’s disease will mostly have impaired glymphatic clearance, which gradually gets worse. Although the loss of AQP4 polarization favors AD pathology, the cause and effect are not yet clarified. In aged brains, the AQP4 channels on astrocytic endfeet relocate to the astrocytes’ soma due to astrogliosis, slowing the rate of CSF–ISF exchange. Impaired glymphatic clearance was also observed in aged transgenic mice with amyloid plaques, but also in younger mice without plaques. Interestingly, injection of amyloid-beta into CSF reduced glymphatic clearance. Higher amyloid-beta levels resulted in lower clearance of tau tangles. In addition, breathing rates during sleep increase with age due to decreasing lung efficiency. These shallower breaths will decrease intracranial pressure and weaken glymphatic clearance. The strength of penetrating arterial pulsations also decreases with age. Figure 4. Model of glymphatic function in Young, Old and Alzheimer’s disease. In young people, CSF travels along periarterial routes, entering the brain parenchyma, and washes solutes and waste products into the veins. In older people, the loss of AQP4 water channels will result in reduced glymphatic clearance. In those with Alzheimer’s disease, the accumulation of amyloid-beta impairs fluid movement within the interstitial space, decreasing glymphatic clearance. 3 point 4. Lifestyle Choices. No suitable drug has yet been developed for Alzheimer’s disease. Research has begun to emerge on individual lifestyle choices and their modulation of glymphatic activity. Behavioral interventions can be both preventative and curative and are frequently preferred over medication. Since we have established the link between glymphatic activity and the absence of suitable treatment, we next investgate an overview of lifestyle choices and their effects on glymphatic clearance, that may in turn exert an effect on neurodegenerative processes. 3 point 4 point 1. Omega-3 Consumption. Marine-based fish oils known as omega-3 polyunsaturated fatty acids, n3-PUFA’s, have been found to modulate glymphatic activity. Epidemiological studies associate increased levels of n3-PUFA’s with lower incidence of neurodegenerative disease, and n3-PUFA supplementation has been suggested to delay or prevent the onset of Alzheimer’s disease. The central nervous system is highly enriched with n3-PUFA’s that exhibit potent anti-inflammatory properties. High endogenous levels of n3-PUFA’s improve impairment of spatial learning and memory induced by amyloid-beta. Both endogenous and exogenous n3-PUFA’s promote amyloid-beta clearance and reduce aggregate formation by inhibiting the activation of astrocytes, protecting against the loss of AQP4 polarization, thus reducing the chance of amyloid-related injury. They also exhibit anti-amyloidogenic activity, modulate aggregation and decrease downstream toxicity. Dietary intake of n3-PUFAs improved cognitive decline in mild Alzheimer’s disease. Supplementation demonstrates higher CSF influx and clearance, with AQP4 remaining polarized at the astrocytic endfeet, increasing the speed of glymphatic clearance. AQP4 knockout mice exhibited no difference in glymphatic activity even with dietary n3-PUFA supplementation, indicating that AQP4 water channels are essential in n3-PUFAs’ improvement of glymphatic function. n3-PUFA supplementation has therefore been suggested to delay or prevent the onset of AD, by improving glymphatic transport and decreasing amyloid aggregation. 3 point 4 point 2. Intermittent Fasting. Intermittent fasting consists of cycles of fasting and then eating; a specific variation of this is alternate-day fasting, consisting of a day of eating followed by a fasting day for a number of days consecutively. In the brain, AQP4 mainly exists in two isoforms: a long isoform, AQP4-M1, and a short isoform, AQP4-M23, which both form hetero-tetramers in the plasma membrane of astrocytic endfeet. Intermittent fasting ultimately downregulates the expression of AQP4-M1, decreasing the AQP4-M1 to AQP4-M23 ratio, and therefore increases AQP4 polarization along the paravenous space, boosting glymphatic clearance. Intermittent-day fasting, meaning, alternatingly fasting on one day and then eating ad libitum the next, lowered the amount of amyloid-beta deposition. This fasting causes the liver to switch to fatty acid oxidation which increases the amount of beta hydroxybutyrate in the blood after 12 hours. Beta hydroxybutyrate crosses the blood–brain barrier and acts as an endogenous histone deacetylase three (HDAC) inhibitor, which has been shown to exert a protective effect in Alzheimer’s disease progression. HDAC inhibitors prevent histone acetylation, which regulates the expression of microRNA-130a, which represses the expression of AQP4-M1, changing the ratio between isoforms. This endogenous HDAC inhibitor also increases the polarity of AQP4 expression on astrocytic endfeet, further increasing glymphatic clearance. Interestingly, the Alzheimer brain has significantly higher amounts of histone deacetylase 3, consistent with its involvement in neurodegeneration. Importantly, cells exposed to amyloid-beta show a decrease in microRNA-130a expression and an increase in HDAC expression, creating a positive feedback loop that will antagonize the positive effect of intermittent fasting on the neurodegenerative process. 3 point 4 point 3. Sleeping Position. Gravity affects the movement of blood and CSF through the brain, and therefore sleep position will likely play a role in the clearance of waste products from the brain. Both intracranial pressure and cerebral hemodynamics are influenced by body posture, and patients with dementia were found to spend a much larger percentage of time in the supine position compared to controls, establishing an association between time in supine position and dementia. An important factor in this clearance pathway is the stretch of nerves and veins in each position. Glymphatic transport is most efficient in the right lateral sleeping position, with more CSF clearance occurring compared to supine and prone. The average person changes sleeping position 11 times per night, but there was no difference in the number of position changes between neurodegenerative and control groups, making the percentage of time spent in supine position the risk factor, not the number of position changes. The suggested mechanisms behind the effects of posture on clearance would appear to result from gravity and a restriction of venous drainage of the carotid veins. Unfortunately, detecting which position you spend most time in is only possible in a sleep laboratory, since self-reported sleep positions are often false. 3 point 4 point 4. Alcohol Consumption. Alcohol can either boost or hinder glymphatic clearance, depending on dosage and whether consumption is chronic or acute. Alcohol’s effect on glymphatic clearance is independent of the wake or sleep state. Prolonged amounts of excessive alcohol consumption were shown to have adverse effects on the central nervous system, with acute and chronic exposure to high doses of alcohol, 1 gram per kilogram, dramatically reducing glymphatic transport in awake mice. Chronic exposure to high levels of alcohol increases GFAP expression, inducing the depolarization of AQP4 channels, but conversely decreasing the levels of inflammatory cytokines. AQP4 polarity is crucial for CSF inflow and the clearance of amyloid-beta, potentially leading to alcohol-induced changes in these water channels to hinder glymphatic clearance. Heavy alcohol consumption for prolonged periods of time greatly increases the risk of developing Alzheimer’s disease. Intermediate alcohol consumption was also found to decrease glymphatic clearance for both acute and chronic usage. Both intermediate and heavy dosage induced non-permanent changes in glymphatic activity, as after 24 hours of sobriety, glymphatic function was fully restored. In contrast, both acute and chronic exposure to low doses of alcohol, 0.5 grams per kilogram increased glymphatic clearance, due to decreased GFAP expression, reducing the risk of Alzheimer’s disease. For the scale reference of a 75 kilogram person, half a gram per kilogram alcohol consumption is equivalent to 37.5 grams of alcohol, which is contained in 94 milliliters of 40 percent vodka, 300 milliliters of 12 percent wine, or 750 milli-liters of 5 percent beer. 3 point 4 point 5. Exercise. Bulk glymphatic flow is accelerated by physical training and notably improves both memory and cognition in neurodegenerative disease. Voluntary running over a six-week duration restored protein homeostasis in the brain, reduced inflammation by decreasing the activation of microglia and astrocytes, improved cognition and reduced the deposition of amyloid-beta through an increase in glymphatic clearance, but showed no effect on the blood–brain barrier permeability. In addition to this, six weeks of physical exercise accelerated glymphatic clearance and reduced amyloid-beta accumulation by increasing the movement of ISF. AQP4 expression in the cortex was also found to be higher along the paravascular space in the exercise group. This improved AQP4 polarization and led to a decrease in both amyloid plaques and neuroinflammation. These findings are consistent with the benefits of exercise on brain health and cognition in the elderly and demonstrates the usefulness of exercise as a neuroprotective lifestyle choice for brain aging and neurodegeneration. According to the WHO, beneficial amounts of exercise consist of at least 150 minutes of moderate or 75 minutes of vigorous exercise a week. 3 point 4 point 6. Chronic Stress. Chronic psychological stress is a common risk factor for Alzheimer’s disease. Short-term stress is crucial for adaptation and survival, but long-term stress can be detrimental to both body and mind. Chronic stress accelerates the accumulation and deposition of amyloid-beta. Mice exposed to stress exhibited decreased glymphatic influx and efflux, loss of AQP4 polarization and a reduction in AQP4-bearing astrocytes. Stress triggers the hypothalamic–pituitary–adrenal (HPA) axis to release glucocorticoids. Alzheimer’s disease is associated with a dysfunctional HPA axis, demonstrated by high levels of cortisol in the blood. Glucocorticoids act by binding to glucocorticoid receptors (GR) or mineralocorticoid receptors (MR) and decrease astrocyte numbers downregulating the number of AQP4 channels. Stress increases the levels of glucocorticoids and therefore GR activation, which also trigger the amyloid precursor protein to form amyloid-beta. Mifepristone, a GR antagonist, significantly improves impaired glymphatic clearance impaired by stress reversing AQP4 expression. Mifepristone might therefore be a useful treatment for Alzheimer’s disease mediated through the glymphatic system. Section 4. Discussion. This paper provides a synthesis of currently tested lifestyle choices which could aid in preventing or slowing the progression of Alzheimer’s disease through increased glymphatic activity. The incidence of Alzheimer’s disease is rising, but there is currently no effective disease-modifying treatment. Similar to other neurodegenerative diseases, Alzheimer’s disease is characterized by the accumulation of aggregated proteins. The accumulation of amyloid-beta peptides and tau within the brain parenchyma causes neuroinflammation, amyloid-beta plaques and tau tangles. This deposition occurs along perivascular spaces. Glymphatic clearance acts within these spaces, moving tau and amyloid-beta aggregates out of the brain and thus reducing neurodegenerative processes. Glymphatic clearance also offers an explanation for why dementias are generally age-related. In mice, clearance of misfolded proteins and other cellular debris is generally efficient but reduces in capacity over time and begins to fail at the end of the reproductive lifespan. This was demonstrated by glymphatic clearance in old mice being reduced by 80 to 90 percent, and may at least partly explain the increased concentration of amyloid-beta in aged brains. One suggested mechanism behind this is the loss of polarization of AQP4 water channels. AQP4 channels are usually polarized along astrocytic endfeet, but can lose polarization, becoming more evenly distributed around the soma and thus slowing the rate of CSF to ISF exchange. Since AQP4 polarity is crucial for CSF inflow and the clearance of amyloid-beta, the loss of AQP4 polarization in the brain contributes to the impairment of glymphatic function. AQP4 deletion results in decreased clearance of amyloid-beta, supporting its involvement in neurodegenerative processes. The vast majority of glymphatic clearance occurs during sleep. There is a 90 percent reduction in glymphatic clearance during wakefulness and twice the amount of protein clearance from the brain intima during sleep. During slow-wave sleep, delta oscillations are nested in high-voltage slow oscillatory neuronal activity, causing large bundles of neurons to harmonize, rhythmically and repetitively depolarizing over 20 to 30 seconds. This increases CSF inflow within the interstitial cavities and boosts glymphatic activity, increasing interstitial solute clearance. Sleep is a primary driver of bulk flow and is crucial in its modulation. These slow oscillations have been linked to sleep pressure, occurring in abundance early in the night and then decreasing over time. Slow-wave sleep is linked to time spent awake, with an increase in waking hours increasing the amount of slow-wave sleep. As well as within each night, sleep changes greatly across our lifespan. The percentage of slow-wave sleep is highest during puberty, and then declines with age, exacerbated in Alzheimer’s disease. Age-related neuronal and cortical grey matter loss is thought to be responsible for the decrease in slow-wave sleep, particularly in the prefrontal cortex where slow oscillations are believed to originate. The neuromodulator norepinephrine regulates sleep, but also glymphatic clearance. During sleep, the decrease in norepinephrine levels causes the expansion of the extracellular space, decreasing resistance and therefore increasing the rate of glymphatic clearance. Norepinephrine also suppresses choroid plexus CSF production. These expansions, together with the increase in CSF production, decrease resistance and boost perfusion, leading to a further increase in the removal of metabolic waste products from the brain. Norepinephrine controls the overall quantity of solute clearance, but intracranial pulsations are the physical force that propel CSF along the parenchyma. Intracranial pulsations have an established relationship with oscillations of blood pressure, which coincide with heart rate. These disperse throughout the brain, aiding metabolism, and at the same time eliminate toxic waste products. Alongside heart rate, lower-frequency events of respiration, and vasomotion contribute to glymphatic pulsations. Slow-wave sleep is linked to glymphatic clearance, but also dementia. A third of Alzheimer’s patients suffer from clinically diagnosed sleep disturbances, and the vast majority Alzheimer’s patients have a shorter total sleep time and impaired slow-wave sleep, with both these deteriorations of sleep often predating its onset. The complex cascade of neurotransmitters and hormones involved in sleep regulation is affected in Alzheimer’s disease. Additionally, in healthy mice, a single night of sleep deprivation was sufficient to increase amyloid-beta deposition. Sleep impairment therefore appears as an influential risk factor for neurodegenerative disease that should ideally be recognized by general practitioners and medical specialists alike. In this manuscript, we have described the results of lifestyle choices on glymphatic clearance; we here provide a summary of the findings. Sleep position, alcohol intake, exercise, omega-3 consumption, intermittent fasting and chronic stress all modulate glymphatic clearance, thereby potentially altering the risk for Alzheimer’s disease. 1. Gravity affects the movement of blood and CSF throughout the brain, and sleep position will therefore play a role in the clearance of waste products from the brain. Neurodegenerative patients spend a much larger percentage of time in the supine position, which suggests a connection between time in supine position and dementia. Glymphatic transport is most efficient in the right lateral sleeping position, with more CSF clearance occurring compared to supine and prone. 2. High levels of both endogenous and exogenous marine-based fish oils known as omega-3 polyunsaturated fatty acids, n3-PUFA’s, are associated with lower incidence of neurodegenerative disease, and n3-PUFA supplementation has been suggested to delay or prevent the onset of Alzheimer’s disease. n3-PUFA’s promote amyloid-beta clearance and reduce aggregate formation by inhibiting the activation of astrocytes, protecting against the loss of AQP4 polarization, and therefore reduce the chance of amyloid-related injury. They exhibit anti-amyloidogenic activity, decrease amyloid-beta production, modulate aggregation and decrease downstream toxicity. 3. Alcohol consumption can either boost or hinder glymphatic clearance, depending on dosage and chronic or acute consumption. Acute and chronic exposure to high doses of alcohol, 1 grams per kilograms, dramatically reduces glymphatic transport in awake mice. This suggests that heavy alcohol consumption for prolonged periods of time greatly increases the risk of developing Alzheimer’s disease. On the other hand, both acute and chronic exposure to low doses of alcohol, a half of a gram per kilogram, increased glymphatic clearance. Low doses of alcohol improved glymphatic function, due to decreased GFAP expression, and avoided the loss of AQP4. Physical training in mice showed a notable improvement in both memory and cognition impairments, associated with neurodegenerative disease. 4. Physical exercise decreased astrocyte and microglia activation, leading to reduced inflammation, and increased the movement of ISF. The increase in ISF movement accelerated glymphatic clearance and reduced amyloid-beta accumulation. The increase in ISF movement is due to improved polarization of AQP4, resulting in a decline in amyloid plaques and neuroinflammation. This confirms the benefits of exercise on brain health and cognition in the elderly and demonstrates the usefulness for exercise as a neuroprotective lifestyle choice for brain aging and neurodegeneration. 5. Chronic stress is a common risk factor for Alzheimer’s disease. Short-term stress is crucial for adaptation and survival, but long-term stress can be detrimental to both body and mind. Chronic stress accelerates the accumulation and deposition of amyloid-beta. Mice exposed to stress exhibited decreased glymphatic influx and efflux, decreased expression and loss of the polarization of AQP4 and a reduction in AQP4-bearing astrocytes. 6. Intermittent fasting ultimately downregulates the expression of AQP4-M1, decreasing the AQP4-M1 to AQP4-M23 ratio, and therefore increases AQP4 polarization along the paravenous space, increasing glymphatic clearance. Intermittent fasting therefore improves cognitive function and decreases amyloid-beta deposition, by increasing polarity mediated through, and by the upregulation of, the AQP4-M1 to AQP4-M23 ratio. Intermittent-day fasting decreases the amount of amyloid-beta deposition. These lifestyle choices in various ways modulate the levels of glymphatic clearance, lowering the risk of, or possibly even preventing, Alzheimer’s disease. Each lifestyle choice has a different mechanistic route, but all seem to function by changing the number or polarity of AQP4 channels. These can be split into two categories, with differing degrees of recommendations. Easily modifiable lifestyle choices include alcohol intake, omega-3 consumption, sleep position and exercise. Alcohol should only be consumed in low doses of half a gram per kilogram, if at all, and avoided in moderate or high quantities. Omega-3 supplementation is recommended. Self-reported sleep position is often unreliable, however with the use of sleep positional therapies, an individual can be trained to alter their sleep position. Each individual should exercise moderately for 150 minutes a week or vigorously for 75 minutes. The less clear-cut lifestyle choices include intermittent fasting and chronic stress reduction. Intermittent fasting has only been investigated thus far in animal models, and can have harmful effects on humans, thus it requires further investigation. Chronic stress is treatable, but this is not as simple as taking supplementation and may require other therapeutic means. Although medication for chronic stress exists, this is a sensitive case-specific option that requires detailed and precise clinical assessment and is beyond the scope of this paper. Easily modifiable or not, lifestyle choices undoubtedly impact glymphatic clearance and should be harnessed to avoid brain ageing and neurodegeneration. A limitation within this paper is the lack of direct information on Alzheimer’s disease sufferers. Although this literature review clearly highlights the effectiveness of lifestyle choices as a prevention of neurodegeneration, most of these findings come from murine studies, as there is only little in vivo human evidence for lifestyle choices altering neurodegeneration. Firstly, these findings need to be replicated in humans. Secondly, since this is emerging research and little literature exists, especially concerning lifestyle choices, each recommendation should be examined further before application. Therefore our suggestion that these lifestyle choices are causally linked is provided with the caveat that it is based on a small number of studies that need to replicated. Thirdly, these findings only demonstrate impaired glymphatic clearance, but the precise causal relationships still remain to be elucidated. Fourth and finally, these lifestyle choices need to be assessed in relation to each other, since we simply do not know whether these effects will summate, synergize or cancel each other out. There seems a compelling need to capitalize on the glymphatic system to harness the potential for reducing dementia rates. Although AQP4 channels have been identified as a potential drug target, a suitable drug is yet to be developed; lifestyle choices therefore remain the best available option for regulating AQP4 numbers and polarization. Future studies should amongst others, see Table 1, empirically confirm the causality between lifestyle choices and improved glymphatic clearance, to quickly develop effective lifestyle interventions. Since existing glymphatic research consists mostly of animal studies, these findings need to be replicated in humans. Other avenues of research may include the role of exosomes, small extracellular vesicles, in transporting protein aggregates. It is as yet unknown if disregulation of the glymphatic system may contribute to neurodegenerative processes by reducing exosome removal. Table 1. This table summarizes the future challenges arising from this paper. Future Studies Surrounding the Glymphatic System and Lifestyle Choices should Aim to: 1. Confirm the link between the glymphatic system and lifestyle choices. 2. Replicate all glymphatic-related murine research in humans. 3. Test easily modifiable lifestyle choices affecting glymphatic clearance in a lifestyle-based intervention in humans. 4. Investigate whether the effects of multiple lifestyle choices on glymphatic activity cumulate or cancel each other out. 5. Confirm that AQP4 channels are the causal pathway behind glymphatic activity. 6. Conduct a randomized controlled trial to confirm whether lifestyle choices have an effect on glymphatic activity. 7. Investigate the effect of Mifepristone on glymphatic activity 5. Conclusions. The glymphatic system is a brain-wide bulk flow waste removal network. Impaired glymphatic clearance contributes to the risk of developing Alzheimer’s disease, due to reduced removal of aggregated proteins such as amyloid-beta and tau. There is no effective treatment for Alzheimer’s disease, and with an increasing incidence and burden on society, the need for an intervention is well recognized. Lifestyle choices may be our current best option for reducing or even stopping the neurodegenerative process, as they constitute non-invasive, readily available, relatively inexpensive and accessible interventions Author contributions, funding and twenty-one references. https://rumble.com/v3t4yzj-index-of-science.-music-by-dan-vasc.html Index of Sciencey stuff:

Most Reverend in Christ, Father and Lord, Lord Cuthbert Tonstall, Bishop of Dunelm in England, John Cochleus, S P D. Most Reverend Father and Lord in Christ, after you have successfully returned from London to your country, increased by your goodness and power and the results of affairs, it was not permitted to me as frequently as before, to perform any of my duties of gratitude and respect to your most reverend lordship safely by letters, mainly because of the larger space distance made on both sides. However, I have written several times to Mister Ridley, as well as to R D T, but since I do not know what of my letters has reached R D T within five years, whence I suspect that some of the intercepted letters have perished, I decided at last to seek the public to intercede, and he was neither a Jew nor a contemptible blachteron, but the pious and learned pontiff Innocent the Third, highly praised by all historians and chronographers alike, and also approved by the public in decretal epistles by the authority of canon law, so that it exists publicly as a witness of my love and reverence for R D T. I hope that this will be far more agreeable to you, and safer from the snares of interceptors, than private letters have been or will be; for many things, and good for many, whom God has not given to a reprobate sense, or whom his own iniquity has not blinded or hardened. For those who are exalted either by the splendor of their birthdays, or by knowledge inflated, or by the success of things rise into exaltation, the precepts of humility from the sacred letters He lays healthily before the eyes, and by declaring the misery of the human condition, deters all from pride. Of course, this admonition seems extremely necessary at this time, in which the shadow of knowledge and most of the ignorant is so inflated, so that our faith and religion are not only debated between cups in an unbelieving and irreligious way, but they are not afraid to decide on new precepts and to give light to the uneducated and illiterate, tailors and furriers. But Innocent says that there is scarcely anything so cheap or so easy that a man fully understands, unless perhaps it is perfectly known, for nothing is perfectly known. However, from this an insoluble redargument immediately follows. Such was the ancient saying of Socrates: I do not know one thing that I do not know. And far more anciently and more religiously it was said by the great and holy man Job: I truly know that it is so, and that it is not Man is justified in comparison with God, if he wills to contend with him, he will not be able to answer him one for a thousand. Thus the wisest Solomon says: I have found only this, that God has made man upright, and that he himself has mixed himself up with infinite problems. Irreligious therefore is this rashness of the wise, by which they thus transgress the ancient boundaries which our fathers have established. The chief of whom, of course, and the originator or founder of all impious innovations, is so swollen with pride that he thinks that more has been revealed to himself than to all the ancient fathers and councils. Truly a wretched man, to whom the Lord says in the Apocalypse: He who says that I am rich, and enriched, and need no one, and you do not know that you are wretched, and pitiable, and poor, and blind, and naked. And Pliny, an ethnic man, rebukes those who are so vainly and arrogantly proud of knowledge. Some animals feel their own nature, others perish to usurp, to fly one thing, to have another strength, to swim another thing; for a man to know that nothing can be done without learning, that he cannot enter, that he cannot eat; Our Innocent clearly explains this misery of man by adding many things which were unknown to Pliny and to all the ethnics. I therefore beg and implore you, most decorated prince, to bear with an equanimity the admonitions of such a pious pontiff under the watchful eye of your name at this time, in which the fear of God is growing cold and worldly avarice and irreligious conversation are growing stronger in all the luxury, pomp and pageantry of the world, into the light reproduced I know, indeed, how much the truly learned and the foremost of scholars and eloquence make you, the most illustrious luminaries of our age, John Fischer, bishop of Rouen in England, William of Budaeus in France, Erasmus of Rotterdam in Germany, so that he may tremble rightly and meritoriously. I am writing to you. However, I use your trust and clemency and kindness learned from you as an interlude for the edification of many who are now vainly proud of their high spirits and placed outside themselves, so that when they have returned to themselves, they may return to their hearts and know themselves. Good-bye to the excellent and unique herald, the protection of the church and the everlasting ornament of the country. From Dresden Misnia to Albi. III. the ninth of February In the year of Sunday's incarnation 1534. De Contemptu Mundi, Pope Innocent III, A Puke (TM) AudioBook Translated by PukeOnAPlate 2024 It begins with a book on the contempt of the world, or on the misery of the human condition, published by Lotharius, cardinal deacon of Saints Sergius and Bacchus, who was later called Pope Innocent the Third. And it is divided into three partial books. PROLOGUE. To the dearest father P. dei Gratia, bishop of Porto, Lotharius, an unworthy deacon, grace in the present and glory in the future. A little leisure, which, amid many troubles of late, which you know, I have taken occasion of, has not entirely passed me idle. But in order to depress pride, which is the head of all vices, I have described in any way the baseness of the human condition. And I have dedicated the title of the present work to your name, beseeching and demanding, that if your discretion finds anything worthy in it, the grace of God write it all down. But if your paternity has suggested, let me describe the dignity of human nature, favoring Christ, in so far as the exalted is humbled by this, so that the lowly is exalted by it. FIRST BOOK. Chapter one. On entering the wretched human condition. Why did I come out of my mother's womb, to see labor and pain, and my days to be spent in confusion? If he, whom the Lord sanctified in the womb, spoke such things of himself, how shall I speak of myself, whom my mother bore in sins? Alas, I would say, my mother, why did you give birth to me, the son of bitterness and pain? Why did I not die in my mother's womb? Did I not immediately perish when I came out of the womb? Why was he born at the knees, suckled at the breasts, and born to burn and eat fire? I wish he had been killed I would have been in the womb, so that my mother would have been my grave and her womb an eternal conception. For I would not have been born, having been transferred from the womb to the grave. Who, then, will give my eyes a fountain of tears, that I may weep over the pitiable entrance of the human condition, the culpable progress of human conduct, the damnable exit of human dissolution? I then considered with tears what man was made of, what man does, what man is going to do. Of course, formed from the earth, conceived in guilt, born for punishment, he does evil things that are not lawful, base things that are not proper, vain things that are not expedient, he will become fuel for fire, food for worms, a mass of rot. I would explain it more clearly, I would eat it more fully. Man was formed from dust, from mud, from ashes, and that which is baser, from the most impure sperm: conceived in the itching of the flesh, in the fervor of lust, in the stench of lust, and that which is worse, in the decay of sin; born to labor, pain, fear, and everything more miserable is, to death. He does bad things, he offends God, he offends his Neighbor, he offends himself. He does disgraceful things by which he pollutes his reputation, pollutes his conscience, pollutes his person. He acts vainly, which he neglects the serious, he neglects the useful, he neglects the necessary. It will become fuel for the fire that always burns and burns unquenchable, food for the worm that always gnaws and eats the immortal, a mass of rot that always stinks and stinks terribly. Chapter two. Of the cheapness of man's own material. Therefore the Lord God formed man from the clay of the earth, which is inferior to the other elements, as is clear from Genesis 2. He made the planets and stars from fire, the winds and air from air, the fish and birds from water, and men and animals from the earth. Therefore, considering the watery man will find himself low, considering the airy he will recognize himself as lowly, considering the fiery he will consider himself very lowly, and will not be strong he will make himself equal to the heavenly ones, and will not dare to prefer himself to the earthly ones, because he will find himself equal to beasts and will recognize his likeness. For the destruction of men and beasts is one, and the condition of both is equal, and man has nothing more than beasts. They came from the earth, and they will return to the earth as well. These words are not of any man, but of the wisest Solomon. What then is man but dust and ashes? For hence man says to God: Remember, I pray thee, that thou hast made me as clay, and shalt return me to dust. Hence also God said to man: You are dust, and to dust you shall return. I am compared (says Job) to clay, and I am likened to embers and ashes. Clay is made of water and dust, both remaining; but ashes are made of wood and fire, both failing. Expressed mystery, but otherwise better expressed. So what is dirt? Are you proud? What dust are you raising? whence dost thou boast of ashes? Chapter three. On the defect of conception. Or perhaps you will answer that Adam himself was formed from the clay of the earth, but you were created from human seed? But he was formed from the earth, but from a virgin, but you were created from seed, but unclean. For who can make the world out of an unclean seed? Who is man, that he should appear blameless and righteous, born of a woman? For behold, I was conceived in iniquities, and in sins my mother conceived me. Not in just one iniquity, not in just one transgression, but in many iniquities and in many transgressions. That is, in the offenses and iniquities of one's own, in the offenses and iniquities of others. Chapter four. Of the shame of the child. For there is a twofold conception, one of seeds and the other of natures. The first takes place in commissions, the second takes place in contracts. For the parents commit themselves to the first, and the children contract to the second. For who does not know that even conjugal intercourse is never committed at all without the itching of the flesh, without the fervor of lust, without the stench of lust? Whence the seeds conceived are foul, stained, and corrupted, from which the soul finally infused contracts the blemish of sin, the stain of guilt, the filth of iniquity, just as liquid infused from a corrupt vessel is corrupted, and the polluted contiguous is polluted by its very contact. For the soul has three natural powers, or three natural powers: the rational, to distinguish between good and evil; irascible, so as to reject evil; concupiscible, so as to desire the good. These three powers are originally corrupted by three opposite vices; the power of the rational through ignorance, so that it does not distinguish between good and evil; irascible power through anger, so that it rejects good; concupiscible force through concupiscence, so that it desires evil. The first begets wrongdoing, the last gives birth to sin, the middle begets wrongdoing and sin. For it is a crime not to do what ought to be done; sin is not to be acted upon. These three vices are contracted from the flesh corrupted by three natural temptations. For in the carnal intercourse of reason the intuition is fenced off, so that ignorance is sown, the itching of lust is irritated, so that anger is propagated, the affections are satisfied with pleasure, so that concupiscence is contracted. This is the tyrant of the flesh, the law of the members, the fuel of sin, the languor of nature, the fodder of death, without whom no one is born, without whom no one dies, who, if he ever passes away in guilt, yet always remains in effect. For if we say that we have no sin, we deceive ourselves, and the truth is not in us. O great necessity and unhappy condition. Before we sin, we are bound by sin, and before we sin, we are bound by sin. Through man one sin entered into this world, and through sin passes through death to all men. Have not the fathers eaten sour grapes, and set their children's teeth on edge? Chapter five. What kind of food is the conception nourished in the womb. But take heed with what food the conception is nourished in the womb. Indeed, with the menstrual blood, which ceases from the woman after conception, so that the conceptions from it may be nourished in the woman, which is said to be so abominable and unclean, that from its contact crops do not sprout, shrubs wither, herbs die, trees lose their fetuses, and if dogs eat them , are brought into a frenzy. The conceived fetus contracts the vice of the seed, so that lepers and elephantiasis are born from this corruption. Hence, according to the Mosaic law, a woman who suffers menstruation is considered impure, and if whoever comes to menses is ordered to be put to death. And because of the impurity of the menses, it is commanded that if a woman gives birth to a male child, she should cease entering the temple for forty days, if a female child, eighty days. Chapter six. Of the infirmity of the child. Why, then, is light given to the wretched, and life to those who are in bitterness of soul? Happy are those who die before they are born, feeling death before they know life. For some are born so ugly and prodigious, that they are seen not as men, but rather as abominations, for whom perhaps it would have been better provided for, if they had never come to be seen, since they are pointed out and exhibited to the public as monsters. But most of them are born with diminished limbs and corrupt senses, the sadness of their friends, the infamy of their parents, the shame of their relatives. I would say this in particular about some, when in general we all perish without knowledge, without words, without virtue? weepy, feeble, infirm, a little distant from the brutes, nay, having less in many? For as soon as they have arisen, they step, but we not only do not walk with erect feet, but also do not crawl with bent hands. Chapter seven. Of the pain of childbirth and the crying of the child. We are all born crying to express our misery. For a male newly born says A, but a female E. Saying E or A, as many as are born of Eve. What then is Eve, but alas ha? Both are painful interjections, pain expressing Indignity. For these things, before the sin of the cross, after the sin Eve deserved to be called, from whence she heard it said to her: you shall wallow in sorrow. No for there is pain like that of a woman in childbirth. Whereupon Rachel, in great pain, gave birth, and as she was dying she called the name of her son Benoni, that is, the son of sorrow. The wife of Phineus gave birth to sudden pains as soon as she died, and at the very moment of her death she called her daughter Ichabod. But a woman, like a shipwrecked woman, when she gives birth, has sadness, but when she has given birth to a child, she no longer remembers the pressure for joy, because a man has been born into the world. Therefore it conceives with uncleanness and stench, it gives birth with sorrow and pain, it nurtures with distress and toil, it guards with insistence and fear. Chapter eight. Of the nakedness of man. He goes out naked, and comes back naked. The poor go, and the poor go. Naked, says Job, I came out of my mother's womb. and return thither naked. We brought nothing into this world, no doubt because we can take nothing away. But if any man enter clothed, let him pay attention to what kind of clothing he wears. It is a disgrace to say, a disgrace to hear, a disgrace to see. A disgusting film covered in blood. This is that wall, of which Thamar says in his speech: Why is the wall broken for your sake? And for this reason he called his name Phares, which means division. Chapter nine. What fruit does man produce? O base indignity of human condition, O unworthy condition of human baseness. Look for herbs and trees. They produce of themselves flowers and leaves and fruit, and alas, you bring forth lice and earthworms. They pour oil, wine, and balm from themselves, and you from yourself spit, urine, and dung. They are about themselves they breathe the sweetness of the fragrance, and you return from yourself the abomination of the stench. As the tree is, so is the fruit. For a bad tree cannot produce good fruit. For what is man according to form, but a kind of inverted tree? whose roots are the hair, the trunk is the head with the neck, the log is the peg with the belly, the branches are those with the pipes, the leaves are the fingers with the joints. This is the leaf that is carried away by the wind, and the stalk that is dried by the sun. CHAPTER Ten. On the disadvantages of old age and the brevity of man's life. At the beginning of the human condition, men are read to have lived nine hundred years and more, but as man's life gradually declined, the Lord said to Noah: My spirit shall not abide in man forever, for he is flesh, and his days shall be one hundred and twenty. of years This can be understood both about the term of life and about the space of repentance. For from that time it is very rarely read that men lived longer, but when human life declined more and more, it was said by the Psalmist: The days of our years are seventy years. But if in the potentates eighty years, and more their labor and pain. But will not the fewness of my days end in a short time? Our days are passing faster than the weaving of the web. A man born of a woman, living a short time, is filled with many miseries, who comes forth like a flower and is crushed, and flees like a shadow, and never remains in the same state. For few now reach the age of forty, and very few reach the age of sixty. Chapter eleven. On the disadvantages of old age. But if a man has advanced to old age, his heart is at once afflicted and his head throbbed, his breath faints and his breath stinks, his face is wrinkled and his stature is bent, his throat is dimmed and his joints wobbly, his nose runs and his hair falls out, his touch trembles and his actions fail, his teeth and ears rot. they are deaf The old man is easily provoked, difficult to recall, quick to believe and slow to disbelieve, tenacious and fond, sad and complaining, quick to speak, slow to hear, but not slow to anger, praises the ancients, despises the moderns, reproaches the present, commends the past, sighs and worries , becomes numb and weak. Listen to the poet Horace: Many troubles surround the old man. Moreover, let not the old boast against the young, nor let the young be insolent against the young old man, because what we are, he was, we shall be some day what he is here. Chapter Twelve. Of the labor of mortals. A bird is born to fly, and a man is born to work. All his days are full of troubles and sufferings, and his mind does not rest during the night. And what is this but vanity? There is no one without labor under the sun, there is no one without failure under the moon, there is no one without vanity under time. Time is the way things change. Vanity of vanities, says Ecclesiastes, and all things are vanity. Oh, how diverse are the studies of men, how diverse are their practices. Yet the end of all is one, and the result is the same, labor and affliction of the spirit. A great occupation was created for all men, and a heavy yoke upon the children of Adam, from the day of their coming out of their mother's womb, until the day of their burial in the grave of all. Chapter Thirteen. Of the study of the wise. Let the wise examine, investigate the heights of the sky, the breadth of the earth, the depths of the sea, and argue about each, discuss about all, always learn or teach. And what will the spirits find out of this occupation but labor and pain and affliction? He knew by this experience that he had said: I gave my heart to know the prudence of algae, doctrine, errors and folly, and I recognized that it was labor and affliction of the spirit, because in much wisdom there is much indignation, and he who adds knowledge adds pain. For though it behooves the searcher to sweat with many vigils and watch with toil and sweat, yet there is scarcely anything so cheap, scarcely so easy, that a man fully understands and grasps at a liquid level, unless perhaps it is perfectly known, for nothing is perfectly known, even though it is inscrutable from this will result in redargument. To anyone the body that decays burdens the soul, and the torrential panting detracts from the thinking mind. Hear what Solomon thinks about this: All difficult things, man cannot explain them in words. There is a man who does not sleep with his eyes day and night, and cannot find any reason for their work. And the more he labored to seek, the less he would find. Therefore those who search for scrutiny fail, because man will come to a deep heart, and God will be exalted. For the searcher of majesty is overwhelmed by glory. For he who understands more, doubts more, and he seems wiser to himself, who loses more. Therefore, part of knowledge is to know what one does not know. But the god did the right thing, and he involved himself in infinite questions. Chapter Fourteen. Of the various studies of men. Let mortals run and run through fences and paths, climb mountains, cross hills, fly over rocks, fly over the Alps, cross pits, enter caves, explore the bowels of the earth, the depths of the sea, uncertain rivers, dark forests, impassable solitudes, they expose themselves to winds and rains, thunders and lightnings, waves and tempests, ruins and precipices. They forge and fuse metals, carve and polish stones, cut and mold wood, spin and weave cloth, cut and sew clothes, build houses, plant gardens, cultivate fields, tend vineyards, burn furnaces, build mills, fish, hunt and hunt. They meditate and think, counsel and organize, complain and quarrel, rob and steal, deceive and bargain, contend and fight, and do innumerable such things in order to accumulate wealth, to multiply their gains, to make gains. they are followed, that they may acquire honors, that they may exalt their dignities, that they may extend their powers, and this also is labor and affliction of mind. If I am not believed, let Solomon be believed: I magnified, says he, my works: I built houses for myself and planted vineyards for myself, I made gardens and orchards, I planted them with trees of every kind, I built for myself cisterns of water to irrigate the forest of sprouting trees, I owned servants and maidservants. and I had a large family, also herds and large flocks of sheep, beyond all who had been before me in Jerusalem. I amassed for myself gold and silver, and the substance of kings and provinces. I made for myself singers and songstresses and the delights of the children of men, cups and pitchers in the service of pouring out wine, and I surpassed in wealth all who were before me in Jerusalem. And when I had turned to all that my hands had made, and to my labors, to whom I had sweated in vain, I saw in them all vanity and affliction of mind, and nothing lasting under the sun. Chapter Fifteen. About different concerns. Oh, how mortals are troubled by anxiety, afflicted by care, troubled by care, terrified by fear, shaken by trembling, taken away by horror, afflicted by pain, disturbed by sadness, saddened by confusion. The poor and the rich, the slave and the master, the married and the free, finally, the good and the bad, all are afflicted with worldly afflictions and are tormented by worldly afflictions. Trust the teacher after experience. If (says he) I do wickedly, woe unto me. And if it is just, I will not raise my head saturated with suffering and misery. Chapter Sixteen. Of the misery of the needy and the poor. For the poor are oppressed by hunger, tormented by hardships, hunger, thirst, cold, nakedness, they are despised, scorned, scorned, and scorned. O miserable condition of the beggar, and if he does not ask, he is ashamed, and if he does not ask, he is consumed by want, but to beg, he is compelled by necessity. God is caused to be unjust because he does not divide justly. The neighbor is accused of evil, which does not fully help. He is indignant, he murmurs, he curses. Notice the wise man's opinion on this: It is better (says he) to die than to be in need. He also goes out to hate his poor neighbor. All the days of the poor man's evil, the poor man's brothers hate him. Moreover, his friends also withdrew far from him: because when you are happy, you will count many friends, but if the times are bad, you will be alone. Therefore, shame is considered according to the person's fortune, rather than fortune is to be valued according to the person. He is considered as good as the rich, as bad as the poor, and rather he should be considered as rich how good, how poor, how bad. But the rich man is freed from excess, and his rashness is restrained, he runs at will, and rushes at what is unlawful. They also become instruments of punishment, which had been entertainments of guilt. Toil in acquiring, fear in possessing, pain in losing, always wearies, strains, and afflicts his mind. For where your treasure is, there is your heart. But we shall speak more fully of this in what follows. Chapter Seventeen. Of the misery of servants and lords. A servant serves, is frightened by threats, wearied by hardships, afflicted by plagues, robbed of riches: which if he does not have, he is forced to drink, and if he has, he is forced not to have. The fault of the master, the punishment of the servant: the fault of the servant, the prey of the master. Whatever the kings rave about, the Achives placate. The hunting of the lion onager in the desert, as well as the pasture the rich and the poor O extreme condition of slavery. Nature gave birth to children, but fortune made slaves. The slave is forced to suffer and no one is allowed to sympathize, he is forced to grieve and no one is allowed to sympathize. So he himself is not his own, so that no one can be himself. Miserable are those who follow the camp, because it is miserable to live as the prey of others. But the Lord, if he is cruel, must be feared because of the wickedness of his subjects; if he is gentle, he may be despised because of the insolence of his subjects. Fear, then, afflicts the severe, and the lowly despises the meek. For cruelty breeds hatred, and familiarity breeds contempt. For the care of one's family is tiring, and the anxiety of the household is troublesome. For it is necessary for him to be always ready, everywhere fortified, so that he can prevent the intrigues of the malicious, repulse the injuries of the assailants, crush the enemies and protect the citizens. Nor is the day sufficient for its malice, but day after day it belches up labor, and the night of the night indicates concern. Therefore the days are laborious, and the nights are spent without sleep. CHAPTER Eighteen. Of the misery of the continent and of the married. If fire can not burn, flesh can not lust, because no matter how much he is punished, that Jebusite can never be expelled. You drive out nature with a pitchfork, yet it still returns. Not all (says he) understand this word, but he who can understand it, let him understand it. Hence, when God himself had ordered certain pontifical garments, that Moses and Aaron should clothe their sons, he did not command only the feminine ones, but said that they themselves should wear feminine ones when they entered the tabernacle of testimony. But the apostle also says: Do not deceive one another, except perhaps by agreement for a time. that you may rest in prayer and return again to the same thing, lest Satan tempt you because of your intemperance. For it is better to marry than to burn. Therefore, the angel of Satan fights against self-control, who carnally stimulates and violently slaps, kindles the fire of nature with the breath of suggestion, supplies matter, gives ability, and serves opportunity. He fights, and species which is suddenly seen, is easily coveted. Therefore, when David was walking in the afternoon in the palace of the royal house, seeing from opposite Bathsheba washing herself, he sent and took her and slept with her, for she was a very beautiful woman. Moreover, he who is with his wife is anxious about the things of the world and is divided. For he is distracted by many straits and divided into various cares, in order to seek and provide for his sons and wife, servants and maidservants. Therefore the tribulations of the flesh they have such The wife strives to have precious ornaments and various furniture, so that her worship is often more valuable than her husband's income; moreover, through the nights and days he weeps and sighs, chatters and murmurs. For there are three things which do not permit a man to remain in the house, smoke, dripping, and his main wife. She (says he) goes more gracefully and is honored by all, but I, the most miserable one, alone in the assembly of women, am despised, despised by all. She only wants to be loved, to be praised by the sun, another's love she claims to be her hatred, another's praise she suspects her shame. Everyone who loves is to be loved, everything that is hated is to be hated. It is worth winning, but it is not worth winning. He does not suffer to be tamed, but tries to dominate. He wants to be able to do everything, but not to be able to do anything. If she is beautiful, she is easily enamored; if ugly, not easily coveted. But what is loved by many is hard to keep, and it is difficult to possess what no one is worthy to possess. The form of another, another with wit, another with humor, another with liberality; and from some part it is captured, that which is approached from all sides. The horse and the ass, the ox and the dog, the garment and the bed, even the cup and the pitcher, are first tried, and afterwards compared. But the bride is scarcely shown at last, lest she should be displeased before she is taken away; yet, whatever chance may befall her, she must always be held. If she is ugly, if she is smelly, if she is sick, if she is foolish, if she is proud, if she is hot-tempered, if she is in any way vicious, a wife cannot be put away by her husband except for fornication alone. But he who divorces cannot marry another, nor can another be joined to a divorced one. For whoever he who divorces his wife, except for the cause of fornication, causes her to commit adultery, and he who marries a divorced woman commits adultery. If the wife has left her husband, she must remain unmarried or be reconciled to her husband. In the same way the husband, if he has left his wife. The weight of the couple is too heavy. For (says Solomon) he is a fool and an impious man who commits adultery, and he is a patron of indecency who conceals the crime of his wife. But if he divorces adultery, he is punished through no fault of his own, since he is forced to keep it while he is alive, for which reason the disciples of Christ also said: If such is the case of a man with his wife, it is not expedient to marry. Who could ever withstand a rival with equanimity? The mere suspicion afflicts the zealot greatly. For although it is written: they shall be two in one flesh; but the jealousy of two men in one flesh is not tolerated. CHAPTER Nineteen. Of the misery of the good and the bad. It is not for the wicked to rejoice, he says to the lords, because by what a man sins, he is tormented by it. For the worm of conscience never dies, and the fire of reason is never extinguished. For I saw those who work iniquity and sow sorrows and reap them, perished by the breath of God, and were consumed by the spirit of his wrath. Pride inflames, envy gnaws, avarice stimulates, anger inflames, gluttony torments, lust dissolves, falsehood binds, murder stains. So also the rest of the marvels of vice, and which are the amusements of man's piety, are the instruments of God's punishment. Envious of another's possessions, he perished in his riches. But the envy of the Sicilians did not find a greater cannon for the tyrant. For vice corrupts nature, as the apostle testifies, who says: Because they have disappeared in their thoughts, the foolish man is darkened their car For this reason God gave them over to the desires of their hearts, to impurity, so that they might insult their bodies, and as They refused to have knowledge of God, so God gave them over to a reprobate mind, so that they would do those things which were not agreeable to them. But even those who want to live godly in Christ suffer persecution. For the saints have experienced mockery and scourging, besides chains and prisons; They went about in sackcloth, in sheep's skins, needy, distressed, distressed, some of them were not worthy of the world. Wandering in deserts and mountains, in caves and caverns of the earth, dangers of rivers, dangers of robbers, dangers from the tribe, dangers from the nations, dangers in the city, dangers from false brothers In labor and suffering, in many vigils, in hunger and thirst, in many hardships, in cold and nakedness. For the just man denies himself, crucifying his members with vices and lusts, so that the world may be crucified to him, and he to the world. He does not have a permanent citizenship here, but he is looking for a future one. He endures a century as an exile, shut up in the body as in a prison. Inhabitant, he said; I am in the land and a stranger like all my fathers. Allow me to cool off before I go and be no more. Alas for me, because my sojourn was prolonged, I dwelt with the inhabitants of Cedar, my soul was much a sojourner. Who is weak, and I am not weak? who offends, and I do not burn? for the sins of our neighbors are the reproaches of the righteous. This is the watering-place which Caleph gave to his daughter Axa as a dowry. CHAPTER Twenty. Of the enemies of man. Therefore, warfare is the life of man on earth. Is it not true warfare, when multiple enemies are always lying in wait on every side to capture, to pursue to destroy, demon and man, world and flesh? The devil with vices and lusts, man with beasts, the clean with the elements, the flesh with the senses. For the flesh lusteth against the spirit, but the spirit against the flesh. It is true that our struggle is not against flesh and blood, but against spiritual wickedness in the heavenly realms, against the rulers of this darkness. For your adversary the devil walks about like a roaring lion, seeking whom he may devour. The fiery weapons of the wicked are kindled. Death enters through the windows, the eye preys on the soul, the world fights against the world senseless. Nation against nation, and kingdom against kingdom, and there will be great earthquakes throughout the land, pestilences and famines, and terrors from heaven and storms. The earth produces thorns and thistles, the water storms and waves, the air storms and thunder, fire flashes and lightnings. Cursed, he says, the ground will sprout thorns and thistles for you in your work. In the sweat of your face you will eat your bread until you return to the earth, because you are earth and now you will go to earth. A wild boar ambushed him from the forest, and a singular beast devoured him, the wolf and the bear, the panther and the lion, the tiger and the onager, the crocodile and the gryphon, the snake and the snake, the basilisk and the wasp, the dragon and the scorpion, the scorpion and the viper, but also the snakes and lice, ants and fleas, gnats and flies, hornets and wasps, fish and birds. For we who were created to have dominion over the fish of the sea, the birds of the sky, and every living thing that moves on the earth, we are now given to them as a prey and given to them as food. For it is written: I will send the teeth of beasts upon them, with the fury of those that drag on the earth, and of serpents. Chapter Twenty One. Of the prison of the soul which is the body. I am a miserable man, who will deliver me from the body of this death? surely he does not want to be brought out of prison, who does not want to come out of his body. For the prison of the soul is the body. About which the Psalmist: Bring my soul out of prison. Nowhere is peace and tranquility, nowhere is peace or security, everywhere fear and trembling, everywhere toil and pain. As long as the flesh lives, it will grieve, and the soul will mourn over itself. CHAPTER Twenty-Two. Of the brief happiness of man. Who has ever led a whole day in his pleasant enjoyment, which was not disturbed in some part of the day by the guilt of conscience, or by an attack of anger, or by the impulse of concupiscence? Who has not been vexed by the bruise of envy, or the ardor of avarice, or the swelling of pride, who has not been moved by some loss, or offense, or passion, who has not been offended by some sight, or hearing, or act? A rare bird in the world, very similar to the black swan. Listen to the wise man's opinion on this: From morning to evening time will change. Vain thoughts succeed him, and the mind is carried away into different things. They hold the drum and the lyre, and rejoice at the sound of the organ. Chapter Twenty Three. Of unexpected pain. For worldly Jaetism is always followed by sudden sadness. And what begins with joy ends in sorrow. For worldly happiness is sprinkled with many bitternesses. He knew this who had said: Laughter will be mingled with sorrow, and joy will occupy the extremes of grief. The children of Job experienced this, for when they were eating and drinking wine in the house of their first-born brother, suddenly a strong wind rushed from the desert country and shook the four corners of the house, which fell and crushed them all. Rightly then did the father say: My harp is turned to mourning, and my organ to the voice of weeping. For it is better to go to the house of mourning than to the house of rejoicing. Pay attention to the healthy advice: In the day of the good you are not oblivious to evils. Remember your last words, and you will not sin forever. CHAPTER Twenty-Four. On the nearness of death. The last day is always the first, and the first day is never considered the last, although it is always appropriate to live as if it were always necessary to die. For it is written: Be mindful, because death does not delay. Time passes, but death approaches. A thousand years before dying, as if it were yesterday, which has passed. For the future is always born, the present always dies, and all that is past is dead. For we die while we live forever, and only then do we cease to die when we cease to live. It is therefore better to die of life than to live to death, because mortal life is nothing but living death. Hence Solomon: I praised the dead more than living, and I judged the one who had not yet been born to be more fortunate than both. Life runs fast and cannot be held back; but death occurs instantly and cannot be prevented. This is the wonderful thing, that the more it grows, the more it decreases, because the more life progresses, the more it comes to an end. CHAPTER Twenty-Five. On the terror of sleepers. The time which is allowed to be quiet, is not allowed to be quiet: for dreams are frightening; disturbing visions. And although they are not in truth sad, or terrible, or laborious, what they dream when they dream, yet in truth they are sad, frightened, and tired to such an extent that sometimes they weep while sleeping, and when they wake up they are very often troubled; they have lost it. Notice what Eliphas the Themanites says about this: In the horror of the night vision, when Sleep is wont to take hold of men, terror seized me and trembling, and all my bones were terrified, and when the spirit passed over me, the hairs of my flesh shuddered. Consider Job saying: If I speak, my bed will comfort me, and I will be revealed, Joking with myself on my bed; You will frighten me by dreams, and by visions you will shake me with horror. Nebuchadnezzar saw a dream that greatly frightened him, and the visions in his head troubled him. Many cares follow dreams, and where there are many dreams, many vanities. They have caused many to err in their dreams, and they have given up hoping in them. For there frequently appear in dreams indecent images, from which, through nocturnal illusions, not only the flesh is polluted, but the soul is also stained. Wherefore the Lord in Leviticus says: If there be among you a man who is defiled in his night's sleep, let him go outside the camp, and not return until he in the evening he is washed with water, and after the sun sets he must return to the camp. CHAPTER Twenty-Six. On the sympathy of friends. Oh, with how much pain we are troubled, with how much trembling we are shaken, when we feel the losses of our friends and fear the dangers of our parents! More than once healthy in fear, quarn weak is disturbed by illness. Here the volunteer is more afflicted by the feeling of pain than by the sight of the effect of fatigue. It is true in poetry: Love is full of anxiety and fear. Whose chest is so iron, whose heart is so stony, that it does not express a groan, does not shed tears, when it looks at the disease and destruction of a neighbor or a friend, that it does not sympathize with the patient, and does not sympathize with the sorrowing? When Jesus himself saw Mary and the Jews who had come with her to the tomb weeping, he was troubled in spirit, troubled himself, and burst into tears. it is, perhaps not because he died, but rather because he recalled the dead to the miseries of life. But let him know that he is culpably hard and grievously guilty who mourns the bodily death of his friend and does not weep for the spiritual death of his soul. Chapter Twenty-Seven. Of sudden misfortunes. Suddenly, when it is not suspected, misfortune happens, calamity rushes in, disease invades, death intercepts, from which no one escapes. Therefore do not boast about tomorrow, not knowing what the next day will bring forth. A man does not know his end, but as a fish is taken with a hook, and as birds are caught in a snare, so men are caught in the evil time when it suddenly comes upon them. Chapter Twenty-Eight. Of innumerable kinds of sickness. Until centuries ago, physical energy could track down as many types of illnesses, as many types of passions, as human frailty could tolerate. Should I say intolerance of diseases is tolerable, or should I say tolerance is intolerable? it is better to combine both. For it is intolerable because of the bitterness of passion, and tolerable because of the necessity of suffering, day by day human nature becomes more and more corrupt. In this way, since most healthy experiments were once made, which today are deadly due to their lack, both the worlds have grown old, both the macrocosm and the microcosm, that is, the greater world and the lesser world. And the longer the old age of both is produced, the worse the nature of both is disturbed. CHAPTER Twenty-Nine. About the different types of arms. What shall I say of the wretched, who are punished by innumerable kinds of tortures? they are slaughtered with clubs and swords; Those to death, to death, those to the sword, to the sword, those to famine, to famine, and those to captivity, to captivity. A cruel judgment, a terrible execution, a sad spectacle, are given as food to the birds of the sky, the beasts of the earth, and the fish of the sea. Alas, alas, poor mothers, who gave birth to such unhappy children. Chapter Thirty. About a certain horrible fascination, such as that a certain woman eats her own child. I would therefore like to recall the horrible deed that Josephus describes of the Jewish siege: A certain woman of noble means and lineage, together with the rest of the multitude, which had flocked to Jerusalem, bore the common fate of the siege. The rest of his resources, which he had transferred from his house to the city, were completely invaded by the tyrants. If anything had been left of the great riches, with which she could lead a meager daily subsistence, the robbers' henchmen rushed in and snatched it away, for which the immense labor tired the woman out of a kind of indignation as if insanity, so that sometimes she incited the robbers to murder by her curses and insults. It is true that he was not irritated no one would have pitied her, and if there had been any food that she might have sought from her, it would have been sought from others, and there would no longer be any more to be desired; already armed against the very laws of nature. For she had a little son under her breast, whom she brought before her eyes. O most unfortunate son, in war, famine, and raids of robbers, to whom shall I reserve you? For even if life could be hoped for, you would still be bound by the yoke of Roman servitude. I have come now, O my son, be food to the mother, fury to the gods, legend to the ages, which was the only thing missing from the destruction of the Jews. And when he had said this, he immediately strangled his son, and then threw them into the fire when it is placed, it roasts, and consumes half of it, but keeps the half covered. And behold, immediately the robbers rushed in, having received the smell of burnt flesh, and threatened him with death, unless he showed without delay the food, which they felt was ready. Then she said: I have reserved the best part for you, and immediately she uncovered the remaining parts of the child. But they were suddenly seized with a great terror, and their limbs were unable to direct themselves, and as if by hardness of heart their voice was stopped in their throats. But she, with a fierce countenance, and more savage than the robbers themselves, says she, is the birth of mine, the son is mine, the deed is mine. Do not make yourselves more pious mothers, or softer women; that if your pity overcomes you, curse my food, which I have already fed on such, I will feed on them again. After this they were terrified and dismayed they depart, who have left this alone, of all their resources, as food for the poor mother. Chapter Thirty-One. Sometimes the innocent is punished and the guilty is acquitted. Let no one trust himself who has experienced punishment, who knows himself to be immune from guilt. He who stands must see that he does not fall. For the innocent is often condemned, and the guilty is acquitted: the pious is punished, and the impious is honored. Jesus is crucified, and Barabbas is freed. Today a just and quiet man is considered useless, a religious man a hypocrite, a simple man foolish. For the simplicity of the righteous is mocked. Lamps despised by the thoughts of the gods. THE SECOND BOOK. dissuading from the sinful progress of human conversion. CHAPTER One. Which people usually affect in common. Men are most wont to be affected by three things: riches, pleasures, and honors. They proceed from corrupt wealth, from base pleasures, from vain honors. For hence John the Apostle says: Love not the world, nor the things that are in the world: for whatever is in the world is the lust of the flesh and the lust of the eyes, and the pride of life. The lust of the flesh belongs to pleasures, the lust of the eyes to riches, the pride of life belongs to honors. Riches breed lust and avarice, pleasures breed gluttony and luxury, honors breed pride and boasting. CHAPTER Two. Of desire. There is nothing therefore more wicked to the miser, and nothing more wicked, than to love money. It is the word of the Wise, which the Apostle confirms, saying: Those who wish to become rich fall into temptation and into the trap of the devil, and into many and useless and harmful desires, which plunge a man into destruction and perdition. For the root of all evil is covetousness. He commits blasphemies and steals, commits robberies and plunders, wages wars and murders, sells and buys fraudulently, demands and receives unjustly, negotiates and lends unjustly, He insists on tricks and threats of fraud, dissolves the agreement and violates the oath, corrupts the testimony and perverts the judgment. CHAPTER Three. Of unjust duties. Consult the evangelical prophet Isaiah. All (says he) love gifts, follow retributions, do not judge the orphan, the cause of the widow does not enter into them. They do not precede retributions, because they do not judge from the love of justice, but retributions precede them, because they point to the love of money. For they always follow a gift, a promise, or a hope, and therefore they do not judge by the pupil from whom the gift is given, or promised, or hoped for. O unfaithful princes, companions of thieves, whosoever loves gifts, follow retributions, never shake your hand from a gift, unless you have first eluded the covetousness of the peotor. The prophet says of you: I will snatch away its princes like wolves, and snatch away the gains in pursuit. Its princes judged in gifts, and the chosen priests taught for a fee, and its prophets divined in money. And the Lord through Moses commanded the contrary in the law: You shall appoint judges and magistrates in all your gates, that they may judge the people with just judgment, and not incline to the other side. You shall not accept a person or gifts, because gifts blind the eyes of the wise and change the words of the righteous. But you will pursue just what is right, and you will live. He says two things, just and just. For some pursue just what is just, others unjustly what is unjust: again, some unjustly pursue what is just, others justly what is unjust. Chapter Four. On the reception of persons. Woe unto you who pray or praise the corrupt, who, driven by love or hatred, say good and evil and evil and good, putting light to darkness and darkness to light, mortifying souls that do not die, and quickening souls that do not live. For you do not consider the merits of causes, but the merits of persons, not rights, but gifts, not justice, but money, not what reason dictates, but what the will affects, not what the law enjoins, but what the mind desires. Not inclining your mind to justice, but inclining your mind to justice, not that this may please, but that this may be permitted. The eye is never so simple in you, that the whole body is bright, but you always mix something with the leaven, by which you corrupt the whole mass. You neglect a poor cause with delay, but promote a rich cause with urgency. You show rigor in them, when you dispense with them out of meekness. You regard them with difficulty,. treat these evacuees with favor. hearing them carelessly, listening to them with precision. The poor man cries and hears the poor, the rich man speaks and everyone applauds. The rich man spoke, and all were silent, and the clouds will carry his rod even as far; the poor man spoke, and they say, who is this man? and if he stumbles, they will overthrow him. He who suffers violence cries out and no one listens, he cries out and there is no one to tell. But if you happen to take up the cause of the sparrows, you encourage them with ease, but if you take up the cause of the rich, you persevere in persuading them. The poor are despised, the wicked are honored; you rose reverently against them, and despised them despicably. If a man enters your meeting with a golden ring in a white garment, a poor man enters in a dirty garment, and you look at him who is dressed in a fine garment, and you say to him, sit here well; my feet, are you not mocking among yourselves and become the index of unrighteous thoughts? For the prophet says about you and against you: They were magnified and rich, fat and oppressed; You will accept the truth of each person, it is God's judgment. For there is no acceptance of persons with God. Chapter Five. Of the sale of the just. But you neither give grace gratuitously, nor return joy justly, because unless it comes, it does not proceed, and it is not given unless it is sold. often You postpone justice so much that you take more than the whole thing away from the litigants, because the cost of the expense is greater than the result of the decision. But what will you be able to answer in the district judgment, who commands: You have received freely, freely give? Lureum in the box, loss in the conscience, you capture the money, but you capture the soul. But what does it profit a man if he gains the whole world, but suffers the loss of his own soul? Or what shall a man give in exchange for his soul? A brother will not redeem, man will redeem, he will not give to God his appeasement, nor the price of the redemption of his soul, he has labored for ever, and he will still live to the end. Hear, O Gods, what the Apostle James says against you: Act now, you rich, weep and howl in your miseries that will come upon you, your riches are rotten, and your clothes are eaten by moths, your gold and silver have rusted. and their pride will be a witness to you, and will eat your flesh like fire. You have stored up wrath for yourselves in the last days. Behold, the wages of the laborers who harvested your fields, which has been defrauded by you, cry out, and their cry entered into the ears of the Lord of hosts. Therefore the truth commanded: Do not lay up for yourselves treasures on earth, where rust and moth destroy, where thieves dig up and steal. Chapter Six. Of the insatiable desire of lovers. O unquenchable fire, O insatiable desire. Who has ever been satisfied with his first wish? When he obtains what he had wished for, he longs for abundance, and always ends in having and never in having. The eye of the covetous is insatiable, and not in the part of iniquity will be satisfied The greedy will not be filled with money, and he who loves riches will not enjoy them. Hell and perdition are ever filled, so are the eyes of man insatiable. But it is usually the daughters of bloodsuckers who say: bring, bring. For the love of money increases as much as the chest itself increases. CHAPTER Seven. Why the greedy cannot be satisfied. Do you want to know, oh desire, why you are always empty, why you are never filled? Be warned: it is not your full measure, which, no matter how much it contains, is still a bigger catch. But the human mind is capable of God, since he who adheres to God is one with God. However much it contains, it is never full unless it has God, whose it always is capable If you want to be satisfied, O greedy person, stop being greedy, because while you are greedy, you will not be able to be satisfied. For there is no meeting of light with darkness, nor of Christ with Belial, because no one can serve God and mammon. Chapter Eight. Of false name of riches. O happy false riches, which truly make a rich man an unhappy son. For what is more unhappy than the riches of the world, which are called riches? For the rich and the needy are the opposites of the sun. But they do not take away the wealth of the world, but bring want. For, says Solomon, a little is more sufficient for the poor than for the rich, because where there are many riches, there are many who eat them. How many and how much the magnates need, he frequently himself I try. Riches therefore do not make a man rich, but needy. CHAPTER Nine. Examples against desire. How many have been deceived by desire! how many has greed destroyed! Balaam drew back the ass and rubbed the feet of the one who was sitting, because he had been seized by the desire of the promised people and had planned to curse Israel. Achan was stoned by the people because he had taken gold and silver from the curse. Naboth was interrupted so that Achas could take possession of his vineyard. Gezi was struck with leprosy because he asked for and received gold and silver and clothes under the name of Eliseus. Judas hangs himself with a snare, because he sold and betrayed Cbristus. Ananias and Sapphira died suddenly because they defrauded the apostles of the price of the land. Tire built her fortifications, and amassed silver like the earth, and gold like the mud of the streets, but behold, the lord will possess her, and will smite her strength in the sea, and these will be devoured by fire. Chapter Ten. Of the superfluous solicitude of lovers. Why does anyone insist on gathering, when he who gathers cannot stand? For like a flower it comes forth and is crushed, and flees like a shadow, and never remains in the same state. Why should he desire much, when a few are sufficient? Having, he says, food and clothing, let us be content with these. Why should he seek the necessities with much solicitude, when they themselves offer themselves without great difficulty? listen What does the truth say about this: Do not be anxious, saying: What shall we eat, or what shall we drink, or with what shall we be covered? For your heavenly Father knows that you need all these things. Therefore seek first the kingdom of God and his righteousness, and these things will be added to you. For I have never seen a righteous man forsaken, nor his seed seeking bread. CHAPTER Eleven. Of avarice. Tantalus thirsts for waves, and is greedy for riches, for he is as much what he has as he is what he does not have, because he never uses what he has acquired, but is always eager to acquire it. Solomon: He is like a rich man when he has nothing, and he is like a poor man when he has many riches. Avaras and hell both eat and do not digest, take and do not give back. The miser does not sympathize with the suffering, nor does he help or pity the poor, but offends God, he offends himself, he offends his neighbor. For he withholds what is due to God, he denies what is necessary, and takes away what is convenient. Ungrateful to God, impious to his neighbor, cruel to himself. To a covetous and tenacious man substance is without reason, and to a livid man what good is gold? He who is wicked to himself, how will he be good to others? And he will not delight in his possessions. He who has the substance of this world, and sees that his brother is in need, closes his bowels from him, how does the charity of God remain in him? For he does not love his neighbor as himself, whom hunger destroys and want consumes, nor does he love God above all things, who prefers gold and prefers silver. Chapter Twelve. Why is avarice the servitude of idols? The apostle rightly defines: Covetousness is the servitude of idols. For as the idolater serves the image, so also the greedy treasure. For he diligently amplifies the worship of idolatry, and he gladly increases the heap of money. He worships the image with all care, and he guards the treasure with all care. He places his hope in idolatry, and he places his hope in money. He fears to mutilate the image, and he fears to diminish the treasure. Chapter Thirteen. On certain properties of avarice. Greedy ready to ask, slow to give, proud to deny. If he spends anything, he loses a lot, sad, bitter and so on the morose sighs and worries, doubts and spends unwillingly. The Magnificat is given, but it debases what is to be given, it gives that it may be gained, but it is not gained that it is given; It empties the appetite to fill the chest, thins the body to extend profit. His hand is folded to give, but extended to receive, closed to give, but open to receive. Moreover, the substance of the unrighteous will dry up like a river, because he who gathers badly quickly scatters. a judgment of lust, but let what proceeds from evil come to evil, and let it not come to good that does not proceed from good. The avaricious, therefore, drinks the damnation of the life that is now, and that which is to come. Chapter Fourteen. On the unjust possession of shares. It is true, then, that the wise man protested, he lost many gold and silver. He who loves gold will not be justified. Woe to those who let it be followed. Behold, the very sinners and the rich have obtained riches in this age. Hence the truth itself commanded the apostles: Do not possess gold, silver, or money in your belts, because just as a camel cannot enter through the eye of a needle, so it is difficult for a rich man to enter the kingdom of heaven. For narrow is the way and narrow is the gate that leads to life. The apostle therefore, following the rule of truth, said: Silver and gold are now mine. Woe to you, therefore, who join house to house, and field to field to the border of the place. The earth is full of silver and gold, and there is no end to its treasures. I was angry because of the iniquity of his greed, and I struck him. Chapter Fifteen. Of lawful resources. Moreover, Abraham was rich, and Job rich, David wealthy, and yet the scripture says of Abraham, because he believed God and it was counted to him for righteousness. And of Job, because there was none like him in the earth, a simple and upright man, fearing God, and shunning evil. As for David, because the Lord found a man after his own heart. But they were as if they had nothing and possessed everything, according to the words of the Prophet: If riches flow in, do not set your heart on them. But we are possessors of all things as if we had nothing, according to the words of the Psalmist: The rich ate and were hungry. For you will find it easier for him who loves riches and does not have, than he who has and does not love. As it is difficult to be in the fire and not burn, it is more difficult to possess riches and not love. Hear the prophet Jeremiah: From the least to the greatest, all seek covetousness, and from the prophet to the priest, all commit deceit. Chapter Sixteen. Of the uncertainty of riches. Everyone who is covetous and avaricious works contrary to nature. For nature brings the poor into the world, nature brings the poor back from the world. For the earth received him naked, and it will also receive him naked. But cupid desires and cares to become rich in the world. (says he) I will destroy my barns, and make them larger, and gather there the multitudes that have been born to me, and all my goods. But it was said to him: O fool, this night your soul will be taken from you, but what you have prepared, whose will they be? You hoard and do not know to whom you are hoarding. For they slept their sleep, and all the rich men found nothing in their hands. The rich when he sleeps, he brings nothing with him, he will open his eyes and find nothing. Do not be afraid, then, when a man has become rich, and when the glory of his house has been multiplied, because when he dies, he will not receive all these things, nor will the glory of his house descend with him, but will leave his riches to strangers, and their tombs, their house forever. From this also the Wise is attested: He who accumulates from his heart unjustly, gathers it up for others, and in his possessions another will luxuriate. Unfortunately, the enemy he had had let go of the heir. CHAPTER Seventeen. Of gluttony. The beginnin

Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Rahan. Episode Seventy-Nine. By Roger Lecureux, drawn by Andre Cheret. The Island of the Living Dead. As if emerging from the sea, the skeletons ran towards the islet. Carried away by one of them, a man screamed in terror. And fear paralyzed the son of Crao. The Living Dead! Could the “Endless River” have thrown Rahan into the territory of shadows!? It was at dusk that his raft broke apart. But he had been able to reach this beach littered with human bones. The skeletons had disappeared into the darkness and wild laughter rose from the top of the island. The dead are happy to have captured a hunter! But they will not take Rahan! Rahan wants to live! Page Two. It was only at daybreak that he was able to abandon the islet that a rocky strip connected to the neighboring island. This is where the living dead have gone! No. It is impossible. Rahan must have had a nightmare! He was observed from the nearby shore. He comes from the “Rock of the Dead”! Let us run away, Jahang! No Eloa! If this Dead Man took on the appearance of a hunter to deceive us, it will cost him! A volley of fine sand blinded him. The man's club did the rest! Argh! I, I think we were wrong, Jahang! A little later. No, Rahan is not a “Living Dead”! It was the endless river that threw him onto the island! You seem sincere! Watch out Jahang! Ra-Konda is coming! If this hunter told the truth we cannot abandon him to this savage! Men approached, probing the thickets with their spears. Page Three. Jahang returned Rahan's knife and rushed towards the forest. His companion fled in another direction. Rahan might do well to imitate them! The men approached. He came from the "Rock of the Dead." His hair is the color of fire. Search! Search! He must be hiding somewhere! The son of Crao, in fact, was taking refuge in a cave. It is strange! It looks like they do not dare approach this cave! They are moving away! Ra-Konda's small troop had just disappeared when screams arose. At an arrow's distance a man was grappling with a sawfish. Without weapons, he will not kill the "Nose of teeth"! Rahan must come to his aid! A remarkable swimmer, it only took him a moment to come to the aid of the stranger in difficulty. Page Four. Ten times the sawfish charged him, circled around him, and charged again. Ten times, he avoided the dreaded “nose-of-teeth.” Finally, he managed to grab onto this “Nose” to deliver the fatal blow. You will never disembowel anyone again, "Nose-of-teeth"! Oh! What? What? The man Rahan had just saved had had his leg amputated. He nevertheless swam decently. I am Paoni, Chief of the River clan. I hoped to bring back some fish to mine, but the "Nose-of-teeth" attacked me! Who are you? A little later. Our clan will be happy to welcome you Rahan! This is my daughter, Eloa. The son of Crao was going to say that he had already seen Eloa and her companion Jahang. Page Five. But she discreetly assumed supplication. If Eloa has a secret, Rahan will not betray her. That night on this island, Rahan saw one thing. Terrible. Yes. The “Living Dead” kidnapped one of our old men. But talking about them aroused their anger! Never speak of them again! Rahan did not insist, under the intrigued gaze of the clan he began a curious task. You will soon be able to walk alone, Paoni. Rahan is preparing a leg for you! What? The chief was enthusiastic when he was able to take a few steps on this pylon. With a little practice, you will almost be able to run like you used to! I will never forget what you did for my father! How can I thank you? By revealing your secret, Eloa. Who is Jahang? Why did you and him flee Ra-Konda? Page Six. Jahang is the son of Quiwah, the leader of the forest clan. We love each other. But Ra-Konda, the sorcerer of our two clans, forbids marriages between those from the shore and those from the forest! If Ra-konda learned that Jahnag and I loved each other, He would order the great mountain to become angry! That is stupid Eloa! No wizard can. Rahan did not have time to acknowledge. Ra-Konda! If he captures you, he will have you thrown to the “blue-skins”! Run away, Rahan, run away! The son of Crao launched himself towards a water hole. Clinging to a ledge, he heard the sorcerer and the hunters approach. And suddenly. Ah! A “Head-with-eight-arms”! The archers of Ra-Konda. The octopus. Two dangers threatened Rahan! Page Seven. Between these two dangers Rahan chose the most immediate. But barely had the ivory blade severed the tentacle. A hunter silhouetted against the sky, his bow drawn. He stared at the son of Crao for a moment. And. No! “Hair of Fire” is not in this hole! Let us look further! Take refuge on the great mountain, Rahan. Only there will you be safe! The man who had come to his aid was none other than Jahang, Eloa's companion. As the hunters moved away, Rahan followed his advice. He reached the side of the volcano without being disturbed. Very few fish. Very little game. Why do “Those-Who-Walk-Upright” not abandon this territory!? Page Eight. He soon dominated the island. The sea had covered the rocky strip, isolating the islet of the “Living Dead.” No! It is impossible! The dead cannot live again! The terrifying vision of skeletons kidnapping a man came back to him. Rahan cannot believe it, and yet he saw these dead people move, jump, and leap! A rustling in the thickets suddenly put him on alert. But it was only Eloa and Jahang. We were looking for you, Rahan. My father decided that the shore clan would welcome you despite Ra-Konda's interdict! So Paoni no longer fears that Ra-Konda will make the Great Mountain thunder? Page Nine. He soon became very serious. Rahan will only stay with you for a few days. As soon as he has built a new raft he will leave this island! Ah! If we could run away with you! Find a land where we would be free, Eloa and I, to meet as we please, to get married! The man who was spying on the young people had lost nothing of what they said. Well! This is a project that Ra-konda will be delighted to learn about! Eloa and Jahang separated sadly. See you tomorrow, Eloa! Near the “Cave-of-the-Heads-with-eight-arms”! But be careful! What is this cave, Eloa? This one, it is infested with monsters. None of the men dare to approach it! This is where we find ourselves with Jahang! Rahan will not betray your secret! Page Ten. They had barely arrived on the shore when La-Konda appeared. The spirits told me that Eloa and Jahang met secretly, violating the law which prohibits marriages between those of the shore and those of the forest! And they are preparing to abandon their clans with the complicity of Rahan! Rahan must be delivered to the "Living Dead"! Men threw themselves at the son of Crao. But he was on his guard. Crack! Argh! He rushed towards the cave of the “Heads-with-eight-arms.” Stop! Do not kill Rahan! It was me who asked him to leave the island with him! The men stayed cautiously away from the cave to which Rahan had just rushed. But if Rahan comes out of here, he will be riddled with arrows. Page Eleven. Save Rahan Ra-Konda! Spare him, and Jahang and I will give up our love! No! Rahan will die! The sorcerer looked at Paoni, the chief of the shore clan, and Quiwah, the chief of the forest clan. Next night will be another full moon night. The sea will recede and the “Living Dead” will start hunting! Would you prefer that they kidnap one of yours, or would you prefer to deliver Rahan to them as an offering? The son of Crao had heard. The men remained on the lookout! Rahan only had one more chance. Discover another way out! He went deeper into the darkness, and suddenly he understood why the clans never ventured there. This cave was a huge den of octopuses! Page Twelve. Their tentacles shot out in all directions, lashing the rocks and the wall. Rahan has never seen so many "Heads-with-eight-arms"! Argh! Cutting, slicing, sectioning, Rahan progressed painfully along the underground vein of the sea. Ra-ha-ha! Never had his ivory knife struck so much! A light finally appeared at the end of the gully. An issue! Rahan may be saved! The octopuses became rarer and he soon found himself in a vast cavern. Under the roof which fell from a gap in the vault, a lake spread out. He was suddenly frozen in stupor. What he saw in this cave was extraordinary. Incredible. Oh! What? What? Page thirteen. On the other side of the lake a gigantic skiff could be seen! The first occupants of the island undoubtedly arrived on this Raft. But the "Heads-with-eight-arms" have made the cave their lair, and this raft has become inaccessible! The seasons have passed, more numerous than the leaves on a tree, and the memory of the raft has disappeared into the night of time. Today, the shore clan and the forest clan are unaware of its existence! The son of Crao soon reached the gap. And. When he emerged into daylight it was halfway up the slope of the volcano. The sea, over there, lashed the disturbing island of the “Living Dead.” Rahan does not want to be handed over to the Undead! He must flee this island as quickly as possible! Page Fourteen. At night he crept to shore and began building a raft. Rahan will not have time to finish it. He will have to come back next night! He was camouflaging the unfinished skiff when screams of fear broke out. The Living Dead! The sea had receded and, coming to the islet, two skeletons jumped on the hard rocky strip. If Rahan has not lost his mind, he must admit that these dead people really live! Taking refuge on the slope of the volcano, he soon saw the undead return to the island. This time, the men have made their escape! Rahan can get some sleep! Clamors of rage awakened the son of Crao. On the shore his raft was blazing! Ra-Konda has discovered it, and he seems to be accusing Jahang and Eloa! Page Fifteen. And Indeed. Rahan would not have dared to risk coming here! These are the two traitors who were preparing their escape! Let them be thrown to the “Blue skins”! Rahan had not heard. But he saw that the hands of Eloa and Jahang were tied, that they were pushed towards a cliff. Rahan will save them! We will die together, Eloa, as we would have liked to live! Our love will not die, Jahang! We will find each other in the territory of shadows! Descending the rocks, the son of the fierce ages arrived at the foot of the cliff. He dived at that very moment. That the couple were thrown into the void by the sorcerer himself. Page Sixteen. Rahan saw the two bodies break the surface. Sharks were already rising from the depths. The ivory blade cut Jahang's bonds. But he did not know how to swim! And the sharks were coming! If Eloa does not know how to "Crawl on water," Rahan will not be able to help them both and face the “Blue Skins!” But Eloa, as a daughter of the shore clan, swam perfectly! As soon as her hands were freed she went to Jahang's aid. As she brought her companion back to shore. The Son of Crao ensured their protection. Page Seventeen. From the top of the cliff, Ra-Konda had seen. Rahan saved these two traitors! Chase them! Kill Them! Kill Them! But Jahang and Eloa rushed towards the volcano. No! We will not pursue them on the Grand-Mountain! You always told us that those who risk it are lost! Caught in his own lies, Ra-Konda raged I will deal with these traitors myself! You, you will capture Rahan! Exhausted by his fight with the sharks, out of breath, the son of fierce ages had climbed onto the rocks. He did not have the strength to resist the men of Ra-Konda. Rahan saved our lives, But he is going to lose his own! Page Eighteen. A little later. Last night the forest clan and the shore clan did not lose a single man. But, tonight, the “Living Dead” will return! May this offering that we make to them appease their anger! Firmly tied up, Rahan had been abandoned on the shore, facing the islet of the living dead. With the night, the sea retreated again, clearing the rocky strip. All of Rahan's efforts to break his bonds had been in vain. The two clans had taken refuge at the foot of the volcano. And suddenly the son of Crao felt his health go cold while wild laughter rose from the island. Two undead were advancing on the narrow tongue of rock! Rahan had no chance of escaping these nightmare creatures! Page Nineteen. Your son will join you, Crao! Rumbling strangely, the undead stared at Rahan. Terrified, he knew he was lost! And then there was the miracle. Leaving this man to their mercy, the creatures rushed towards the forest. Rahan was confused. Another miracle followed. We will never know why they spared you, Rahan! But you have to flee the shore before they come back! In the forest, there was panic. Disabled by his wooden leg, Paoni was going to be caught by the Living dead! Page Twenty. Jahang and Eloa had just released Rahan when. Oh! Look! They captured my father! Carrying away their inanimate victim, the creatures returned to their island. Father! Father! My Father! Father! Distraught, Eloa rushes onto the rocky causeway as the waves begin to whip again. But she suddenly slipped on the rock, disappeared under a wave and reappeared. Eloa! I am coming, Eloa! I am coming! The son of Crao had not had time to hold back Jahang who, although not knowing how to swim, was rushing to his companion's aid! He was grabbing Eloa's hand when a strong wave overwhelmed the causeway, carrying them both towards the island of the Undead! Page Twenty-one. At that moment Ra-Konda appeared, followed by the two clans. If the "Living Dead" spared Rahan, it is because he is one of them! Kill him! Kill him! Cornered, the son of fierce ages had only one chance to escape from these men. The tongue of rock which accessed the island! As he jumped into the rocks beaten by increasingly violent waves, the arrows whizzed around him. Thrown back on the island, still panting, Eloa and Jahang had seen. Why is Ra-Konda so cruel! Why is he attacking Rahan like this! Oh! In his turn, Rahan had just been carried away by a wave, which carried him towards the sea! No! You will not swallow Rahan, River-without-end! He will fight with you! Page Twenty-two. He will fight as long as he has a breath of life left! Anyone else would have given way in this unequal struggle against the raging waves. But Rahan never gave up! Unimaginable efforts allowed him to reach the island. Ra-ha-ha! Between this one, and the island now surged an impetuous current. And it will be like this until the next round moon! We are at the mercy of the “Living Dead”! The situation of the trio, isolated in the very lair of the creatures, was dramatic! And Ra-Konda was jubilant! Eloa and Jahang want to be united despite my wishes. They will be, but in the territory of shadows. If The Sorcerer did not arouse any enthusiasm it was because of what the shore clan had lost. That night, Paoni and Eloa, and those from the forest had lost Jahang, the son of his leader Quiwah! Page Twenty-three. Screams and wild laughter rose from the top of the island. What strange rites did the “Living Dead” have to perform? Perhaps they have already killed my poor father!? Rahan will know soon, Eloa! Rahan no longer wants to know fear and dread! He wants to see these creatures closer, in their own lair! I will go up there with you, Rahan! No, Jahang. Your duty is to watch over Eloa! Stay with her. A moment later, the son of Crao climbed up the rocks. The cries and laughter that now reached him more clearly were not human. It seems normal for the "Undead" to have another language! What will Rahan discover in their lair? Page Twenty-four He suddenly noticed the sound of moaning. They came from a niche that was carved out of a large rock. To move such a heavy rock the undead must have ten times the strength of Rahan! But Rahan had once discovered the way to overcome this kind of obstacle. The rock moved, rolled. Eloa's father lay in this cave, moaning as if coming out of a terrible nightmare. Oh! Paoni! Where are the “Undead” Paoni? What did they do to you? Speak Paoni! Speak!? Still under the influence of fear, the chief of the shore clan could not respond! And suddenly! Page Twenty-Five. In the darkness Rahan suddenly felt as if the claws of death were gripping his shoulder. He struck the source! Ra-ha-ha! His blow was successful, because the “Living Dead” jumped back and fled the cave. Let us run away from Paoni! Let us flee before they come back in numbers! Up above, the wild laughter had ceased. But nothing happened as Paoni went back down towards the beach. Father! Father! I thought they killed you! Who are they Father? I do not know, Eloa. Because I lost consciousness as soon as they captured me! Who are they? No doubt the dead, Eola! Dead people who have found life again and want revenge on the living! No, Paoni! That is impossible! Page Twenty-Six. The son of Crao rejected this idea of a resurrection of the dead. These scars that Rahan wears on his shoulder were not made by a dead man! And we know that "Those who walk upright" after their death lose flesh and blood! It is true. Look, Rahan's knife! When Rahan struck he felt flesh, and blood remains on his blade! Which means that these creatures that frighten us are not "Dead." But beings of flesh and blood! Daylight returned and the mist dissipated around the island. But the shore remained inaccessible. Ra-Konda united the two clans. He must, as always, threaten them with the thundering of the “Grand Mountain”! Page Twenty-Seven. The undead will not worry the clans for a long time, since Paoni, Eloa, Jahang and Rahan are at their disposal! You forget that Jahang is my son, Ra-Konda! He only made the mistake of loving Eloa, A Girl from the Shore! The sorcerer must have felt the hostility rising, because he threatened. Never speak such words again, Quiwah! Otherwise, the fire from the great mountain will sweep over the island! It will only spare Ra-Konda, your sorcerer to whom you owe respect and obedience! However, on the island. Oh! Look down there! A “Four-hands”! This is the first one Rahan has seen on your island! The very young monkey disappeared into the rocks. As soon as daylight falls Rahan will go back up there! If the undead surprise you, throw yourself into the water. Since they seem to fear it! Page Twenty-Eight. Night found Rahan climbing the islet. Jahang had, this time, been allowed to accompany him. Listen Rahan!? They do not laugh anymore! They growl with anger! “They” rage because you have been taken from them, Paoni! Oh, Look! Two living dead descended into the rocks, towards the strip barred by the sea. A moment later they came and went, gesticulating in front of the waves. Rahan was right! They would like to look for another victim on the island. But they fear water! There! Another! A luminescent skeleton, strangely contorted, was about to emerge from a cave. Do not move, Jahang! Eloa will need you! You must live. For her! Knife in hand, the son of Crao rushed towards the cave. Page Twenty-Nine. At the very bottom of the cavern, the wall of phosphorus emitted an unreal, greenish light. Oh! Suddenly! Greek! The young monkey seen during the day burst out from a corner, and slipped between their legs. Rahan and Jahang froze at the entrance to the cave. The undead, coming up from the shore, rushed towards them. You have to find out where he is going! Oh! They are only men, Jahang! We will face them! The strange creatures came bounding forwards. They burst into the luminescent cavern. And. Oh! Contrary to what Rahan had thought. They were not men! Page Thirty. They were not men, but "Four-hands," of the most feared species! Gorillas! Argh! Unaccustomed to fighting, Jahang was immediately disarmed, and thrown against the wall. And the son of Crao found himself alone, facing the monsters! The unequal fight was nevertheless fiercely contested. His ivory knife opened a chest, but he could not resist the second gorilla. Half unconscious he was dragged to another cave. The one from which mysterious and wild laughter arose. Page Thirty-One. He discovered his spirits in this cave but thought he would faint again, so horrible was what he saw. The ground was littered with the bones of humans. The eaters of men! Ominous beings stared at Rahan. Ghark! Garok! The gorilla obeyed, and it was stationed at the entrance to the cave. These beings were undoubtedly the wildest and most primitive that the son of Crao had ever encountered. Haork! Haork! They do not know how to speak, but they knew how to train the "Four Hands"! They never leave this cave but they send the "Four Hands" to hunt for them. To hunt for men! Rahan considered the countless bones at the foot of the cliff. And he shuddered as he imagined the terrible events that took place in this den of wild men! Page Thirty-Two. However. The “Undead” are just “Four-hands”, Paoni! One of them knocked me out. And Rahan is missing! Those monsters probably killed him! Jahang's fears were not far from being justified! If Rahan does not escape the wild men, he will be slaughtered, torn to pieces and devoured! The beings had abandoned the ivory knife, the use of which they must have been ignorant of. But the “Four hands” watched over the entrance! Rahan only has one chance to escape. The river without end! Ra-ha-ha! The son of Crao dived towards the weapon, and pushed back some beings who intervened. And rushed towards the breach which opened onto the ocean. If Rahan does not dive far enough, he will crash onto the shore! Page Thirty-Three. With prodigious suppleness, he projected himself forward. Ra-ha-ha! Rahan! He has escaped from the “Living Dead”! We need to get to the island! What is happening there is too terrible! Quickly. Quickly. Rahan will explain later! The sea was still rough. But Rahan and Eloa supported Jahang and Paoni, and managed to reach the shore. Tell us, Rahan. What did you discover? At the very top of the island lives a small clan of wild beasts who feed on human flesh! These men-monsters have a sort of reverence for human bones, since they paint them in their caves. Page Thirty-Four. It is high time to put an end to it! Spare Paoni, But kill the other three! Fleeing under the flights of arrows, Jahang led his companions towards the forest. A little later. We are safe here! No man from our two clans will dare to venture as far as the "Mouth of the great mountain”! The surroundings of the crater were littered with trees felled by lightning. We cannot live hunted until the end of time! We must reconcile the clans, and convince them that Ra-Konda is deceiving them! And Rahan knows what we are going to do! If the face of the son of Crao lit up, it was because a magnificent idea had come to him. A marvelous idea. Page Thirty-Five. Rahan let two days and two nights pass before acting. Bring together those from the shore and those from the forest! Tell them that Ra-Konda has decided to end things and is going to let them talk! We will speak to them together, Ra-konda! The sorcerer and his few followers believed that a demon was falling! Oh! Zlang! Ra-ha-ha! It only took the son of Crao a few seconds to take control of the situation! Do not move, you people! Otherwise Ra-konda will join the territory of shadows sooner than expected! Page Thirty-Six. Bring the two clans together on the beach! Do as Ra-Konda said! While Rahan restrained him, Ra-Konda struggled in vain. A little later. Kill Rahan! Kill this blasphemer who dares to humiliate your wizard! Paoni's men and Quiwah's men came running. Some brandished their assegais. But Rahan used Ra-konda as a shield. Do not listen to the orders of this false sorcerer anymore, brothers! Ra-Konda was unable to clarify the mystery of the “Living Dead”! So he is not a clairvoyant wizard! And he always lied to you by claiming to dictate his will to the Grand-Mountain. Here is the proof. He does not even foresee that the great mountain would thunder just today! A clamor of fear erupted. Page Thirty-Seven. The smoke rose, more and more dense. The anger of the Grand-mountain will be terrible! It will vomit its entrails on the forest, on this shore! Everything will be destroyed! Everything! But Rahan can still save you if you agree to follow him! But keep your weapons! You will need them! Rahan rushed towards the great mountain! Rahan never deceived us! You have to believe him! You have to follow him! Overcoming their anxiety, the two clans undertook the expedition. And Rahan guided them to the gap he had discovered. And my daughter. Where is my daughter? You will find her soon, Paoni! Everyone, go down into this cave! It was astonishment for everyone. To discover an underground lake and this immense raft on which Eloa and Jahang were already standing! We will be able to flee the anger of the great mountain and this cursed island! But we must face the “Heads-with-eight-arms”! Page Thirty-eight. It was safe and sound that your grandfathers' grandfathers arrived on this island! They formed only one clan! But bad beings like Ra-konda divided them to impose their will! It is time to feel like you are part of the same clan, brothers! I think it is done, Rahan! Yes, it is done! Paoni and Quiwah competed in earnest, each encouraging his men. The big raft slid down the narrows, making its way through the horrifying mass of octopuses. Be careful, Paoni. Thank you, Quiwah! And that was the great day. The sea had calmed down but the great mountain exhaled ever denser smoke. Page Thirty-nine. Left alone on the shore the sorcerer shouted imprecations. Let us go back and get him. No! Ra-konda has divided us for too long! Paoni is right! From now on we will only be one clan! We will discover a territory where life will be good! And these young people will have the right to love each other, like Eloa and Jahang! And to think that we would never have abandoned the island without the anger of the great mountain! Rahan, Eloa and Jahang exchanged a mischievous look. A few flames rose from the volcano, but it would not roar. And they knew he would not growl! This fire would undoubtedly burn until nightfall, but then the island would no longer be in sight. And the two clans, reconciled, would never know. Page Forty. That over the course of two days, applying Rahan's idea, they had filled the crater with trunks of shrubs and brushwood. As agreed, Jahan had lit this gigantic blaze at the very moment Rahan brought the two clans together on the shore! And so, now, a sorcerer who had so often threatened others, was watching in terror for an eruption that would never take place! And why would some wild men, forever deprived of human game, sooner or later give up cannibalism? The island of the living dead, the island of nightmares disappeared on the horizon. The son of Crao had already forgotten it. He only thought of leading the reconciled clans to a new land and the happiness of Eloa and Jahang whose love had triumphed over all! Because love could, even in these fierce times, triumph over everything!

Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Rahan. Episode Seventy Eight. By Roger Lecureux, drawn by Andre Cheret. The clan of Gentle men. The territory is now ours! Death to those who would try to take it back from us! Warlike clamors punctuated each sentence of the harangue of Rawang-the-chief. They did not reach Rahan who tried in vain to flush out a prey sheltered under a stump. But the son of Crao heard other rumors, very similar ones. It was a series of long and sad petitions. It is when misfortune strikes them, that “Those-who-walk-upright” thus invoke the spirits! Page Two. Those he discovered shortly after were prostrate around an old man, a woman and an adolescent. Why are you distressed, Brothers? Perhaps Rahan can help you? Rahan can do nothing for the clan of gentle men! No one can resist Rawang-the-savage, who stole our territory. A territory so full of game that our hunters had no need for weapons! Their traps are enough! But Rawang, Alas, was jealous of our happiness! The son of Crao learned how this clan, guided by a loyal leader and the "Council of Three Voices," representing the elders, the women, and the children, led a happy and peaceful life. Until this very morning when they were chased from their territory by the warriors of Rawang. Page Three. While the gentle man fled their leader had tried to parley. Why so much hatred Rawang! We can share game and water sources! We. Rawang does not share! Argh! Rahan hates fights between "Those-Who-Walk-Upright". But he despises cowardice! Why did you not defend your territory, your happiness, your happy life? What could we have done against savages? Ours have long since lost the habit of combat! The resignation of these men irritated the son of Crao. The fate of your clan depends on the courage of its members and the will of the "Council of Three Voices". Rahan, in fact, can do nothing for you! Farewell brothers! Page Four. The sun was still high when he was surprised near a spring. This water belongs to us, “Fire hair”! Follow us! Since Rawang killed the leader of the gentle men, he thinks he is the master, does he not? He is the master! And he decides your fate! A little later. The “Fire Hair” hunter is called Rahan. Here is his weapon! If we do not make an example, tomorrow others will come and steal our water! The verdict of Rawang-the-savage fell from the top of the immense trunk. Kill him! And hang his corpse at the entrance to the forest! The first lances fluttered towards the son of Crao, who was surrounded on all sides and had no chance of escaping! Rahan is lost! Unless, unless. Page Five. Rahan will not reach the territory of the shadows without his knife! With the agility of a “Four-hands” he climbed the rungs that allowed access to the niche platform of Rawang. As he rose, the spears became less dangerous. He was soon beyond their reach. But, above him, Rawang was watching for him! You will not avoid this one "Fire Hair"! Rahan must get up there before Rawang grabs another weapon! Clinging to the last rungs, the son of fierce ages hoisted himself onto the platform. Rawang emerged from his strange hut, brandishing a head breaker! Page Six. Rahan will not let you steal his life! By projecting this vine lasso into the leader's legs, Rahan wanted to break the assault. But the result was more decisive! Argh! Rahan has killed Rawang! To death! To death! A few warriors were already hoisting themselves onto nearby trunks. They were quickly up to the son of Crao, but the latter, taking refuge in the hut of Rawang, had nothing to fear from their spears. With this water and this meat, Rahan will be able to last several days! But after? The vigilance of the hunters did not relax! And if they could not reach Rahan, he could not flee his refuge! A long wait began. Page Seven. At daybreak, the son of Crao saw them scrambling around, piling up brush and branches. A pyre! These savages have decided to burn Rahan! Very quickly, a circle of high flames surrounded the large trunk! Rahan, sooner or later, would perish in this inferno! The heat was already unbearable. Rahan could gain time by taking refuge on another trunk. But he will not be able to stick the spear deep enough, for it to support his weight! The flames rose higher and higher. And while the warriors tirelessly fed the pyre. The clan of gentle men, lying in ambush on a height, observed. Rahan is alone! And he dares to resist those of Rawang! Page Eight. Between the curls of smoke, the son of Crao could still see the other trunks. How to stick in this spear? Oh! Rahan knows what he has to do! He saw himself again, leaning on his bamboo lever stuck between two branches. Thrown into the wood, the spear would not hold! But Stuck under the bamboo. She will support Rahan! Although weighed down by the long vine, the spear rose, described a curve and fell back on the nearest trunk. Ra-ha-ha! Rahan had aimed with remarkable skill. The spear, locked between two rungs, held securely. Abandoning his refuge that had been reached by the high flames, he let himself fall into the blaze and flew over it. Page Nine. And found himself on the ground, outside the circle of fire! But he was not saved because the surprised warriors reacted Once again he only had the resource of a totem trunk. There were a few men, who climbed up behind him. One after the other, they had to give up the game! Argh! Argh! Rahan knows that this path leads him nowhere! But he will resist as long as he has a breath of life left! Splach! Argh! He found himself on the top of the trunk, towering over the vociferous warriors of Rawang. Devoured by the flames, his first refuge was nothing more than a gigantic torch. Page Ten. This respite that he had just won would be short-lived. The men started a fire, underneath a new pyre! You are as cowardly as you are cruel! Rahan is alone. With only his knife! And none of you dare come and confront him! Ha-ha-ha! Fire is a much safer weapon against demons of your kind! The flames roared below Rahan, who knew he was lost. But that always animated the fierce will to “hold on until the last breath of life.” Rahan can save a little more time! Two trunks of the "Council of Three Voices" were still spared by the fire. The jump was risky. But he gathered himself like a beast. Page Eleven. And plunged into the void. The clamors of rage from Rawang's men mixed with others that he did not hear. Ra-ha-ha! He missed the rung. Another broke under his weight. And that was the fall! He did not hear the cries that resounded from all sides. He did not see the meek men who, armed with simple arms. Threw themselves on those of Rawang, and shoved them with such ardor that a stampede ensued. The first vision that the son of fierce ages had when he regained his senses was that of serious and resolute faces. Your example has given us confidence, Rahan! We have chased the wild men from our territory! Page Twelve. The large totem trunk was still burning and would probably be consumed for several days. What will become of the clan without our leader? The “Council-of-Three-Voices” is he not there to guide them? The voice of the ancients. The Women's voices. That of youth. Which clan would not envy such a wise leadership!? Continue to hate fighting, brothers! Stay the clan-of-gentle-men! But never forget that. Gentleness and kindness do not mean weakness! We will remember it! The trio consulted for a moment. And. You can stay with us as long as you desire, Rahan! This unanimity touched Crao's son. Yes, he would stay for a while. But it would only be a step in his adventurous discovery of men.

Rahan. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html The son of the fierce ages. Episode Seventy Seven. By Roger Lecureux, drawn by Andre Cheret. The “Four Legs.” Screaming and shooting their arrows, the men forced the herd into the ravine. A few wild horses rushed there. The son of Crao had never seen horses, but he had once known a clan which domesticated similar animals, the "Zebras". Why kill the "Four Legs"! They are harmless to “Those Who Walk Upright”! The herd and the hunters were now far away. Rahan cannot do anything more for you! His throat pierced by an arrow, the foal was dying. And suddenly. Page Two. A solitary horse appeared, rushing towards Rahan, who understood. No, No! It was not Rahan who stole your little one's life! It was. Argh! He thought his skull was bursting! Your head is as hard as the “star-throwing stone” Fire hair! Who are you? When he came to, the moon was shining in the sky. I am Rahan, the son of Crao! When we discovered you, in the ravine, you were as good as dead! But since life has not left you. You will be able to take revenge on this cursed "Four-legged" who almost sent you to the "Territory of Shadows"! No! Rahan does not take revenge! Page Three. The “Four Legs” Wanted to defend his little one! Rahan cannot blame him! You have some curious ideas about the “Four Legs”! We hate these beasts! We hunt them as soon as they venture into our territory! My brothers are wrong! These beasts can be useful to “Those-who-walk-upright”! The son of Crao spoke of this clan he had once known. He spoke of the fast and docile “Zebras” that he himself had ridden. Yes, brothers. The “Four-legs” can save hunters from fatigue! They can take them very far, very quickly! Ha-ha-ha! Ride on the back of a “Four-legs”! That blow to the head made you lose your mind, Rahan! We never believe such things! Page Four. The skepticism of this hunters irritated the son of fierce ages. Rahan will prove to you that he is telling the truth! He will capture a "Four-legged"! It will be very easy! At dawn, Rahan returned to the ravine. As he hoped, the horse was still roaming not far from the dead foal. Do not flee, "Four-legs"! Rahan means you no harm! Rahan forgot that he had only known "Zebras”, that were already domesticated. Oh! Argh! Do not get mad “Four legs!” Ten times he tried to approach the animal. And it would run away, frightened. Or else, put up a fight. Ha-ha-ha! And this fool hopes to make us believe that hunters can subdue these demons! But. What is he doing? Page Five. The son of Crao had just climbed into the tree, just above the foal. Since Rahan cannot get closer, he will surprise you, "Four-legs"! When the horse came back, once again, to smell the foal, he let himself fall. Ra-ha-ha! The echo of his cry had not died down before a kick threw him to the ground! He had not remained on the beast's spine for even a few seconds. Who was already running away at full gallop. You will not succeed in discouraging Rahan "Four Legs"! He will catch up with you sooner or later! The most extraordinary chase began, which lasted until night, when Rahan lost track of the wild animal. Page Six. He only found it again at dawn. The “Four-legs,” scared, was backing away from a puma! The son of Crao sprang forward at the same time as the beast jumped. No, Pumak! You will not slaughter the "Four-legs!" It belongs to Rahan! Ra-ha-ha! The horse remained motionless and Rahan thought the game was won. You see, "Four Legs" Rahan is your friend! He saved you! Let us go. Let us go. Let him approach! He walked around it cautiously and. You will see. You and I will prove to the hunters that. Page Seven. Argh! The son of the ferocious ages once again found himself on the ground! The indomitable thoroughbred had resumed its course. But he was unable to outrun Rahan who pursued him with increased ardor. The animal, returning to the ravine, finally showed signs of fatigue. His gallop became slower. And Rahan was able to reach his height. And hold on to his long mane, and put one leg over his back. The men of the clan witnessed the miracle. A Miracle that only lasted an instant! Oh! Page Eight. Rahan is as stubborn as you, "Four legs"! He found a way to stay on your back! Exhausted by his race, the horse remained motionless. He did not flinch when the man approached slowly, a vine in his hand. A vine that he had tied to one of his ankles! When he reacted, it was too late. Rahan had whipped the line against the underside of the belly, and caught the end over its spine. And mount the beast! Rah-ha-ha! Once again, she kicked and reared to get rid of the burden. But Rahan had quickly circled the vine around his other leg! This time Rahan will stay on your back, “Four legs”! Page Nine. Indeed, thanks to this underbelly, the son of Crao could no longer be thrown to the ground. But the horse, as if taken mad, rushed towards the cliff! You. You will kill us both! Rahan could no longer remove the vine without the risk of stabbing the animal. Stop it! “Four Legs” Stop! Finally realizing the danger, the horse reared up a few steps from the granite obstacles. Oh! But it was to launch into a hellish gallop towards the gorge where the torrent roared! No! No! No! The men of the clan heard the howl of Rahan's terror when the mad horse threw itself into the void! Argh! Page Ten. The son of Crao no longer had time to free himself. He saw the foaming swirls rising towards him. Fizoom! And the flood closed around him! He drew his ivory blade! He noticed with amazement that the “Four Legs” was returning to the surface! The “Four Legs” also know how to “Crawl on Water”! His mount, in fact, was swimming. And even swam very well! Amused, and terrified for the first time by this sensation, Rahan allowed himself to be carried away by the animal. Is it the torrent that made you so calm? Or Rahan's will? Page Eleven. Rahan cut the vine and jumped to the ground. His heart was beating very hard. Was the horse going to escape from him once again, and disappear into this scree? The thoroughbred reared but it was to shake itself off. No! Do not do it again! Then he began to trot around the man. Are you not running away? That is right! Very good! Here "Four legs." Eat! Eat! We are friends now! The horse only hesitated for a brief moment, Then started to chew the tuft of herbs. The son of Crao knew he had triumphed. The “Four Legs” was as calm, as docile as the “Zebras” that he had known! Page Twelve. When Rahan appeared to the clan, peacefully riding the “Four-legs” there was astonishment. Do you believe Rahan now? You will no longer kill the "Four Legs"! You will make them your friends, your companions! You gave us a great lesson in courage and will! How can I thank you brother!? Oh. Quite simply by preparing for Rahan the drink which calms the pain and. The herbs that heal wounds! While the hunters surrounded the "Four Legs" who obediently allowed himself to be petted, Rahan felt happy. His limbs were certainly sore, but had he not had a wonderful experience? Perhaps he had just tamed the first horse, which five thousand centuries later would be said to be "man's noblest conquest"? who knows?

Rahan. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Episode Seventy-Six. By Roger Lecureux, drawn by Andre Cheret. The cave of deception. Even on the verge of death, a “Spotted Skin” was still defending himself! So what was wrong with this one? Curiously enough, the big cheetah did not resist the hunters who dragged it into the clearing! Intrigued, Rahan did not reveal his presence. But these men, who were now freeing the beast, suddenly saw him. Who are you? Where do you come from, you who spy on us? But it is not important! You are not going to tell your people what you just saw! The long assegai flew towards the son of Crao. Page Two. Who dodged it and suddenly fell on the two men. Rahan Does not like the way you ask questions! And here is his answer! Ra-ha-ha! The response of this “Four hands with white skin” had been so rapid, so vigorous, that the hunters did not insist. These cowards do not even care about their "Spotted Skin" anymore! Strangely indolent, the beast had stretched out. His almost lifeless gaze did not seem to see Rahan. And Rahan stroked him without him reacting. When. The great spirit of the hunt did not lie to us in guiding us to this clearing! The “Dappled Skin” is here! Page Three. Back "Fire hair"! This game belongs to us! The spirit of the hunt promised us! These men were not from the same clan as those whom Rahan had put to flight. As they were going to strike the beast, he became indignant. A hunter worthy of his name does not kill a defenseless beast! Look at this one, she is sick and. If you do not move away, it will be you who will become game, "Hair of Fire"! The man who raised his spear did not have time to bring it down. Argh! Rahan will not let you slaughter this "Spotted Skin!" It was not the spirit of the hunt that brought her here. But two hunters! The son of Crao related what he had seen a moment earlier. Page Four. And here is proof that Rahan is not lying! The son of fierce ages pointed to the shield abandoned by one of the fugitives. The hunters seized their shield and their faces expressed astonishment then anger. You have to bring it to Ergong! Without another word, they turned about and disappeared. Rahan does not understand any of this "Spotted skin!" But he hopes that you will regain your vigor soon! The son of Crao never resigned himself to a mystery. Abandoning the somnambulant cheetah, he followed in the footsteps of those who had dragged it here. However, in a nearby cave. And the man with the “Fire Hair” saw us untie the “Spotted Skin,” father! Then he attacked us like a demon. You fled like cowards! You must repair this mistake, my son! Page Five. The “Fire Hair” man must die before he reveals what he saw! Find him! Do not return to the cave until you have killed him! In ambush on the outskirts, Rahan recognized the two hunters. Maybe they will look for the "Spotted Skin"? What will Rahan discover in their cave? He carefully crawled to the cave, and slipped inside. Everything was silent but suddenly, in the light of the torches. Oh! The “Flat beasts”! An old man applied a blood-colored paste to the rock. From his agile hands was born a new “Flat beast.” The son of fierce ages had already seen such sanctuaries, where certain clans believed they would find the favors of the gods of the hunt. The old man is alone. Rahan has nothing to fear from him! Page Six. Rahan suddenly showed himself. Rahan salutes the one whose skillful hands generate such beautiful “flat Beasts”! Oh! You, You made my old heart jump! But. But. The old man's eyes shone. Once the surprise passed, he recognized the man described by his sons, the man with the “Fire Hair”! He made himself very welcoming. Welcome to this cave brother! Are you hungry? Are you thirsty? My name is Yahoka. Yes, the son of Crao was hungry and thirsty. Eat and drink, brother! there is no shortage of food here! At the bottom of the cavern were piled up countless wedges of dried meat. And even living animals dozed in cages! Yes, there was enough here to feed an entire clan for two seasons! Page Seven. While Rahan ate and drank Yahoka spoke of the "Flat beasts" and said he was inhabited by the "God of the hunt." All the hunters come to consult me! Everyone trusts my predictions! Rahan saw two come out of this cave. He. He. The. Had. Met. The son of Crao suddenly felt a strange uneasiness. Ha-ha-ha! Here you are at the mercy of Yahoka! The flat beasts on the wall could only be distinguished very vaguely. He felt his limbs go numb, his strength abandon him. Rahan's vision returned. He heard and could speak, but he was unable to react. You. You did. Rahan drank a. Drink that kills. Who kills? No, the drug only deadens the energy, the vigor. It is Yahoka, who will kill you! The son of fierce ages allowed his ivory knife to be confiscated without flinching! Page Eight. Ha-ha-ha! You are as stupid as all those hunters who believe in the power of Yahoka! You must see them, these hunters, who come to consult Yahoka and his sons! You have to see them prostrate themselves before the “Flat beasts”! Supplicating to the “Flat beasts” does not bring game under the hunter’s spear! Of course! My sons and I know it! But we know how to keep the hunters' confidence! From time to time, I predict to them the exact place where they would discover this or that game. And my sons go and release the promised game there, drugged so that it does not stray too far! This is what they did this morning, with a “Spotted Skin.” Page Nine. When the hunters discover and kill their game, they worship Yahoka even more. The great spirit of hunting! Why these lies? Why this deception? How naive you are, “Fire hair”! Look at this meat, all this meat! Every time a man comes to consult the "Flat Beasts" he undertakes to offer us a share of his hunt! And so, Yahoka and his sons never lack food! Without ever taking any risks! Rahan finds it odious to abuse his fellow human beings in this way! The son of Crao could only express his indignation in words. And he could only stagger back in front of Yahoka, who was taking all his time before striking. And to think that you put my sons to flight! Ha-ha-ha! You are the one who is scared now, are you not? Page Ten. Oh! Ha-ha-ha! Rahan had grabbed a torch but it escaped his fingers, that were without strength! Leaning against the “Flat beasts”, the son of fierce ages sagged limply. And Yahoka, at that moment, took on the appearance of death. Come to me, Rahan, come! The ivory blade, strong and sharp, was about to fall! It is time for you to join the land of shadows! Do not move Yahoka! We just heard part of your confession! But it is useless! The shield of one of your sons, found near the "Spotted Skin," is proof that you have been lying to us for many moons! What we thought was your power was just a ruse! Page Eleven. But you will not abuse ours anymore! The clan banishes you until the end of time Yahoka! Go and find your sons! Flee this territory and never return! Otherwise. While the “Great Spirit of the Hunt” found the legs of his youth to flee. Rahan felt his strength returning little by little. Seeing death arrive without being able to make a move! Rahan has never been so scared in his life! Rahan thanks you brothers! We are the ones who thank you! If you had not faced the sons of Yahoka, we would not have found this shield. And the deceptions of this cheat could have deceived our hunters for a long time! Will you stay with us? Perhaps Rahan will come back when he has found his knife! Page Twelve. Yahoka had indeed fled with the ivory weapon. But Rahan was not able to follow in his footsteps until much later, when all the effects of the drug had worn off. And it was the next day that he discovered two corpses. The sons of Yahoka had been victims of a beast. Oh! The “Spotted skin”. The big leopard was lurking a little further away, near another lifeless body, that of Yahoka himself! You took revenge, “Spotted Skin”! You, like Rahan, have regained your vigor! The “Great spirit of the hunt” still clutched the ivory knife, with which he had not had time to strike. When Rahan retrieved his weapon, the feline growled, then began to purr. He recognized the man. He remembered. And the son of Crao, who knew how to read the eyes of wild animals, knew that he had nothing to fear from this one.

Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Rahan. Episode Seventy Five. By Roger Lecureux, drawn by Andre Cheret. The Children of the River. The son of Crao, who had slept on this sandbank to escape the threat of wild animals, was for this moment facing another danger. A fifth, arrow stuck a few steps from him. We will avenge our own, “Fire hair”! The little girl who shot these arrows was not fifteen years old and her companions were even younger! She showed great awkwardness, but risked waiting to long for him! He dove into the troubled waters. Page Two. You missed him, Fahina! He is rejoining his cursed clan! I will not miss him next time! But what is he doing? He is not a fish after all! The children were watching offshore for the man's reappearance, when a whirlpool appeared in the water, very close to them. What? Oh? What? Rahan does not like serving as game! You are going to explain to him why you wanted to steal his life! While Rahan disarmed the surprised little girl, the panicked children returned to the bank. But wait, little men! Rahan means you no harm! Oh! Watch out for the “Two noses”! A huge pachyderm burst out of the thickets and was about to charge the two children, who were petrified by fear. Help Fahina! Help! Save us! Quickly! Quickly! Page Three. The son of Crao was already aiming at the only organ of the "Two-nose" that he knew was vulnerable. The eye! Rahan hopes to be more skillful than Fahina! But! He stretched this bow too hard, and it was too frail for him! Misfortune! My brothers are lost! Not yet Fahina! Rahan leapt forward. He only had a few seconds to get between the children and the monster! He achieved that. Attack “Two-Nose”! Rahan knows you have more muscle than brains! Attack! Taking refuge on a low branch, the children witnessed the strangest of clashes. Rahan excited the Rhinoceros, and allowed himself to be charged. Page Four. And led him towards the river, where he dived in! And the pachyderm had to stop its course. Ten times he repeated this maneuver! Ha-ha-ha! Ah! You get tired of this little game before Rahan! The hunter with “Hair of Fire” is called Rahan. He is brave! But why is he helping us, Fahina? I do not know. You finally give up, “Two-nose”! Furious to see this man constantly escaping from him, the rhinoceros abandoned the area. He disappeared The son of Crao was rejoining his proteges, when. Vengeance! Vengeance! No! No! Do not strike him! Rahan just saved our lives! Because of his hair, we thought he was part of the river clan! Page Five. Rahan learned how, two seasons earlier, the parents of all these children had been kidnapped by the feared warriors of the river clan. With the departure of the adults, these children had to ensure their subsistence! Fahina, the oldest, had become their “Chief.” Rahan imagined the terrible life these little men had been leading for two seasons! Perilous hunts. Nights of anxiety. But we know that those of the river do not kill their captives! They make them their slaves! For moons and moons we have been following the river to find our loved ones! The son of fierce ages could not remain insensitive to the distress of these children You will find your mothers and fathers! Rahan will help you! Page Six. In the following day he directed the construction of a raft. We will go faster by the river than through the jungle, Fahina! And if, as you say, the "Blonde Hunters" live ten days' walk from here, we will soon discover their territory! One morning, the skiff took Rahan and the sons of the woods to the unknown. Why are you devoting yourself to us Rahan? Because Rahan once lived as you have been living for two seasons! The son of Crao remembered his wild childhood, his fierce struggles to survive, Rahan does not like it when men's little ones are separated from their own! Oh! Look over there! Huge hippos yawned in the sun. Page Seven. The “Flat tooths” are not to be feared, Fahina! The "Skin of Wood" is much more dangerous! A large saurian had just emerged. A terrible blow from the tail almost overturned the skiff. If Rahan does not kill him, he will break the raft! Those who do not know how to "Crawl on water” will be devoured! The son of Crao had faced crocodiles many times. He knew how to strike at the vital point. This was the only incident of this raid on the river. And, two days later. The boats of the “Blond Men”. Their village must be close! And indeed, a little later. Over there! They are ours! Men and women were prostrate in an enclosure, and only three hunters were guarding them! Page Eight. The others probably hunt in the forest! This will be easier than Rahan thought! Wait for him here, little men! The son of fierce ages knew how to be as silent as his shadow. The sleeping guards did not even feel that their spears were being confiscated! But the third saw the intruder, and suddenly hammered on his big tom-tom. If his people hear Rahan is lost! He cannot take on an entire clan! But he couldn't dodge the mace blow! Argh! Page Nine. Stunned, he was at the mercy of the guards who woke up with a start. One of them had already recovered his spear. Your audacity deserves death! But! Chtok! What. I. I. You hit him, Fahina! You hit him! You did not miss your target for once! The two guards scanned the foliage, looking for the invisible archer. Rahan took advantage of this diversion to jump towards the enclosure. And threw up the trunk barricading the door. A clamor resounded. The time has come to end it, brothers! Forward! Ahead! Page Ten. You are li. The son of fierce ages could say no more! Through the wide open gate the stream of captives surged. He was overwhelmed, grabbed by ten hands, dragged along the ground, struck from all sides. Vengeance! Vengeance! The “Blond Men” made us suffer too much! But suddenly. No! No! Stop! Rahan is not an enemy! It is he who delivered you! Oh! Fahina! Fahina! Kohic! Akar! All the others! Look! All our little ones are here alive! Emotion filled the throats of the freed captives. How were you able to survive? How did you get here? Later brothers, later! For now we must flee! Listen! Page Eleven. “Those of the river” have heard the tom-tom! They are returning! And they are armed and you are not! As the screams quickly get closer. It was a rush towards the shore. A moment later, captives and children boarded the raft and the boats of the “Blonde Men.” When the latter appeared, the flotilla was out of arrow range! We are saved! Will you forgive our mistake, “Fire hair”? We had decided to escape for a long time. When the enclosure opened and we saw your hair. We thought you were one of them! Rahan has known generous blond men and others without pity! He met some very good brown men and others who behaved like wild beasts! Page Twelve. It is not their hair but what they have in their hearts and minds that make “Those-Who-Walk-Upright” what they are! You are right, brother. We thank you for. It is Fahina that we have to thank! Fahina who knew, over two seasons, how to replace the mothers of these young men! Who knew how to protect them! The fast current carried the clan to a new territory. Fahina, who never lost hope of finding her loved ones! All these men were happy, all these women were happy, all these children were happy. And the son of Crao felt as happy as they did. If he still had difficulty smiling, it was quite simply because the “Misconception” of those who would become his companions had left some traces!

Rahan. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Episode Seventy Four. By Roger Lecureux, drawn by Andre Cheret. The Worshipers of the Dead. The son of Crao knew how "Those Who Walk Upright" end up, after having reached the territory of shadows. But this skull that he saw amazed him to such an extent that he forgot the cruel horde that had been stalking him since dawn. As he climbed the steps cut into the rock, his amazement grew. This. This. Is not possible! Rahan must dream! No! No! Hunters of this size do not exist! They cannot exist! But the proof was there! This skull that glowed under the moon had belonged to a gigantic, fantastic being! Page Two. This skull, which dominated the gorge as if from the top of an altar, seemed to prohibit access to the cliff. It was so big that a man could have entered it through the eye sockets! No! No! It is impossible! Rahan knew how to control his apprehensions and fears. He approached and. Oh! Rahan was right to doubt! The skull was not made of bone, but carved from a chalky rock. As he made this astonishing observation, clamors arose. Profanation! The enemy dared to lay his sacrilegious hands on death! Page Three. Rahan is not an enemy! It was to flee those of the cruel horde that he came to your territory! Shtok! Chotk! Shtok! A rain of stones fell on the son of fierce ages. Who jumped towards the skull, and hoisted himself towards the orbit. The rain of stones stopped immediately. You have just committed the most heinous sacrilege, “Hair of Fire”! The men remained at a distance, as if petrified by this new desecration. It was the fathers of the fathers of our fathers who, in the dawn of time, paid this homage to death! And no man has ever defiled the Queen of Shadows! We will not kill you because you are not worthy of death! Page Four. But we will not let you run away! When hunger and thirst deliver you to us, you will be tortured every day, until the leafless season! The clan surrounded his strange refuge without daring to approach it. They revere this totem too much to throw their stones! But Rahan will not be able to escape! We will watch around the queen of shadows day and night "Hair of Fire" and you will have to surrender sooner or later and pay for your sacrifice! Usually Rahan respects the customs of “Those-who-walk-upright”! But he finds yours very stupid! Because you have to be stupid to worship death! Death! Death that has pursued Rahan since dawn! The son of Crao pointed out the few men of the cruel horde who climbed the monumental stone staircase. Page Five. We captured "Fire hair", but he escaped! Deliver him to us! Worried, those on the cliff retreated towards their cave. But the chief and the sorcerer faced the newcomers. "Fire hair" belongs to us! Our clan will punish his sacrilege! He is ours! And we will bring him back to ours! Men from the cruel horde were already rushing towards the skull-totem. Although unarmed, the chief and the sorcerer tried to oppose the others. In vain. Argh! Kroan and Laiyar will join you, queen of shadows. They. They. Will be. Soon near you! They. They are happy. Happy. Page Six. Appalled by the useless sacrifice of the two men, Rahan stood his ground. Stealing the life of a disarmed opponent. Is worthy of the Cruel clan! Zlanc! But you will not steal Rahan's! Argh! Braced in the orbit, the son of Crao fiercely resisted his attackers. Crack! And he parried all of their blows with surprising reflexes and vivacity. Argh! Go back to your own! Striking with his fist, his foot, or his knee, he was unassailable. Ra-ha-ha! Page Seven. Advance! Let us chase away this sacrilege! More angered by the outrageous desecration of the queen of shadows than by the death of their leaders. The men on the cliff finally reacted! Those of the cruel horde had to flee under their projectiles. We will come back! We will wipe out your clan! We will kill all of you, your women and your children! It was only a reprieve for Rahan. Those on the cliff once again surrounded the queen of shadows! They gave themselves a new leader. Yako vows to loyally guide the clan, until the day death calls him on. To the happy territory of shadows! Page Eight. No one is ever kept from this territory, brothers! Because death continues until the end of time! It is not death that must be venerated but life! Life is the sun! Forests! The rivers! Why do you prefer darkness to all these wonders? For a very long time the son of Crao harangued these hunters, who had never heard such words. The young people were more sensitive to his arguments than the old ones. See. Rahan has “Outraged” “the queen-of-shadows” but he is still alive! He wants to be alive! The tree does not uproot itself! The animal does not throw itself away. Under the Hunters spear! Everything that is alive repels death! Why did “Those Who Walk Upright” search for it? Your life is sacred, brothers! You must not offer it to these savages, as did Kroan and Laiyar! “Those-of-the-Cruel-Horde,” ten times more numerous, had just reappeared! Page Nine. They rushed towards the staircase, the only way of access to the cliff. Until today, they were content to ban us from the game-filled valley. But today because we did not deliver "Fire hair" to them, they want to decimate our clan! These beings are the cruelest that Rahan has ever encountered! You are defenseless in front of them and they will massacre you if you do not flee! We will not run away! We will repel them! So, let Rahan fight alongside you! Oh! No! Do not do that! Yako and a few elders, armed with simple sticks, were rushing down the stairs that those of the cruel horde were beginning to climb! This disregard for their lives was going to be fatal to them. Page Ten. They collapsed under the arrows. It was not bravery, but madness! They gave their lives needlessly! The young hunters no longer cared about the son of Crao. They reacted finally! “Fire hair” is right! We are too young to join the Queen of Shadows! We must be alive! Alive! You are alive brothers! Under the deluge of stones, the cruel horde flowed back. But those on the cliff soon ran out of projectiles! And the attackers invaded the staircase for a new assault! No more stones! No more Rocks! We will not push them away! Yes! You still have the queen of shadows! Help Rahan! Page Eleven. Setting an example, the son of fierce ages arched his back against the enormous skull-totem. The elders cried out. Sacrilege! Sacrilege! But all the young people rushed forward, and gathered around Rahan, and pushed, and pushed. So many of us have sacrificed their lives to the Queen of Shadows! She must help us! The chalk skull slid slowly towards the staircase which those of the cruel horde were climbing. Oh! And they suddenly saw it silhouetted against the sky, oscillating for a moment, to fall over! Argh! They did not have time to flee. The skull swept over them, crushing or bruising some, throwing others into the void! Page Twelve. Their cries of fear and pain were drowned out by a terrible noise. The gigantic skull had just burst open at the foot of the cliff. Crash! They would have cut our throats without mercy! But they will not come back! Thanks to you, Rahan! The survivors of the cruel horde, still terrified, fled the gorge. Where lay the pieces of this sinister totem that the “Adorers of Death” had venerated for too long! By sacrificing the "Queen of Shadows", you saved your clan! You knew how to defend your lives! You have not resigned yourself to dying and that is good! If some elders still gave Rahan hostile looks, most of the hunters contemplated the valley, the forests, the sun, the distant river. For the first time they seemed to appreciate the life that rustled everywhere around the waters. The son of Crao was happy, he had helped them win this victory over themselves!

Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Rahan. Episode Seventy-three. By Roger Lecureux, drawn by Andre Cheret. The Blue Eye. Yes it is Rahan! It is him. The son of fierce ages, or the reflection of Rahan in the blue pupil of Toungna, which had made him “Undead”! It was at the beginning of the "Season-of-Green-Leaves" that Rahan was surprised by fishermen, while he was practicing throwing his knife. Look at his hair! At his eyes! They have the color of the sky. Like the ones of Tougna! See! It is natural that he is twice as skillful as Tougna, since he has two blue colored eyes! That his skill was attributed to the color of his eyes greatly amused the son of Crao. Rahan has known countless hunters who had blue eyes! Some were skilled, others were not! A little later. We have captured a hunter, Tougna! He is capable, at thirty paces, of throwing his knife. In a bamboo smaller than this Finger! The leader of the fishermen had the curious peculiarity of having one brown eye and the other blue! Which gave his face an unusual and worrying appearance. No man is more skillful than Tougna! Page Two. In anger, Tougna threw his javelin, slicing right through a fish that was drying in the sun. See what Tougna can do with his clear eye! Rahan can do better. If you wanted to land this fish. It has to be done this way! The knife flew away and his ivory blade cut the fine vine! You want to humiliate me in front of mine, “hair of fire”! You deserve to die! No, Tougna! Clan law forbids us from taking the lives of “Those Who Walk Upright!” Eh? It is true. But it does not forbid us from keeping this hunter captive. Until his natural death! Let us throw him into the Cave of the forgotten! Page Three. The son of Crao was dragged onto a low cliff, and pushed into a gully. A fall followed. From which he only emerged unscathed by a miracle. This underground tomb well deserved its name “Cave-of-the-forgotten” It offers no other way out than the opening from which the daylight faintly fell, but this hole was inaccessible! A narrow crack in the granite wall allowed him to see the village of the fishers. This vision would henceforth be the only one the captive would have of the outside world. Thus began his terrible torture. Rahan will never escape! His bones will rot in this cave as these have rotted! Page Four. And days follow days. Sometimes, through the narrows, a few fish were thrown at him, and a little water was poured over him. Gently. Once he tried to hold on to this vine. But it was brutally torn from him. Do not do that again, "Fire Hair"! Ever! Otherwise, food will be scarce! The world of the son of Crao was now limited to the skeletons lying in the darkness. And the opening. And the fissure. The crack! Every Morning, Tougna came to observe his Captive there. You are Strong, Rahan! Maybe your body will resist for a long time! But reason will abandon you! Tougna is convinced, and he has persuaded his people that his skill comes from “His blue eye!” And that stupid monster is jealous of Rahan who has two! Page Five. One day the tormentor went so far as to return his precious knife. You can always try to dig through the cliff! Ha-ha-ha! The weapon only served to eliminate his beard, which irritated the son of Crao. If this knife was useless to him. He found with it, a sort of companion. Turn. Turn. Alas, Rahan will never be able to obey you like before! Obsessed by the eternal darkness of his grave, he imagined the golden landscapes. The wonderful skies that he would never see again. And the “Season-of-yellow-leaves” followed that of the “Green-Leaves”. The resistance of the captive astounded the fishermen, and amazed some. Page Six. This is perhaps why, one day, the vine which was lowering the calabash of water did not come back up! Does Rahan have an ally? Will he soon be free? He no longer dares to believe it! His throat tight, he hoisted himself towards the opening, rising towards it. That was when Tougna's laughter rang out! Ha-ha-ha! Tougna was right to be wary. A traitor wanted to help you “Fire hair.” But Tougna arrived in time! And Rahan fell back into the “cave of oblivion”! The anger of Tougna was great that day. “Hair of Fire” never begs for our pity and yet you admire his courage, do you not! But since some deceivers want to help him, it will be Tougna who will now bring the food to the captive! The torture of the son of fierce ages was going to become even more terrible! Page Seven. To get out of his grave he had imagined everything, tried everything. The bones from which he had thought he could make steps had collapsed under his weight. And the opening offered no hold for the grappling hook he had made. He marked each day with a sign on the rock. And his signs were now innumerable. How long has Rahan been here? How many days and nights? As numerous as rushes in a marsh? The trees are beginning to become bare, heralding the “leafless season." Faced with Rahan's resistance, Tougna's jealousy became hatred. Betraying clan law without his people being aware, he more and more often abandoned the pittance on the cliff instead of throwing it to the captive! Page Eight. Many more days passed. Tormented by hunger and thirst, the son of Crao. Felt himself weakening and his reason wavered sometimes. And he found himself more and more often confiding in his ivory knife. Do you remember the happy times? When we were both free? He then saw himself in the green valleys, free! The idea of killing himself had sometimes crossed his mind. You will end Rahan's suffering! No! Rahan must last until the end! Until his last breath! Page Nine. As the storms increased, the clan of fishermen abandoned the shore and retreated to a plateau. But Tougna continued his visits! You no longer have the strength to stand up, “Fire-Hair”! Ha-ha-ha! Your end is near! But one morning the tormentor did not come. And Rahan heard the "Great River" roar. He saw the waves rising towards the sky. The clan took refuge on a height to escape the fury of the waves. The tidal wave surged with fantastic violence, submerged the shore, and launched an assault on the cliff. And suddenly. Oh! Rahan may be saved! The water cascaded through the crack, seeped through the ground, and rose, and rose, and rose. Page Ten. The innumerable marks, each of which represented a day of suffering, disappeared. The water was still rising! Rise again great river! Rise! Rise! Nature, so often hostile to Rahan, came to his aid! He soon swam under the opening. “Freedom” was up there. Liberty was at the end of this long inaccessible opening, into which he now rose. The water suddenly stopped rising. But it did not matter to him. The grappling hook that had been prepared for many days could finally be used. And. Ra-ha-ha! Never had the clamor of victory thundered with such force! He finally saw the sky again! And the horizon! And the great river! Page Eleven. The flood was already receding. And the fishers there screamed at the miracle. Since nothing got the better of Rahan, you will have to fight him, Tougna! We will finally know if one eye the color of the sky is worth two! The tormentor hesitated. But the harpoons of his people spurred him towards the cliff from which the son of fierce ages descended, still dazzled by the day, and staggering a little. They were soon face to face. You are going to die, "Fire hair"! Rahan has never killed a man before, but the one who stole three seasons of his life is no man! The tormentor raised his harpoon and the hatred in his blue eyes gave way to fear. Rahan too, was also ready to throw his ivory knife! He thought of these three seasons of suffering. No Tougna did not deserve the title of man! So? Should he let himself be killed by this monster? The color of his eyes would have nothing to do with it. But Rahan knew he would be the quickest and most skillful.

Biological Functions of Autophagy Genes: A Disease Perspective. Beth Levine and Guido Kroemer. Cell. 2019 January 10. Volume 176 (1 to 2). Pages 11 to 42. doi:10.1016/j.cell.2018.09.048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347410/ Index of other science articles: https://rumble.com/v3t4yzj-index-of-science.-music-by-dan-vasc.html Abstract. The lysosomal degradation pathway of autophagy plays a fundamental role in cellular, tissue and organismal homeostasis and is mediated by evolutionarily conserved autophagy-related (ATG) genes. Definitive etiological links exist between mutations in genes that control autophagy and human disease, especially neurodegenerative, inflammatory disorders and cancer. Autophagy selectively targets dysfunctional organelles, intracellular microbes and pathogenic proteins, and deficiencies in these processes may lead to disease. Moreover, ATG genes have diverse physiologically important roles in other membrane trafficking and signalling pathways. This review discusses the biological functions of autophagy genes from the perspective of understanding, and potentially reversing, the pathophysiology of human disease and aging. Introduction. A decade has elapsed since our review in 2008 in Cell on “Autophagy in the Pathogenesis of Disease”. During this period, more than 33,000 new articles related to autophagy were published, a Nobel prize was awarded for the discovery of the molecular mechanisms of autophagy to Levine and Klionsky in 2017, and to Mizushima in 2018. Considerable interest has also emerged in autophagy modulation as a potential target in clinical medicine. The fundamental concepts discussed in our 2008 review remain unchanged. The lysosomal degradation pathway of macro autophagy, herein referred to as autophagy, plays a crucial role in cellular physiology, including adaptation to metabolic stress, the removal of dangerous cargo, for example, protein aggregates, damaged organelles, intracellular pathogens, the renovation during differentiation and development, and the prevention of genomic damage. Generally, these and other functions protect against numerous diseases, including infections, cancer, neurodegeneration, cardiovascular disorders, and aging. Under certain circumstances, autophagy may be detrimental either via its pro-survival effects, such as in cancer progression, or via possible cell death-promoting effects. Over the past ten years, significant progress has been made in understanding the molecular mechanisms of autophagy, the regulation of autophagy, and the effects of autophagy on physiology and pathophysiology. New major conceptual advances underscore the plurality of functions of the autophagic core machinery in various membrane trafficking and signaling events and delineate the exquisite specificity with which autophagy targets selected cargo for degradation. These advances, together with discoveries in human genetics linking ATG gene mutations to specific diseases, provide a multidimensional perspective of mechanisms by which ATG gene-dependent pathways protect against mammalian disease. Herein we review selected highlights of the past decade of research on the biological functions of autophagy genes, primarily from a perspective of understanding and treating human disease. Autophagy and other Autophagy Gene-Dependent Pathways. The original scientific definition of autophagy, from the Greek for “self-eating”, is the delivery of cytoplasmic cargo to the lysosome for degradation. There are at least three distinct forms of autophagy, chaperone mediated autophagy, micro autophagy and macro autophagy, which differ in terms of mode of cargo delivery to the lysosome. Macro autophagy is the major catabolic mechanism used by eukaryotic cells to maintain nutrient homeostasis and organelle quality control. It is mediated by a set of evolutionarily conserved genes, the autophagy-related (ATG) genes, originally discovered in yeast genetic screens. With a few exceptions, all ATG genes are required for the efficient formation of sealed autophagosomes that proceed to fuse with lysosomes. In higher eukaryotes, many ATG genes are functionally diversified to facilitate delivery of extracellular cargo to the lysosome, to promote the plasma membrane localization or extracellular release of intracellular cargo, and to coordinate intracellular communication with various cell signaling pathways, Figure 1. These other functions are not, sensu stricto, autophagy and accordingly, will be referred to as ATG gene-dependent pathways. There are broad implications of ATG gene functions in different membrane trafficking and signaling pathways for mammalian cell biology, physiology and disease. Degradative Autophagy: The reason for the existence of Autophagy Genes. The function of ATG genes as originally discovered is to orchestrate and mediate the formation of double-membraned structures that deliver intracytoplasmic contents to the lysosome for degradation. This process is conserved in all eukaryotic organisms, occurs at basal levels in nearly all cell types, and is increased by diverse intracellular and extracellular cues. It is essential for cellular homeostasis, cellular protein and organelle quality control, and organismal adaptation to environmental stress. These principles are firmly supported by nearly two decades of studies involving genetic ablation of the autophagy machinery in diverse eukaryotic species. This lysosomal degradation pathway is usually described as involving a set of around 16 to 20 core conserved ATG genes. The ATG proteins encoded by these genes are traditionally classified into distinct biochemical and functional groups that act at specific stages of autophagosome initiation or formation. In this scheme, see other recent reviews for details, the ULK1 serine threonine kinase complex, involving ULK1, FIP200, ATG13 and ATG101, plays a major role in autophagy initiation, phosphorylating multiple downstream factors. Two distinct Beclin 1, class 83 phosphatidylinositol 3-kinase (PI3KC3) complexes generate phosphatidylinositol 3-phosphate (PI3P) to act in auto phagosome nucleation, or endolysosomal and auto phago lysosomal maturation. Vesicles containing ATG9A, the only transmembrane core ATG protein, supply membrane to auto phagosomes. WIPI, WD repeat domain phosphoinositide-interacting, proteins and their binding partners, ATG2A or ATG2B, function in early stages of membrane elongation at the site of PI3P generation. Autophagosome membrane expansion and completion involves two ubiquitin-like protein conjugation systems: the Ub-like ATG12 conjugates with ATG5 and ATL16L1 and the Ub-like LC3 subfamily, ATG8 in yeast, conjugates with membrane-resident phosphatidylethanoloamine, PE. Unlike in yeast, the ubiquitin-like protein conjugation systems are not essential for auto phagosomal membrane completion in mammalian cells, although they determine the efficiency of the process. This classification of the ATG proteins has provided a useful framework for studying and understanding autophagy. However, its apparent simplicity is at variance with extensive data indicating a highly complex level of interconnectivity among the ATG proteins and newly described functions of ATG proteins at different stages of autophagy. Based on unbiased proteomic analyses, most ATG proteins interact with other ATG proteins that reside outside of their “classic” functional complex. Experimentally, some of these interactions are known to be important for autophagosome formation. For example, FIP200, a member of the ULK1 kinase complex, interacts with ATG 16L1 to properly target it to the isolation membrane, also known as the phagophore, of the nascent autophagosome. ATG14, a component of the autophagy-specific PI3KC3–C1 complex, also functions in SNARE-driven membrane fusion. Similarly, Atg13, a component of the yeast Atg1, mammalian ULK1 kinase complex, interacts with Atg9 to recruit Atg9 vesicles to the pre-autophagosomal structure. The broader interconnectivity and functional multiplicity of core autophagy proteins in autophagosomal biogenesis requires further elucidation. Moreover, as indicated by a recent conditional genetic interactions study using diverse yeast omics datasets, new systems biology approaches will likely identify additional genes required for autophagy, especially those that may function in a stimulus-dependent, cell type-dependent or species-specific manner. The core ATG proteins, conserved from yeast to humans, are necessary but not sufficient for degradative autophagy. The degradation of autophagosomal cargo cannot proceed without successful fusion to an available and functional lysosome. Research in the past decade has unmasked some of the key factors required for lysosomal biogenesis, autophagolysosomal fusion, lysosomal function during autophagy and autophagic lysosome reformation. Adenoviral-mediated gene delivery of TFEB, a master transcriptional regulator of lysosomal biogenesis, improves outcomes in various rodent disease models, including Parkinson’s disease, lysosomal storage disorders, tauopathies, alpha 1-antitrypsin deficiency, and hepatic hyper-ammonemia. Auto phago lysosomal fusion requires changes in lysosomal pH, certain cytoskeleton motor proteins (dynein), tethering factors, the HOPS complex, the Rab GTPase, RAB7, SNARE proteins, the Q-SNARE, syntaxin 17 on autophagosomes which interacts with R-SNARE proteins, SNAP29 and VAMP8 on endosomes, lysosomes, phospholipids, and members of the LC3 Gabarap family that are bridged to tethering factors or SNARES by adaptor proteins. Screens in C elegans identified novel metazoan-specific genes required for fusion steps in degradative autophagy. One example relevant to human disease is EPG5, which encodes a RAB7 effector. Autosomal recessive mutation of EPG5 results in Vici syndrome, a neurodevelopmental and multisystem disorders, see Table 1. Mutations in genes that regulate lysosomal acidification such as ATP6AP2 and presenilin 1 are associated with X-linked Parkinsonism and Alzheimer’s disease, see Table 1. Thus, we must consider regulators of lysosomal biogenesis, the fusion machinery, and determinants of lysosomal function in our efforts to decipher how deficient autophagy leads to disease and how autophagy can be regulated to prevent or treat disease. Beyond Self-Eating: Autophagy Genes Function in Phagocytosis. Several core ATG genes function in a process that shares some similarities with autophagy but involves digestion of unwanted extracellular, rather than intracellular, material. During this process, termed LC3-associated phagocytosis (LAP), single-membraned macroendocytic vacuoles, macropinosomes, phagosomes and entotic vacuoles, engulf extracellular cargo (such as bacteria, dead cells or live cells), become decorated by lipidated LC3, and are directed to the lysosome for degradation. LAP is distinguished from autophagy by four main features: (1) The origin of the vacuolar contents, extracellular versus intracellular, (2) The requirement of cargo engagement of an extracellular receptor for activation, (3) The type of membrane that fuses with the lysosome, single membrane versus double membrane, and (4) The utilization of a subset versus all of the core ATG proteins. LAP requires NADPH-oxidase (NOX2) to generate reactive oxygen species (ROS), certain components of the Beclin 1, VPS34 complexes, PI3P generation, LC3-conjugation to the single membrane of the phagosome, and all components of the LC3 conjugation machinery. However, it does not require other core ATG proteins, such as components of the ULK1 complex or the autophagy-specific Beclin 1, VPS34 complex component, ATG14. Somewhat enigmatically, LAP requires Rubicon, an inhibitory component of the autophagy-specific Beclin 1, VPS34 complex. The precise effects of LC3 decoration of phagosomes on their fusion with lysosomes and on lysosomal function are unknown. The presence of LC3 on phagosomes may enhance efficiency of phagolysosomal maturation, perhaps through a mechanism similar to that of LC3, GABARAP family members in autophagolysosomal maturation. LAP was originally described in murine macrophages during phagocytosis of particles that engage Toll-like receptors (TLRs) and is involved in type I interferon (IFN) secretion in response to DNA immune complexes and other TLR9 ligands. Physiologically important functions of LAP have been identified by comparing phenotypes of mice with myeloid-specific deletion of LAP-specific genes, for example Rubicon or NOX2, and autophagy-specific ATG genes, for example FIP200 or Atg14. LAP is required for degradation of photoreceptor outer segments by retinal pigment epithelium (RPE), a process necessary for intact vision. LAP is induced by the fungus, A fumigatus, and the intracellular bacterium, L monocytogenes, and enhances host defense against these pathogens. Mice lacking several components of the LAP pathway develop an autoimmune systemic lupus erythematosus (SLE)-like disease, perhaps due to a defect in the clearance of dying cells that triggers enhanced pro inflammatory signaling and autoantibody production. Given the crucial roles of receptor-activated phagocytosis in human physiology, it is likely that LAP, like classical autophagy, will emerge as an important pathway in human disease. While the two pathways utilize overlapping genetic machinery, a critical distinction renders them antagonistic. Specifically, Rubicon is required for LAP but suppresses autophagy, and recent studies confirm a mutually inhibitory relationship between LAP and autophagy in photoreceptor degradation in RPE cells. It is not clear why these two pathways are counter-regulated, possibly, cells may need to shut off the alternative pathway during stress to avoid competition for overlapping resources. At a mechanistic level, it is uncertain how Rubicon functions to promote Beclin 1, VPS34 kinase activity at the phagosome, but inhibit it at other organellar sites. Interestingly, the WD repeat-containing C-terminal domain of ATG16L1 is essential for LC3 recruitment to endolysosomal membranes in LAP, but dispensable for canonical autophagy, illustrating another difference in the molecular roles of an ATG protein in autophagy and LAP. The genetic overlap and mutual antagonism of LAP and autophagy have practical implications for autophagy-targeted therapies. Theoretically, specificity in autophagy induction might be enhanced by activating the ULK1 complex rather than downstream shared nodes in autophagy and LAP (although the ULK1 kinase complex may have substrates outside of autophagy). The appeal of targeting Rubicon, a negative regulator of autophagy whose knockout in mice has beneficial effects, for example improved high-fat diet-induced hepatic steatosis and increased cardiac protection during lipopolysaccharide-induced sepsis, may be tempered by potential adverse effects of LAP inhibition, such as increased susceptibility to fungal diseases and autoimmunity. Furthermore, treatments that target shared ATG proteins may result in unpredictable effects on each pathway, assuming these proteins are rate-limiting and the two pathways compete for access to these shared core ATG proteins. The identification of LAP as a lysosomal degradation pathway that utilizes certain core ATG genes requires us to adopt a wider interpretative lens for studies of mice with deletions of these genes. Does deficient LAP versus deficient autophagy contribute to pathological phenotypes in mice with whole body or tissue-specific deficiency of genes such as beclin 1, ATG5, ATG7, or ATG16L1? To what extent does increased autophagy versus decreased LAP contribute to Rubicon knockout phenotypes? Do the GWAS associations between polymorphisms in some of these genes and diseases that involve disordered immune regulation, such as asthma, SLE, and inflammatory bowel disease, see Table 1, suggest a role for altered LAP in their pathogenesis? The observation that a deficiency of LAP-associated, but not of non-LAP-associated, ATG genes results in a SLE-like syndrome in mice, underscores the importance of this question. Specific molecular markers to distinguish LAP from autophagy in both animal models and human disease are needed. Beyond Lysosomal Degradation: Autophagy Genes Function in Secretion and Exocytosis. ATG genes are used not only for targeting intracellular cargo to the lysosome for degradation, but also for pathways that involve the targeting of intracellular cargo to either the plasma membrane or extracellular environment, Figure 1. Generally, these pathways have been grouped under the umbrella term “secretory autophagy”, however, as the “phagy” part is missing from the process, we prefer the more linguistically precise term of ATG gene-dependent secretion. There are many different types of ATG gene-dependent secretion, reviewed elsewhere from a cell biology perspective, but the mechanisms governing most of these processes are not well understood. Here, we focus on these pathways as they may relate to mammalian physiology and disease. Unconventional secretion involves the extracellular release of proteins that lack amino-terminal signal peptide leader sequences and bypass “conventional” transit through the endoplasmic-reticulum, ER, Golgi apparatus to reach the plasma membrane. A role for ATG proteins in this process was first discovered in yeast secretion of the acyl-CoA-binding protein, Acb1. In mammalian cells, unconventional secretion of leaderless proteins, such as the pro-inflammatory cytokines processed by the inflammasome, IL-1 beta and IL-18, also require the autophagy protein, ATG5. The precise mechanisms underlying ATG gene-dependent unconventional secretion remain unclear. It is not certain whether targets are captured in an autophagosomal lumen and, or the intermembrane space between the double membrane of the autophagosome, nor is it certain how targets are delivered to and released from the plasma membrane. Autophagosome-like vesicles containing IL-1 beta bypass syntaxin 17-dependent fusion with lysosomes and instead use specific SNAREs and syntaxins involved in vesicle fusion with the plasma membrane for cargo secretion. A function of ATG genes in secretion of pro-inflammatory mediators, and more broadly, other leaderless proteins, could have vast importance for inflammatory disorders and a wide range of other diseases. However, it is currently difficult to assess the physiological importance of ATG gene-dependent secretion of IL-1 beta and IL-18 in vivo, as macrophage, or hematopoietic cell specific deletion of Atg5, Atg16l1, and Atg7 in mice is associated with increased, rather than decreased, levels of IL-1 beta and IL-18 production. These findings may reflect basal functions of ATG genes in the negative control of inflammasome activation, whereas the ATG gene-dependent secretion of pro-inflammatory mediators may be unmasked during certain stress conditions, such as inflammasome activation triggered by lysosomal membrane damage. The possibility of an autophagy-dependent secretome in vivo warrants further investigation and may lead to the identification of proteomic signatures of autophagy activation as clinically useful serum biomarkers. Theoretically, autophagy-inducing therapies might lead to untoward effects via the unconventional secretion of pro-inflammatory mediators or other pathogenic proteins. Perhaps the best-established link between ATG gene-dependent secretion and mammalian physiology and disease relates to the exocytosis of secretory granules and lysosomes. Notably, human genome wide association studies (GWAS) that revealed a polymorphism in a core ATG gene, ATG 16 L1 T300A, as a major risk allele for Crohn’s disease spurred the discovery of a fundamental role for the ATG protein conjugation machinery in secretory granule exocytosis. In mice, the hypomorphic expression of Atg 16 L1, referred to as the Atg 16 L1 T300A knock-in mutation, Paneth cell-specific deletion of Atg16L1, Atg5, or Atg7, or the whole-body deletion of Atg4b results in abnormal granule morphology and a defect in granule exocytosis and lysozyme secretion by Paneth cells. Paneth cells are a specialized ileal epithelial cell type that controls the intestinal microbiota by secreting lysozyme and antimicrobial peptides. Similar defects in Paneth cell morphology are observed in patients with, but not those without, the ATG 16 L1 T300A Crohn’s disease risk allele. The precise membrane trafficking mechanisms by which ATG proteins facilitate secretory granule exocytosis in Paneth cells or other cell types remain unknown. However, a recent study indicates that lysozyme is localized in large LC3-positive vesicles in Paneth cells from wild-type but not Atg 16 L1 T300A mice. Thus, in a manner similar to autophagosome-like vesicles involved in unconventional protein secretion, secretory granules may be earmarked for exocytosis by the presence of LC3 on their surface. A related, but topologically distinct, link between autophagy and secretory lysosome exocytosis was uncovered in another specialized type of secretory cell, the osteoclast. Osteoclasts resorb bone by a mechanism that involves secretory lysosome fusion with bone-apposed plasma membrane composed of ruffled borders, with the discharge of matrix-degrading molecules into the site of osteal degradation. In mice, the ATG protein conjugation machinery and the Rab GTPase, Rab7, are essential for generating an LC3-labeled ruffled border, cathepsin K release and normal bone resorption, thus indicating a role for ATG genes in mediating polarized secretion of lysosomal contents to the extracellular space. In this scenario, the plasma membrane, not the secretory lysosome, is labeled by LC3. Thus, during secretion, the ATG protein conjugation machinery and resulting lipidated LC3 can function either in the formation of normal secretory granules that properly fuse with the plasma membrane or in the creation of a specialized plasma membrane that fuses with secretory lysosomes. The predicted clinical outcome of defects in ATG gene-dependent osteoclast functions would be osteopetrosis, a disease marked by abnormally dense bone. Consistent with this prediction, mutations in PLEKHM1, a Rab7 effector, and the v-ATPase alpha 3 subunit involved in lysosomal acidification, are each associated with osteopetrosis in patients. In contrast, aging, which is associated with reduced autophagy in most cell types, is accompanied by osteopenia and osteoporosis in mice and humans. This may reflect the roles of ATG genes in other cell types in the bone that favor bone growth and normal bone density, including protection against endoplasmic reticulum (ER) and oxidative stress in osteoblasts and osteocytes and maintenance of the proper function of bone mesenchymal stem cells. Thus, studies in bone represent an elegant example of how the autophagic machinery can exert different specialized functions in distinct cell types within a given organ, functions that may have opposite effects, such as bone resorption and bone formation, to orchestrate overall tissue homeostasis. As osteopenia, osteoporosis and associated skeletal fractures are a major cause of morbidity and mortality in aging humans, this area warrants further investigation as a potential clinical target for autophagy upregulation. Numerous other defects in protein secretion in ATG gene knockout mice have been described, although it is unclear whether they reflect a direct role for ATG genes in autophagy-independent trafficking or more indirect consequences of autophagy deficiency on secretory processes. These include defects in the assembly and secretion of octogonial core proteins which leads to abnormalities in vestibular development and defects in pancreatic beta cell insulin granule morphology and secretion, melanogenesis and pigmentation, and mucus secretion of airway epithelial cells and intestinal goblet cells. Accumulating evidence suggests that ATG proteins also have pleiotropic effects on the cellular release of exosomes, a process that is mediated by fusion of the multivesicular body (MVB) with the plasma membrane. Autophagy induction can prevent, whereas ATG gene silencing or pharmacological inhibition can increase, extracellular release of exosomes, including those containing pathogenic protein cargoes, such as alpha-synuclein, prions and amyloid precursor protein. This regulatory mechanism is presumed to involve MVB fusion with auto phagosomes, thereby diverting MVB transport away from the plasma membrane. Increased exosome release in the setting of impaired autophagy may function as an alternative quality control pathway to maintain cellular homeostasis and prevent cell death due to proteotoxicity. However, there are also examples in which ATG genes stimulate exosome production. Atg5, but not Atg7, has been shown to decrease late endosome acidification by disrupting the v-ATPase, thereby promoting the production of exosomes that enhance tumor metastasis. Similarly, the ATG3-ATG12 conjugate which is required for LC3 lipidation during basal, but not starvation, conditions interacts with the ESCRT protein, Alix, and positively controls Alix-dependent exosome biogenesis. Given the expanding repertoire of exosome-dependent processes, including neurodegeneration, immune signaling, metabolism, tumor metastasis and viral infection, the effects of the autophagic machinery on the fate of the MVB lysosomal degradation or exocytosis, may partly underlie the pathophysiological effects of ATG gene mutation. The ATG machinery modulates retromer function to control the endosome-to-cell-surface recycling pathway. During metabolic stress, LC3 on autophagic structures binds to the RabGAP protein TBC1D5 to sequester it away from an inhibitory interaction with the retromer complex. This sequestration allows retromers to associate with endosomal membranes and mediate plasma membrane translocation of the glucose transporter, GLUT1, a facilitator of glucose uptake. GLUT1 is required for the low levels of basal glucose uptake required to sustain cellular respiration, and its plasma membrane localization normally increases when cells are exposed to low glucose. Perturbation in ATG protein conjugation may significantly cripple this metabolic homeostatic mechanism involving GLUT1 trafficking and, in addition, affect the cell surface localization of other as-of-yet-unidentified receptors. Autophagy Genes in Other Dynamic Membrane Events. Non-autophagic functions of ATG genes in membrane trafficking modulate the infection of host cells by viruses, bacteria and other pathogens. These include processes described above such as LAP, which may be partially antagonized by virulent micro-organisms that enter professional phagocytes, and LC3-regulated exocytosis, which is involved in the egress of viruses that either reside inside autophagosomes or whose envelopes become decorated with LC3. Many additional ATG gene-dependent membrane reorganization events, or interference with such events, also regulate infection. For example, several ATG genes are required for the formation of intracytoplasmic membrane-associated replication factories of certain medically important RNA viruses, such as hepatitis C viru. Similarly, the formation of multi-membranous vacuoles that support replication of the bacterium, B. abortus, involves ATG genes required for class 3 PI3K activity but not those required for LC3 conjugation. In contrast, IFN gamma inhibits T gondii replication by a process involving LC3, Gabarap lipidation and recruitment of IFN gamma inducible GTPases to the parasitophorous vacuole, where they disrupt the membrane and destroy the parasite’s replicative niche. Similarly, IFN gamma mediated control of murine norovirus, a model for human epidemics of gastroenteritis, involves labeling membrane-associated viral replication complexes with lipidated LC3 and recruitment of IFN gamma inducible GTPases. Thus, marking replication-associated membrane structures by LC3 conjugation may represent a conserved mechanism underlying IFN gamma mediated control of intracellular pathogen replication. Further understanding of the precise processes by which different subsets of ATG proteins provide or destroy host membranes necessary for different stages of pathogen replication may lead to the development of new anti-infective strategies. Beyond Membrane Trafficking: Autophagy Proteins Have Other Functions. The autophagy proteins not only help orchestrate the cross-talk of diverse vesicular trafficking pathways, but also interface with multiple other cellular pathways, including, but not limited to, cell death pathways, cell cycle regulation, and innate immune signaling. The interaction of FIP200 with Atg13 is essential for autophagy in vivo and neonatal survival in mice, but the non-autophagic function is sufficient to maintain embryogenesis through a mechanism involving protection against TNF alpha induced apoptosis. Atg7, independently of its E1-like enzymatic activity and function in autophagy, regulates p53-dependent cell cycle arrest and apoptosis, and the neonatal lethality of Atg7 knockout mice is partially rescued by inhibition of the DNA damage response through deletion of the protein kinase Chk2. In mice, deletion of Atg9a, but not Atg5, results in a defect in necrosis at the bone surface during developmental morphogenesis. The precise mechanisms underlying these, and additional, functions of individual ATG proteins in cell death and cell cycle regulation are not well understood. ATG proteins regulate inflammatory and immune signaling both through autophagy-dependent mechanisms, such as by the autophagic removal of damaged mitochondria that produce ROS and activate RIG One signaling and the NLRP3 inflammasome, and autophagy-independent mechanisms that generally involve ATG protein interactions with immune signaling molecules. For example, the ATG5-ATG12 conjugate inhibits type One IFN signaling in response to viral infection by binding to the CARD’s, caspase activation and recruitment domains, of RNA recognition molecules such as RIG one and MAV’s. Similarly, the cytosolic DNA sensing innate immunity pathway mediated by cGAS, cyclic GMP-AMP, cGAMP, synthase and STING, Stimulator of interferon genes, is regulated by autophagy proteins. The generation of cGAMP by cGAS activates ULK1, which phosphorylates and inhibits STING-dependent cytokine production. As unrestrained STING signaling, either via inherited mutations in the ADAR and ribonuclease H2 complex or gain-of-function mutations in STING, causes human auto inflammatory diseases, ULK1 activating agents have been proposed as potential treatments for such disorders. Beclin 1 binds cGAS to suppress cGAMP synthesis and halt interferon production. Atg9a may also function as a negative regulator of innate immune signaling by decreasing the assembly of STING and TBK1 in the presence of double-stranded DNA. Of note, these same RNA-sensing and cytosolic DNA-sensing signaling pathways are activators of autophagy, which is itself an important innate immune effector pathway. Thus, ATG proteins play a crucial role in both mediating innate immunity and in providing feedback inhibition to fine-tune inflammatory signaling so as to avoid deleterious consequences. The Selectivity of Autophagy: a Guardian of Cellular Homeostasis. For nearly half a century, the process of macro autophagy was believed to lack cargo specificity. In fact, the morphological identification of an auto phagosome required visualizing the simultaneous presence of diverse cytoplasmic contents, such as ER, ribosomes and mitochondria inside a double-membraned vacuole. However, a transformative body of work over the past decade has fully dispelled this notion. We now know that there can be extreme specificity in governing the choice of cargo that is degraded by the autophagosome and an intricate system for earmarking and capturing such cargo. This process, termed selective autophagy, may be more crucial in protection against most mammalian diseases than “bulk autophagy”, which is primarily a homeostatic mechanism during nutrient stress. Many parts of the cell can be “selected” for degradation by autophagy, Figure 2 and Table 2. Numerous studies have reported the selective autophagy of various organelles, including mitochondria, ER, peroxisomes, lipid droplets, ribosomes, midbody rings and the nucleus. Autophagy selectively degrades aggregation-prone misfolded proteins such as those involved in the pathogenesis of certain neurodegenerative, skeletal and cardiac muscle, and liver diseases. In addition, it degrades the individual proteins that serve as adaptors to bridge cargo with the nascent phagophore as well as specific inflammatory and immune signaling molecules. Moreover, selective autophagy can target pathogens that reside inside vacuoles or directly inside the cytosol for lysosomal degradation. Once captured, cargo degradation proceeds through a route that involves the same molecular machinery as bulk autophagy. Different forms of selective autophagy are often named by a term comprising a prefix derived from the cargo. For example, mito, ER, ribo, nucleo, pexo, lipo, and the suffix “phagy”. For selective autophagy of microbial invaders, the term xenophagy is commonly used. Major advances have been made in understanding certain aspects of selective autophagy, particularly how cargo binds to the forming phagophore, Figure 2. In most known instances, the cargo either contains an identifiable LC3-interacting region or LIR motif that directly binds LC3, or it must be labeled with a tag such as ubiquitin, which then binds adaptor proteins that contain both a ubiquitin-binding domain and a LIR motif, thus serving as a bridge between the cargo and the LC3, or Gabarap’s, conjugated to the phagophore membrane. Alternatively, specific proteins (particularly those involved in the inflammasome or IFN signaling) can bind to TRIM (tripartite motif) family members, which serve as adaptors that interact with Gabarap’s to target such proteins for autophagic degradation. Of note, the proteins we refer to as “adaptors” are often called autophagy “receptors”. However, as these are bridging molecules that are not integral parts of cellular membranes that undergo ligand-dependent activation, the designation as “receptors” can be confusing. Several layers of control are needed to properly dictate the targeting of cargo for autophagy. In theory, cargo should be disposed of when it is constitutively harmful, for example, intracellular pathogens, potentially dangerous to the cell, for example, mitochondrial damage, or obsolete as a result of cellular differentiation, for example, organelles during erythrocyte maturation. In the scenario where LC3 directly binds to a protein on an organelle containing a LIR motif, there must exist ways to hide or expose the LIR motif in a regulated-fashion. Two mechanisms identified thus far include: (1) Stimulatory and inhibitory phosphorylations of residues near or in the LIR motif (such as occurs for the mitochondrial outer membrane protein, FUNDC1, that mediates hypoxia-stimulated mitophagy and (2) The exposure of a normally hidden LIR motif, such as occurs when proteasomal-dependent rupture of the outer mitochondrial membrane exposes the inner mitochondrial membrane LC3-binding protein, prohibitin 2. Under circumstances where LC3 binds to an adaptor protein, there must exist ways to recruit the adaptor to the cargo destined for degradation. This process generally involves the concerted action of E3 ligases that ubiquitinate targets, for example, Parkin, SMURF1, kinases that recruit E3 ligases, for example, PINK1, or that phosphorylate LIR domains of adaptors, for example, TBK1, deubiquitinating enzymes, DUB’s that counter E3 ligase activity, for example, USP30, USP15, and acetylation, deacetylation of mitochondrial and ER target proteins. All mechanisms for earmarking cargo must be tightly coordinated with the formation of autophagosomes to ensure final cargo disposal. Some potential nodes of coordination have recently been described. Certain autophagy adaptors, most notably the TRIM family proteins, bind not only substrate proteins and LC3, Gabarap family members but also assemble the ULK1 and Class 3 PI3K complexes to initiate autophagosome formation. ULK1, a “master kinase” that phosphorylates multiple sites on downstream core autophagy proteins, is recruited to and phosphorylates proteins involved in selective autophagy, such as the LIR domain of the mitochondrial membrane protein, FUNDC1. An organelle-specific LC3, Gabarap binding protein, the ER membrane protein, CCPG1, interacts with a key component of the autophagy-initiating ULK1 complex, FIP200. Thus, the machinery involved in selective autophagy substrate recognition may play an active role in autophagy initiation. For selective autophagy targeting events that involve substrate ubiquitination, the precise mechanisms that dictate the choice between autophagic versus proteasomal degradation are uncertain. In yeast, substrate aggregation and oligmerization of the ubiquitin-binding proteins may favor autophagic degradation. The lysine residues used for linkage and the length and nature of the ubiquitin chains have also been proposed to contribute to pathway selection, but definitive evidence is lacking. Moreover, despite elegant studies characterizing the ubiquitylome of selective autophagy cargo, such as mitochondria and intracellular pathogens, the ubiquitin substrates required for autophagic targeting remain largely undefined. Selective autophagy seems to involve multiple concurrent targeting mechanisms that act in a cooperative, potentially hierarchical and, or partially redundant manner to ensure proper removal of cargo. This “combinatorial design” may allow specific cell types to more precisely regulate when and how selective autophagy occurs for a given cargo. The partial redundancy also renders it more feasible to study loss-of-function phenotypes of genes required for selective autophagy but dispensable for bulk autophagy, as compared to those required for bulk autophagy, as they are less likely to be lethal to the cell or organism. As selective autophagy genes are partially redundant, this may explain why their loss-of-function mutation seems to be better tolerated in the human population than loss-of-function mutation of core ATG genes. Indeed, mutations in many of the known molecules involved in selective autophagy are associated with susceptibility to a variety of human diseases, Table 1. Mutations in the genes encoding the adaptor proteins p62, SQSTM and optineurin, the E3 ligase Parkin, and the kinases PINK1 and TBK1, are among the most common causes of familial and early onset neurodegenerative diseases, including Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis. Hereditary sensory and autonomic neuropathy type II is caused by mutations in an ER-specific LC3 binding protein, FAM134B, required for ER-phagy. Mutations in TRIM20, also known as pyrin, that impair its ability to target inflammasome components for autophagic degradation result in an inherited autoinflammatory disorder, familial Mediterranean fever. Inflammatory bowel disease-associated genes encode proteins that function in multiple steps of autophagy, including the selective targeting of bacteria by the adaptor, Calcoco2, NDP52, and the E3 ligase, SMURF1. The numerous links between mutations in selective autophagy genes and human diseases underscore the likely physiological importance of different forms of selective autophagy, Table 2. However, the precise mechanisms that connect genotype to phenotype remain largely undefined. For example, it is not known why mutations in Parkin and PINK1 are associated with Parkinson’s disease, whereas mutations in optineurin, TBK1, and p62, SQSTM1 are associated with amyotrophic lateral sclerosis and frontotemporal dementia, Table 1. In addition to potential cell non-autonomous effects of mutations in these genes in tissues outside of the brain, cell type-specific differences in various populations of neurons and glia may exist with respect to: (1) Dependency on subsets of selective autophagy genes. (2) Expression and activity of DUBs and other negative feedback mechanisms that regulate selective autophagy, and, or (3) levels and types of stress that mandate different types of selective autophagy responses to maintain homeostasis, such as mitophagy or other forms of selective autophagy such as aggrephagy that are relevant to neurodegenerative diseases. Parkin knockout mice, unlike flies lacking Parkin, do not develop spontaneous neurodegeneration, but they do develop dopaminergic neuronal degeneration, resembling that observed in human Parkinson’s disease, when crossed with “mutator” mice with a proof-reading-defective mitochondrial DNA polymerase (PolG) that accumulate mitochondrial mutations. The localization of disease in dopaminergic neurons may be related to increased mitochondrial stress in these cells as compared to other neuronal populations in the brain. Intriguingly, the motor defect and neurodegeneration in Parkin-null, mutator mice can be rescued by deletion of STING, a regulator of Type One IFN responses to cytosolic DNA. Thus, aberrant inflammatory signaling as a result of defects in mitophagy may contribute to the pathogenesis of neurodegenerative disease in patients with Parkin or PINK1 mutations. While most, if not all, forms of selective autophagy are likely to contribute to normal physiology and protection against disease, mitophagy has been the most extensively studied. Mitophagy is an essential component of mammalian developmental and differentiation processes, including elimination of paternal mitochondria from the fertilized egg, removal of mitochondria during red blood cell maturation and beige-to-white adipocyte differentiation. In addition to Parkinson’s and other neurodegenerative diseases, defective mitophagy is thought to contribute to organ-specific and systemic inflammatory diseases, cancer development and, or progression, and potentially aging. The removal of damaged mitochondria by mitophagy maintains normal cellular metabolism, reduces mitochondrial generation of ROS that trigger inflammation and genotoxic stress, and prevents mitochondrial release of pro-apoptotic factors. Thus, maintenance of proper mitochondrial function by mitophagy is crucial for cellular and organismal health. Other forms of selective autophagy, including xenophagy, likely operate in an analogous manner to mitophagy, in that the mechanisms by which they regulate physiology and disease are a function of the normal “duties” of their substrate and the ensuing pathological consequences of abnormal substrate accumulation, see Table 2. Our expanding knowledge of the mechanisms and physiological functions of selective autophagy may open up new, albeit unchartered, pathways for drug discovery. Knockdown of the mitochondrial deubiquitinase, USP30, rescues mitophagy defects and disease in flies with pathogenic mutations in Parkin, suggesting a potential role for the inhibition of DUBs that target selective autophagy E3 ligases in the treatment of Parkinson’s and other diseases. Indeed, novel highly selective inhibitors of USP30 that accelerate mitophagy have recently been reported. As phosphorylation of substrates is also a common mechanism involved in selective autophagic targeting, it may be possible to activate specific kinases to enhance selective autophagy. Potentially, it may also be possible to develop novel strategies to attach high-affinity LIR domains selectively to harmful cargo so that they can be more efficiently captured by an LC3-decorated nascent autophagosome. Autophagy Regulation: A Nexus for Therapeutics? Autophagy was originally studied in yeast and mammalian cells as a nutrient stress response pathway. During the past decade, we have dramatically expanded our knowledge of autophagy regulation, particularly the spectrum of physiological and pathophysiological stimuli that control autophagy, the mechanisms that regulate the activity of the core autophagy proteins, and the interconnectivity of autophagy with other cellular stress response pathways. These concepts have been reviewed elsewhere, here, we highlight selected aspects relevant to physiology and disease. Post-translational protein modifications such as phosphorylation, ubiquitination, and acetylation play a central role in coordinating the activity of ATG proteins. In most cases, the upstream kinases, phosphatases, ubiquitin ligases, DUB’s, and acetyltransferases simultaneously modify both ATG proteins and proteins involved in other cellular stress-response pathways that are co-regulated with autophagy. As a result, pharmacological targeting of these enzymes will elicit broad-based modulation of multiple intertwined stress-response pathways. Depending on the enzyme and its substrates, such nonspecific targeting may be harmful in some instances, and useful in others. One important example is the stimulation of AMPK, a low energy-sensing kinase activated by ATP depletion, which phosphorylates multiple proteins to both stimulate catabolic pathways, including autophagy, and restrain anabolic pathways, including mTORC1 signaling, thereby ensuring limitation of ATP consumption and generation of new ATP via breakdown of metabolic products. In recent years, AMPK has been shown to not only activate autophagy through inhibition of mTORC1, but also directly phosphorylate several ATG proteins, including ULK1, ATG9A, Beclin 1, and VPS34. In addition, AMPK promotes mitophagy through effects on ULK1 and stimulates TFEB-dependent activation of the CLEAR, Coordinated Lysosomal Expression and Regulation, network of genes required for autophagy. This pro-autophagic activity of AMPK occurs concurrently with its effects on mitochondrial homeostasis and on lipid and glucose metabolism. AMPK activation may underlie the beneficial effects of metformin, a drug widely prescribed for the treatment of diabetes. Metformin activates AMPK indirectly through mitochondrial depletion of ATP, and direct AMPK activators that yield effects similar to metformin are in pre-clinical development. The extent to which autophagy stimulation contributes to beneficial effects of AMPK activation in mice or patients is not known, but it seems likely that autophagy represents a critical part of an AMPK-activated hub that protects against various metabolic diseases, including diabetes, obesity, and non-alcoholic fatty liver disorders, as well as certain cancers and aging-related phenotypes. In Drosophila, deficiency of the Beclin 1 orthologue (ATG6) impairs the ability of metformin to prevent intestinal stem cell aging, and lifespan extension by neuronal AMPK expression requires the fly ULK1 orthologue, ATG1. In mice, AMPK upregulation of autophagy is correlated with improved function of aging muscle stem cells, additionally, muscle-specific AMPK deficiency results in defective autophagy, fasting-induced hypoglycemia, and aging-associated myopathy. In yeast, core ATG genes are required for AMPK-mediated lipid droplet degradation and survival during acute glucose deprivation. The lysine acetylation, deacetylation of ATG proteins has emerged as a central node of autophagic control regulated by metabolic sensors involved in lipid, glucose and protein metabolism. Moreover, this control center may function independently from, but intertwined with, AMPK and mTORC1. During acute nutrient depletion, cells undergo a rapid decrease in levels of cytosolic acetyl coenzyme A (AcCoA), which leads to the deacetylation of cellular proteins. Sirtuin 1, which is downstream of AMPK, deacetylates multiple ATGs, for example, ATG5, ATG7, ATG12, Beclin 1, VPS34, LC3) and thereby promotes autophagy, as does reduced activity of the acetyl transferase EP300. Hence, endogenous activators of sirtuin-1, for example, nicotine adenine dinucleotide NAD plus, endogenous inhibitors of EP300, for example, spermidine, a dietary polyamine), and reduced availability of AcCoA (a rate-limiting step for EP300 function) all stimulate autophagy. Compounds that act on these pathways, thereby mimicking the effects of caloric restriction, so-called “caloric restriction mimetics”, are an active area of investigation, and genetic evidence suggests that autophagy is essential for their beneficial effects in vivo. Reservatrol, an indirect sirtuin activator, requires the autophagy machinery for its favorable effects on longevity in nematodes. Spermidine-induced autophagy is required for several of its beneficial health effects in model organisms, including lifespan extension in flies, worms, and mice, prevention of cardiac aging in mice, improvement in neuronal function in aging flies, and preservation of myocyte stemness in mice. Moreover, caloric restriction mimetics improve anti-tumor immune surveillance and enhance chemotherapy responses in autophagy-competent, but not autophagy-incompetent, mouse tumor allografts. Over the past decade, the lysosome, an organelle traditionally viewed as the downstream “workhorse” for autophagosomal cargo degradation, has been shown to also play a crucial role in the upstream regulation of autophagy. The nutrient-sensing kinase complex, mTORC1, detects both cytosolic and intra-lysosomal amino acids through distinct mechanisms to inhibit autophagy. Amino acids, such as arginine, inside the lysosomal lumen are sensed by the amino acid transporter SLC38A9, which interacts with the lysosomal V ATPase, Rag, Ragulator complex to activate mTORC1. This both restrains autophagy during baseline conditions and provides feedback inhibition to terminate autophagic responses to acute nutrient depletion. mTORC1 activation in the fed state and, or hyperactivation, as a result of mutations in regulatory signals, switches the cell to a state of anabolic growth and energy storage. Although essential for cell growth and proper metabolic regulation, sustained mTORC1 activation at the organismal level is associated with a variety of pathophysiological consequences, including impaired neonatal gluceoneogenesis and survival, accelerated age-related decline in pancreatic beta-cell function, late-onset muscle atrophy, altered lipogenesis and adipogenesis, immune suppression, epileptic seizures and autistic traits, tumorigenesis, and aging. While in some cases, impaired induction of autophagy has been documented in mice with hyperactive mTORC1 signaling and is postulated to contribute to pathological phenotypes, for example, impaired neonatal gluconeogenesis, late-onset muscle atrophy, the precise role of autophagy inhibition in most diseases associated with mTORC1 signaling remains unknown. There has been some interest in using FDA-approved mTOR inhibitors for the treatment of neurodegenerative disorders that may benefit from autophagy induction. However, the safety and efficacy of using mTOR inhibitors to induce therapeutic autophagy is uncertain, given the broad range of essential catabolic functions regulated by mTORC1 along with the lack of full specificity of existing agents to target mTORC1 rather than mTORC2, which functions primarily as an effector of insulin, PI3K signaling. Both AMPK and mTORC1 participate, in opposite directions, in a signaling axis that links autophagy, the lysosome, and the transcription factor EB (TFEB) and related family members. During the acute response to autophagic stimuli, transcriptional activation is not required, as evidenced by the observation that enucleated cells (cytoplasts) undergo autophagy. However, sustained autophagy requires TFEB, a transcription factor that (when inactive) binds to Ragulator at the lysosomal membrane, is phosphorylated by mTORC1, and retained in the cytoplasm by 14 3 3 proteins. Following mTORC1 inhibition, TFEB dephosphorylation releases it from the cytoplasm, allowing its nuclear translocation and subsequent activation of the CLEAR gene network, which includes genes encoding lysosomal hydrolases, lysosomal v-ATPase pumps, lysosomal regulators and autophagy regulators. As noted above, AMPK also activates TFEB-dependent gene expression, this occurs through multiple different mechanisms. In addition, a recent study showed that phosphorylation of acetyl-CoA synthetase 2 (ACSS2) promotes its transport into the nucleus, where it binds to TFEB and favors the acetylation of histone H3 residues within the promoters of TFEB target genes. In addition to TFEB, other transcription factors from the same family, such as micropthalmia-associated transcription factor, MITF, and TFE3, or from other families, for example, FOXO3A, HSF1 or TP53, stimulate autophagy. Bromodomain 4, BRD4, a transcription factor that represses autophagy and lysosomal genes, is displaced from chromatin in response to starvation by a signaling cascade involving an AMPK-SIRT1 axis. Thus, multiple known, and probably yet-to-be-identified, transcription factors regulate the synthesis of genes required for autophagy, including both the formation of the autophagosome and degradation of its contents by lysosomes. Not surprisingly, the activity of these transcription factors is tightly regulated by numerous signaling factors that also regulate core ATG protein function by post-translational modifications. Modulation of the activity of TFEB, a master regulator of both lysosomal biogenesis and autophagy, has emerged as a potential therapeutic strategy. Conceptually, this approach is attractive, since limitations in lysosomal numbers and function either occur intrinsically as part of many rare, but devastating, difficult-to-treat, primary diseases, such as lysosomal storage disorders, LSD’s, or are acquired during the progression of diseases associated with the clearance of toxic aggregates progress, such as Huntington’s, Parkinson’s, Alzheimer’s disease and tauopathies. In mice, TFEB overexpression ameliorates several LSDs, neurodegenerative diseases, and alpha 1-antitrypsin deficiency, and it also promotes lipophagy, thereby reducing obesity and associated metabolic syndrome. The mechanisms by which TFEB overexpression partially corrects lysosomal malfunction in LSDs are not fully understood, but may involve induction of lysosomal exocytosis for the secretion of undigested material. One potential obstacle to strategies for enhancing TFEB family activity is the risk of tumorigenesis associated with constitutive activation, for example, renal clear cell carcinoma with TFEB and pancreatic cancer with MITF, TFE3, and TFEB. While MITF, TFE3, TFEB-dependent autophagy-lysosomal activation is thought to sustain metabolic reprogramming in pancreatic cancer cells by maintaining intracellular amino acid pools, further genetic investigations are warranted to confirm that ATG genes are involved in these effects. Moreover, enhanced activity of BRD4, a transcriptional repressor of autophagy, drives another type of cancer, NUT midline carcinoma, suggesting the effects of transcriptional regulators of autophagy on tumorigenesis may be cell-type specific. It is unclear whether specific subsets of the TFEB-regulated gene network can be induced to avoid genes that contribute to tumorigenesis without losing beneficial effects on the autophagy-lysosomal pathway. An alternative strategy is to activate TFEB on an intermittent basis and, or for limited periods to avoid potential oncogenic effects. Intriguingly, one of the most widely used medications in the world, aspirin, has been reported to upregulate TFEB in brain cells, via activation of PPARC alpha, induce lysosomal biogenesis, and decrease amyloid plaque pathology in a mouse model of Alzheimer’s-like disease. Aspirin (and its active metabolite salicylate) also induces autophagy via inhibition of the acetyltransferase EP300 and via AMPK activation, mTORC1 inactivation. However, there is as-of-yet no direct genetic evidence that autophagy contributes to the health benefits of aspirin. Highly specific activation of autophagy may be possible through strategies that enhance the activity of the upstream components in the core autophagy pathway, meaning the ULK1 serine, threonine kinase complex and, or Beclin 1, VPS34 lipid kinase complexes. As a key allosteric regulator of VPS34 lipid kinase activity, Beclin 1 activity is tightly regulated by multiple post-translational modifications, ubiquitination, acetylation, phosphorylation, which govern its stability, heterodimeric binding to ATG14 or UVRAG, homodimerization in an inactive form, and, or binding to negative regulators. Diverse stress kinases, including AMPK, as well as the upstream ATG protein, ULK1, mediate stimulatory phosphorylations of Beclin 1. The oncogenic kinases, Akt and EGFR, and the EP300 acetylase inhibit the autophagic activity of Beclin 1, mutation of their target post-translational sites in Beclin 1 demonstrates that suppression of Beclin 1-dependent autophagy promotes tumor growth in mouse xenograft models. Enhanced proteasome-mediated degradation of Beclin 1 due to decreased binding of the deubiquitinase, ataxin 3, may contribute to dysregulated autophagy in cells of patients with polyglutamine expansion protein-related diseases, such as Huntington’s and spinocerebellar ataxia type 3.. Disruption of Bcl-2 binding to Beclin 1 represents a central mechanism by which autophagy is activated in response to stress stimuli, such as starvation, exercise, and immune signaling. This disruption can be triggered by phosphorylation of the BH3 domain of Beclin 1 by DAPK, ubiquitination of the Beclin 1 BH3 domain by the E3 ligase TRAF6, phosphorylation of Bcl-2 by JNK1, or competition by BH3-only proteins. Mice containing knock-in non-phosphorylatable mutations in Bcl-2 that prevent disruption of its binding to Beclin 1 are deficient in starvation and exercise-induced autophagy, have decreased exercise endurance, and fail to manifest the beneficial effects of exercise on glucose metabolism. Conversely, mice with a knock-in mutation in Beclin 1 that decreases Bcl-2 binding exhibit increased autophagy and extended lifespan and healthspan, including protection against Alzheimer’s-like disease and HER2-mediated breast cancer. Thus, disruption of Beclin 1, Bcl-2 binding may be a safe and effective approach to induce autophagy in vivo, preclinical studies are in progress to develop agents that act through this mechanism. Cell-penetrating peptides, Tat-Beclin 1, derived from a flexible hinge region of Beclin 1 important for VPS34 membrane association and lipid kinase activity are sufficient to induce autophagy in vitro and in vivo. In mice, Tat-Beclin 1 protects against West Nile virus, chikungunya virus and E. coli bacterial infections, lipopolysaccharide-induced cardiac dysfunction, pressure overload-induced heart failure, hyperammonemia in liver failure and urea cycle disorders, and bone loss in LSDs and in FGF-deficiency. It also enhances chemotherapeutic effects of murine cancers in immune competent mice, reduces the growth of human HER2-positive breast cancer xenografts in immune-deficient mice, and acts synergistically with erastin to increase animal survival in an orthotopic pancreatic cancer model. In rats, intrahippocampal injection of Tat-Beclin 1 improves long-term spatial memory. In a zebrafish model of human polycystic kidney disease, Tat-Beclin 1 ameliorates renal cyst formation. Further studies are needed to examine whether Tat-Beclin 1 induces these effects through autophagy, autophagy-independent effects of Beclin 1, or alternative mechanisms. Moreover, precise definition of its mechanism of action may lead to the development of novel small drug-like molecules that mimic its activity. Recent structural advances elucidating the atomic details of the Beclin 1, VPS34 complexes may provide a basis for rational drug design to selectively activate autophagy-specific Beclin 1-associated VP34 lipid kinase activity. Autophagy in Tissue and Whole-Body Homeostasis. The health of multicellular organisms requires the coordinated regulation of cellular life and death decisions, cell fate determinations, preservation of genomic integrity, immune responses, and metabolic circuitries. The autophagy machinery, via its diverse functions described above, and yet-to-be-discovered mechanisms, plays a crucial role in these processes. Herein, we highlight some recent advances related to the role of autophagy in cell death, preservation of stem cells, tumor suppression, longevity and defense against metabolic diseases. Autophagy as a Homeostat During both routine “housekeeping” and responses to acute stress, cells must find ways to maintain adaptive cytoprotective levels of autophagy while simultaneously avoiding potentially maladaptive levels and, or detrimental effects of autophagy. This balance involves self-control of the levels of autophagy, mechanisms of preventing degradation products from becoming toxic to cells, avoidance of degrading essential cargo, and suppression of unwarranted cell death, which likely is a combined function of the aforementioned processes. Cellular self-titration of levels of autophagy involves multiple different inhibitory feedback loops, including feedback regulation of nutrient sensing signals by the generation of amino acids, acetyl-CoA and respiratory substrates, cytosolic retention of pro-autophagic transcription factors by ATG7, and TFEB-mediated activation of mTORC1. Cellular toxicity by degradation products may be avoided during autophagy, as evidenced by the observation that the generation of lipid droplets generated by autophagy-dependent dismantling of lipid membranes during starvation-induced autophagy sequesters fatty acids, thereby protecting mitochondria against lipotoxicity and preserving cellular viability. It is not known whether starvation-induced autophagy preferentially induces removal of certain, perhaps aged, structures, and if so, by what mechanisms, or whether it is non-specific. Mitochondria elongate during starvation, which spares them from the autophagic capture that generally occurs after fission. Numerous yet-to-be-discovered mechanisms likely protect mitochondria and other organelles from excessive autophagic capture during stress-induced autophagy. The aforementioned negative feedback loops restrain autophagy to adaptive (rather than maladaptive) levels, allowing this homeostatic pathway to exert cytoprotective effects during stress, and thereby, prevent apoptotic and necroptotic cell death. In addition, ATG gene-dependent processes, such as increased plasma membrane localization of the GLUT1 glucose transporter, may increase the threshold of damage required to kill cells and thereby promote successful organismal adaptation to stress. Promotion of cell survival in vivo during stress-induced autophagy may depend on concurrent antagonism of the sodium, potassium ion, ATPase pump, which normally consumes a large fraction of the ATP available to the cell. Interestingly, during acute bouts of exercise or nutrient limitation, potent physiological stimuli of autophagy that generally do not result in cell death, endogenous cardiac glycosides that target sodium, potassium ion ATPase are upregulated 50 to 500 fold, resulting in decreased cellular ATP consumption. However, when organisms are pushed beyond physiological limits of energy deprivation, adaptive mechanisms are insufficient to keep cells alive and to prevent tissue damage. In the liver of patients with anorexia nervosa or in neonatal rodents subjected to severe cerebral ischemic injury, a morphologically and genetically distinct form of cell death occurs called autosis, which requires both ATG genes and sodium, potassium ion, ATPase activity. It is not clear how the cell’s major consumer of ATP, meaning the sodium, potassium ion, ATPase pump) and the cell’s major mobilizer of ATP-generating substrates during stress conditions, meaning autophagy, interact to regulate life and death decisions of the cell. However, this interaction may represent a fundamental energy homeostatic mechanism that becomes pathologic during different types of ischemic conditions. Another recently identified bona fide form of autophagic cell death, meaning demonstrating a genetic requirement for ATG genes, involves GBA1, the gene encoding the lysosomal enzyme, glucocerebrosidase (GCase, which metabolizes glucosylceramide (GlcCer) to ceramide and glucose. GB

Index of Science videos: https://rumble.com/v406mdz-index-of-robert-heinlein-audiobooks..html Open Voice: Versatile Instant Voice Cloning. Zengyi Qin, MIT, and others. We introduce OpenVoice, a versatile instant voice cloning approach that requires only a short audio clip from the reference speaker to replicate their voice and generate speech in multiple languages. OpenVoice represents a significant advancement in addressing the following open challenges in the field: 1) Flexible Voice Style Control. OpenVoice enables granular control over voice styles, including emotion, accent, rhythm, pauses, and intonation, in addition to replicating the tone color of the reference speaker. The voice styles are not directly copied from and constrained by the style of the reference speaker. Previous approaches lacked the ability to flexibly manipulate voice styles after cloning. 2) Zero-Shot Cross-Lingual Voice Cloning. OpenVoice achieves zero-shot cross-lingual voice cloning for languages not included in the massive-speaker training set. Unlike previous approaches, which typically require an extensive massive-speaker multi-lingual (MSML) dataset for all languages, OpenVoice can clone voices into a new language without any massive-speaker training data for that language. OpenVoice is also computationally efficient, costing tens of times less than commercially available API’s that offer even inferior performance. To foster further research in the field, we have made the source code and trained model publicly accessible. We also provide qualitative results in our demo website. Prior to its public release, our internal version of OpenVoice was used tens of millions of times by users worldwide between May and October 2023, serving as the backend of MyShell.ai. One. Introduction. Instant voice cloning (IVC) in text-to-speech (TTS) synthesis means the TTS model can clone the voice of any reference speaker given a short audio sample without additional training on the reference speaker. It is also referred to as Zero-shot TTS. IVC enables the users to flexibly customize the generated voice and exhibits tremendous value in a wide variety of real-world applications, such as media content creation, customized chatbots, and multi-modal interaction between humans and computers or large language models. An abundant of previous work has been done in IVC. Examples of auto-regressive approaches include VALLE and XTTS, which extract the acoustic tokens or speaker embedding from the reference audio as a condition for the auto-regressive model. Then the auto-regressive model sequentially generate acoustic tokens, which are then decoded to raw audio waveform. While these methods can clone the tone color, they do not allow users to flexibly manipulate other important style parameters such as emotion, accent, rhythm, pauses and intonation. Also, auto-regressive models are relatively computationally expensive and has relatively slow inference speed. Examples of non-autoregressive approach include YourTTS and the recently developed Voicebox, which demonstrate significantly faster inference speed but are still unable to provide flexible control over style parameters besides tone color. Another common disadvantage of the existing methods is that they typically require a huge MSML dataset in order to achieve cross-lingual voice clone. Such combinatorial data requirement can limit their flexibility to include new languages. In addition, since the voice cloning research by tech giants are mostly closed-source, there is not a convenient way for the research community to step on their shoulders and push the field forward. We present OpenVoice, a flexible instant voice cloning approach targeted at the following key problems in the field: In addition to cloning the tone color, we ask, how can we have flexible control of other important style parameters such as emotion, accent, rhythm, pauses and intonation? These features are crucial for generating in-context natural speech and conversations, rather than monotonously narrating the input text. Previous approaches can only clone the monotonous tone color and style from the reference speaker but do not allow flexible manipulation of styles. How to enable zero-shot cross-lingual voice cloning in a simple way. We put forward two aspects of zero-shot capabilities that are important but not solved by previous studies: One, if the language of the reference speaker is not presented in the MSML dataset, can the model clone their voice? Two, if the language of the generated speech is not presented in the MSML dataset, can the model clone the reference voice and generate speech in that language? In previous studies, the language of the reference speaker and the generated language by the model should both exist in great quantity in the MSML dataset. But what if neither of them exist? The challenge is how to realize a super-fast speed real-time inference, without downgrading the quality, which is crucial in a massive commercial production environment. To address the first two problems, OpenVoice is designed to decouple the components of a voice as much as possible. The generation of language, tone color, and other important voice features are made independent of each other, enabling flexible manipulation over individual voice styles and language types. This is achieved without labeling any voice style in the MSML training set. We would like to clarify that the zero-shot cross-lingual task in this study is different from that in VALLE-X. In VALLE-X, data for all languages need to be included in the MSML training set, and the model cannot generalize to an unseen language outside the MSML training set. By comparison, OpenVoice is designed to generalize to completely unseen languages outside the MSML training set. The third problem is addressed by default, since the decoupled structure reduces requirement on model size and computational complexity. We do not require a large model to learn everything. Also, we avoid the use of auto-regressive or diffusion components to speed up the inference. Our internal version of OpenVoice before this public release has been used tens of millions of times by users worldwide between May and October 2023. It powers the instant voice cloning backend of MyShell.ai and has witnessed a user growth of several hundredfold on this platform. To facilitate the research progress in the field, we explain the technology in great details and make the source code with model weights publicly available. Two. Approach. The technical approach is simple to implement but surprisingly effective. We first present the intuition behind OpenVoice, then elaborate on the model structure and training. Two point 1. Intuition. The Hard Part. It is obvious that simultaneously cloning the tone color for any speaker, enabling flexible control of all other styles, and adding new language with little effort could be very challenging. It requires a huge amount of combinatorial datasets where the controlled parameters intersect, and pairs of data that only differ in one attribute, and are well-labeled, as well as a relatively large-capacity model to fit the dataset. The Easy Part. We also notice that in regular single-speaker TTS, as long as voice cloning is not required, it is relatively easy to add control over other style parameters and add a new language. For example, recording a single-speaker dataset with 10K short audio samples with labeled emotions and intonation is sufficient to train a single-speaker TTS model that provides control over emotion and intonation. Adding a new language or accent is also straightforward by including another speaker in the dataset. The intuition behind OpenVoice is to decouple the IVC task into separate subtasks where every subtask is much easier to achieve compared to the coupled task. The cloning of tone color is fully decoupled from the control over all remaining style parameters and languages. We propose to use a base speaker TTS model to control the style parameters and languages, and use a tone color converter to embody the reference tone color into the generated voice. Two point 2. Model Structure. We illustrate the model structure in Figure 1. The two main components of OpenVoice are the base speaker TTS model and the tone color converter. The base speaker TTS model is a single-speaker or multi-speaker model, which allows control over the style parameters, for example, emotion, accent, rhythm, pauses and intonation, accent and language. The voice generated by this model is then passed to the tone color converter, which changes the tone color of the base speaker into that of the reference speaker. Base Speaker TTS Model. The choice of the base speaker TTS model is very flexible. For example, the VITS model can be modified to accept style and language embedding in its text encoder and duration predictor. Other choices such as InstructTTS can also accept style prompts. It is also possible to use commercially available (and cheap) models such as Microsoft TTS, which accepts speech synthesis markup language (SSML) that specifies the emotion, pauses and articulation. One can even skip the base speaker TTS model, and read the text by themselves in whatever styles and languages they desire. In our OpenVoice implementation, we used the VITS model by default, but other choices are completely feasible. We denote the outputs of the base model as X (Of LI, SI, and CI), where the three parameters represent the language, styles and tone color respectively. Similarly, the speech audio from the reference speaker is denoted as X (Of LO, SO, and CO). Tone Color Converter. The tone color converter is an encoder-decoder structure with an invertible normalizing flow in the middle. The encoder is a 1D convolutional neural network that takes the short-time Fourier transformed spectrum of X (Of LI, SI, and CI) as input. All convolutions are single strided. The feature maps outputted by the encoder are denoted as Y (Of LI, SI, and CI). The tone color extractor is a simple 2D convolutional neural network that operates on the mel-spectrogram of the input voice and outputs a single feature vector that encodes the tone color information. We apply it on X(Of LI, SI, and CI) to obtain vector v (Of CI), then apply it on X (Of LO, SO, and CO) to obtain vector v(CO). The normalizing flow layers take Y (Of LI, SI, and CI) and v(CI ) as input and outputs a feature representation Z (Of LI, and SI ) that eliminates the tone color information but preserves all remaining style properties. The feature Z( Of LI, and SI) is aligned with International Phonetic Alphabet (IPA) along the time dimension. Details about how such feature representation is learned will be explained in the next section. Then we apply the normalizing flow layers in the inverse direction, which takes Z(Of LI, and SI ) and v(Of CO) as input and outputs Y (Of LI, SI, and CO). This is a critical step where the tone color CO from the reference speaker is embodied into the feature maps. Then the Y (Of LI, SI, and CO) is decoded into raw waveforms X (Of LI, SI, and CO) by HiFi-Gan that contains a stack of transposed 1D convolutions. The entire model in our OpenVoice implementation is feed-forward without any auto-regressive component. The tone color converter is conceptually similar to voice conversion, but with different emphasis on its functionality, inductive bias on its model structure and training objectives. The flow layers in the tone color converter are structurally similar to the flow-based TTS methods but with different functionalities and training objectives. Alternative Ways and Drawbacks. Although there are alternative ways to extract Z (Of LI, and SI), we empirically found that the proposed approach achieves the best audio quality. One can use HuBERT to extract discrete or continuous acoustic units to eliminate tone color information, but we found that such method also eliminates emotion and accent from the input speech. When the input is an unseen language, this type of method also has issues preserving the natural pronunciation of the phonemes. We also studied another approach that carefully constructs information bottleneck to only preserve speech content, but we observed that this method is unable to completely eliminate the tone color. A Remark on Novelty. OpenVoice does not intend to invent the submodules in the model structure. Both the base speaker TTS model and the tone color converter borrow the model structure from existing work. The contribution of OpenVoice is the decoupled framework that separates the voice style and language control from the tone color cloning. This is very simple, but very effective, especially when one wants to control styles, accents or generalize to new languages. If one wanted to have the same control on a coupled framework such as XTTS, it could require a tremendous amount of data and computing, and it is relatively hard to fluently speak every language. In OpenVoice, as long as the single-speaker TTS speaks fluently, the cloned voice will be fluent. Decoupling the generation of voice styles and language from the generation of tone color is the core philosophy of OpenVoice. We also provided our insights of using flow layers in the tone color converter, and the importance of choosing a universal phoneme system in language generalization in our experiment section. Two point 3. Training. In order to train the base speaker TTS model, we collected audio samples from two English speakers, with American and British accents, one Chinese speaker and one Japanese speaker. There are 30K sentences in total, and the average sentence length is 7 seconds. The English and Chinese data has emotion classification labels. We modified the VITS model and input the emotion categorical embedding, language categorical embedding and speaker id into the text encoder, duration predictor and flow layers. The training follows the standard procedure provided by the authors of VITS. The trained model is able to change the accent and language by switching between different base speakers, and read the input text in different emotions. We also experimented with additional training data and confirmed that rhythm, pauses and intonation can be learned in exactly the same way as emotions. In order to train the tone color converter, we collected 300K audio samples from 20K individuals. Around 180K samples are English, 60K samples are Chinese and 60K samples are Japanese. This is what we called the MSML dataset. The training objectives of the tone color converter is two-fold. First, we require the encoder-decoder to produce natural sound. During training, we feed the encoder output directly to the decoder, and supervised the generated waveform using the original waveform with mel-spectrogram loss and HiFi-GAN loss. We will not present details here, as it has been well explained by previous literature. Second, we require flow layers to eliminate as much tone color information as possible from the audio features. During training, for each audio sample, its text is converted to a sequence of phonemes in IPA, and each phoneme is represented by a learnable vector embedding. The sequence of vector embedding is passed to a transformer encoder to produce the feature representation of the text content. Denote this feature as L is an element of Real c times l, where c is the number of feature channels and l is the number of phonemes in the input text. The audio waveform is processed by the encoder and flow layers to produce the feature representation Z is an element of Real c times t, where t is the length of the features along the time dimension. Then we align L with Z along the time dimension using dynamic time warping, an alternative is monotonic alignment, to produce L bar is an element of Real c times t, and minimize the KL-divergence between L bar and Z. Since L bar does not contain any tone color information, the minimization objective would encourage the flow layers to remove tone color information from their output Z. The flow layers are conditioned on the tone color information from the tone color encoder, which further helps the flow layers to identify what information needs to be eliminated. In addition, we do not provide any style or language information for the flow layers to be conditioned upon, which prevents the flow layers from eliminating information other than tone color. Since the flow layers are invertible, conditioning them on a new piece of tone color information and running its inverse process can add the new tone color back to the feature representations, which are then decoded to the raw waveform with the new tone color embodied. Three. Experiment. It is hard to be objective in the evaluation of voice cloning for several reasons. First, different research studies usually have different training and test sets. The numerical comparison could be intrinsically unfair. Even though their metrics such as Mean Opinion Score can be evaluated by crowdsourcing, the diversity and difficulty of the test set would significantly influence the results. For example, if many samples in the test set are neural voices that concentrate on the mean of human voice distributions, then it is relatively easy for most methods to achieve good voice cloning results. Second, different studies usually have different training sets, where the scale and diversity would have considerable influence of the results. Third, different studies can have a different focus on their core functionalities. OpenVoice mainly aims at tone color cloning, flexible control over style parameters, and making cross-lingual voice clone easy even without massive-speaker data for a new language. These are different from the objectives of previous work on voice cloning or zero-shot TTS. Therefore, instead of comparing numerical scores with existing methods, we mainly focus on analyzing the qualitative performance of OpenVoice itself, and make the audio samples publicly available for relevant researchers to freely evaluate. Accurate Tone Color Cloning. We built a test set of reference speakers selected from celebrities, game characters and anonymous individuals. The test set covers a wide voice distributions including both expressive unique voices and neutral samples in human voice distribution. With any of the 4 base speakers and any of the reference speakers, OpenVoice is able to accurately clone the reference tone color and generate speech in multiple languages and accents. We invite the readers to this website for qualitative results. Flexible Control on Voice Styles. A premise for the proposed framework to flexibly control the speech styles is that the tone color converter is able to only modify the tone color and preserves all other styles and voice properties. In order to confirm this, we used both our base speaker model and the Microsoft TTS with SSML to generate a speech corpus of 1K samples with diverse styles, emotion, accent, rhythm, pauses and intonation, as the base voices. After converting to the reference tone color, we observed that all styles are well-preserved. In rare cases, the emotion will be slightly neutralized, and one way that we found to solve this problem is to replace the tone color embedding vector of this particular sentence with the average vector of multiple sentences with different emotions from the same base speaker. This gives less emotion information to the flow layers so that they do not eliminate the emotion. Since the tone color converter is able to preserve all the styles from the base voice, controlling the voice styles becomes very straightforward by simply manipulating the base speaker TTS model. The qualitative results are publicly available on this website. Cross-Lingual Voice Clone with Ease. OpenVoice achieves near zero-shot cross-lingual voice cloning without using any massive-speaker data for an unseen language. It does require a base speaker of the language, which can be achieved with minimum difficulty with the off-the-shelf models and datasets. On our website, we provide an abundance of samples that demonstrate the cross-lingual voice clone capabilities of the proposed approach. The cross-lingual capabilities are two-fold: When the language of the reference speaker is unseen in the MSML dataset, the model is able to accurately clone the tone color of the reference speaker. When the language of the generated speech is unseen in the MSML dataset, the model is able to clone the reference voice and speak in that language, as long as the base speaker TTS supports that language. Fast Inference with Low Cost. Since OpenVoice is a feed-forward structure without any autoregressive component, it achieves very high inference speed. Our experiment shows that a slightly optimized version of OpenVoice, including the base speaker model and the tone converter, is able to achieve 12 times real-time performance on a single A10G GPU, which means it only takes 85 milliseconds to generate one second of speech. Through detailed GPU usage analysis, we estimate that the upper bound is around 40 times real-time, but we will leave this improvement as future work. Importance of IPA. We found that using IPA as the phoneme dictionary is crucial for the tone color converter to perform cross-lingual voice cloning. As we detailed in Section 2 point 3, in training the tone color converter, the text is first converted into a sequence of phonemes in IPA, then each phoneme is represented by a learnable vector embedding. The sequence of embedding is encoded with transformer layers and compute loss against the output of the flow layers, aiming to eliminate the tone color information. IPA itself is a cross-lingual unified phoneme dictionary, which enables the flow layers to produce a language-neutral representation. Even if we input a speech audio with unseen language to the tone color converter, it is still able to smoothly process the audio. We also experimented with other types of phoneme dictionaries but the resulting tone color converter tended to mispronounce some phonemes in unseen languages. Although the input audio can be correct, there is a high likelihood that the output audio will be problematic and sounds non-native. Four. Discussion. OpenVoice demonstrates remarkable instance voice cloning capabilities and is more flexible than previous approaches in terms of voice styles and languages. The intuition behind the approach is that it is relatively easy to train a base speaker TTS model to control the voice styles and languages, as long as we do not require the model to have the ability to clone the tone color of the reference speaker. Therefore, we proposed to decouple the tone color cloning from the remaining voice styles and the language, which we believe is the foundational design principle of OpenVoice. In order to facilitate future research, we have made the source code and model weights publicly available. References to eighteen other publications in text.

Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html Rahan. Episode Seventy Two. By Roger Lecureux, drawn by Andre Cheret. The Mud that Devours. The strong smell of mud that floated over the marsh he had just crossed had hidden from him that of the hunters who lay in ambush. That was why the son of Crao had no time to react. Do not resist, "Fire Hair"! This spear will open your heart! But the faces of these three men surprised him even more than the ambush itself! Age alone differentiated these faces whose features were identical. As if each face was a reflection of the two others! Perhaps the stranger with the “Fire Hair” does not come as an enemy? Why capture him? All those who come from beyond the Troubled Waters are enemies! Let me kill him! You are not wearing the "Sacred Bracelet", Queha! Only Nahor has the right to decide the fate of this man! Page Two. Entering the nearby village, Rahan felt like he was living a strange dream. All the children looked the same! All the teenagers looked the same! All adults looked alike! And all the women looked the same too! The same features, the same looks, and the same smiles! In fact, it was impossible to distinguish one from the other! The son of Crao quickly understood that the members of this strange clan recognized each other by their voices! Their leader appeared. And Rahan noticed the heavy vertebra that encircled the man's wrist. By the "Sacred Bracelet" which gives him all powers, Nahor orders. The death of the one who came from the “troubled waters”! He will be delivered at dawn to the “Muds-that-devour”! Nahor has spoken! Some hunters cheered the brutal verdict. Page Three. But others protested. You are very cruel, Nahor! Why steal the life of a hunter we know nothing about!? Because Nahor hates those who do not have our face! And as long as he wears the “sacred bracelet” he must be obeyed! This is the law of the clan! Suddenly screams arose! Gahur! Gahur just fell into the green water! He is going to be eaten! The whole clan rushed towards the pond, uttering cries of anguish, and helplessness. They do not know how to "Crawl on water"! If Rahan saves Gahur, maybe he will gain their trust! Believing that his prisoner had escaped, Nahor wanted to cling to Rahan. He found himself on the ground. You will not get far, "Hair of Fire"! We will find you! Page Four. On the shore the masses of women imploring the spirits. The men, resigned, looked at the child who, a few stones throw away, was going to drown. Step aside! Step aside! Rahan will save Gahur! A clamor of astonishment greeted the plunge of the son of fierce ages. Down there, the child had just sunk! And Rahan was already joining him, bringing him back to the surface. Life has not yet left the little man! Throw your assegais! Kill him! Kill him! Hate blinds you, Nahor! You forget that he wants to save Gahur! On the shore, men were shouting. The “Bad” ones of the clan had no doubt. They will not be able to join Rahan on this island! The son of Crao swam vigorously towards the island, in the middle of the pond. Page Five. He had noticed the large vertebra attached to the child's wrist. This one was recovering his spirits. Gahur was playing on a stump in the middle of the green water. He slipped. What does this over-sized bracelet mean to you, Gahur? It means that Gahur, one day, will be the leader of the clan like Nahor is today! Gahur mentioned the custom of his clan, where every two “Seasons-of-green-leaves,” the one who one day would become the leader was selected. He was entrusted with a “Sacred Bracelet” which he was never to take off. Thus live together the future leaders of ten, twelve, fourteen, and sixteen "Springs." He, Gahur, was the youngest. And it is Nahor-the-cruel, the oldest, who currently reigns over the clan. Not all hunters approve of Nahor, but they must respect his law! Page Six. From the shore, men were still shouting threats. Rahan could easily escape them! But how would Gahur rejoin his people? The son of fierce ages waited for nightfall. Hold on to Rahan, Gahur! Rahan will take you back to your brothers! Returning to this shore carried great risks. Yet, with the night, a reassuring calm had settled on this shore. Perhaps the hunters convinced Nahor to let you live? Gahur had not expressed this hope that. Chtok! Argh! Ha-ha-ha! Nahor knew you would come back! It is the “Mud-that-devours” that is waiting for you! Page Seven. The son of Crao was taken into the village, near the totem topped with a "skin of wood" skull. They had left him his knife. But the way he was restrained prevented him from grabbing his weapon. When the sun rises over the green water, the captive will die! Let everyone return to their huts! An old man lingered. You saved little Gahur, and Nahor demands your death! It is cruel, but we cannot do anything for you! We cannot violate his law! When Nahor dies, Ro-A will succeed him. Ro-A is good. His law will be better. Why did you leave Rahan his knife? Because Nahor hates everything that lives elsewhere. And things made by men! The old man left grumbling. Page Eight. Abandoning the captive to his thoughts. The marshes shimmered under the moon and Rahan imagined himself getting bogged down in the “Mud that devours.” The idea of this atrocious death shook him. No! No! Rahan must flee! He undoubtedly has allies in this clan. But how would he know his friends from his enemies among all these hunters who look alike, like the “tears of the sky”! All his efforts to break his bonds remained in vain. But suddenly. The skull of the “wood skin”! His teeth! They will cut the vines! He dragged himself to the bamboo-totem. He shook it with his shoulders. If the skull falls next to Rahan, the noise will alert the hunters! Page Nine. After many shakes, the skull finally wobbled. Rahan, although hampered, tried to place himself under it’s landing point. But he did not succeed! Crash! A dull noise resounded which seemed louder than an “Angry cry from heaven." He leaned back. Because a young hunter came running, identical to all those of his age. Friend? Enemy? How to find out! A future chief! He is going to see the skull! The hunter was indeed wearing the vertebra on his wrist. Did you call, “Fire hair”? I am Ro-A. But I cannot do anything for you! This is the law of Nahor! When I am chief, my law will be very different. Yes, different. Ro-A retreated into his hut. Rahan was sure he had seen the skull on the ground, but had pretended to ignore it! Page Ten. Ro-A is therefore on Rahan's side! Ah, why do these men all look the same! Sawing on the crocodile's jaw, the vines gave way one by one. And the son of Crao, free, leapt towards the forest. But worrying shimmers stopped him. Mud! In the night, Rahan will throw himself into the “Mud that devours”! As he sought refuge in a tree, he wandered through the marshes which surrounded the village. Rahan will wait until daylight to flee! It was a little before daybreak that clamors alerted him. They were coming up from all sides. The whole clan is on the hunt! They are tracking Rahan! Oh! Howls of terror suddenly covered the clamors. A lone hunter was sucked into the mud! It is too horrible! Rahan cannot let him die! Page Eleven. The son of fierce ages tore the man from the devouring mud and dragged him onto dry land. Ra-ha-ha! And it was only then that he saw the “Sacred Bracelet.” He had just saved Nahor himself! Ha-ha-ha! This mistake will ruin you, “Fire hair”! Crack! Argh! The leader rushed like a beast. Rahan, dazed, caught a glimpse of Nahor lifting a huge stone above him to finish him off! Page Twelve. The instinct of self-preservation made him suddenly relax his legs. He avoided the stone. And still dazed, saw the other man quickly become engulfed in the mud. Argh! The wrist with the “Sacred Bracelet” was about to disappear under the mud when hunters appeared. Screams erupted. Cries of vengeance or cries of deliverance? Rahan never knew, as he preferred to escape. Come back “Hair of Fire”! Come back! Since Nahor is no more, Ro-A becomes our leader! His law will be just and good! Come back, you who saved Gahor, come back! Rahan was already too far away to hear. Jumping the pockets of "Mud-that-devours", he had only one goal. To flee this strange clan. Flee this clan where it was impossible to distinguish the "Good" from the "Bad", and the friends from the fiercest enemies.

Rahan. Episode Seventy-One. By Roger Lecureux, drawn by Andre Cheret. The Sacrifice of Maoni. With a pounding heart, and holding out the offering of pink water lilies, the son of Crao slowly climbed the staircase cut into the rock. Let all the hunters leave the cave! Only Rahan has won the privilege of seeing Maoni's face! Page Two. It all started the day before, in the heart of the mosquito-infested swamps. Rahan knows how to keep the “biting beasts” away! They fear the smell of “Sun Fruits”! The cloud of insects that harassed him actually moved away as soon as he coated his body with lemon juice. It is a wonderful secret that Crao taught Rahan! He thus crossed the marsh, no longer worrying about the terrible mosquitoes which swirled around him without daring to attack him. Here and there the water lily flowers had the color of the sky in the east. He finally hoisted himself onto dry land, when. Oh! Rahan did not want to interrupt your meal, "Long-tongue"! The son of Crao had never seen an anteater before. He preferred to flee this beast which, abandoning the anthill, suddenly charged him. Rahan is not an ant, "Long-tongued"! He is not! Oh! Page Three. Stumbling on a root, he did not have time to get up. The big anteater was on him. His claws were going to lacerate his face. The ivory blade disappeared into the thick fleece. The blow had been so precise. Ra-ha-ha! That the beast, as if struck by lightning, collapsed instantly. Rahan did not want to take your life "Long tongue"! But he could not let himself be torn apart! The son of fierce ages had not sheathed his knife when ten men burst out of the thickets. In this territory the “Tamas” are sacred, “Fire Hair”! Because they devour the ants that our hunters fear so much! But since you came to the aid of the “Beasts-who-gnaw”, we will see if they are grateful to you! Bury him up to his neck, brothers! Page Four. A little later. Ha-ha-ha! Before the sun returns, "The beasts-that-eat" will have devoured your eyes, your ears, and your tongue! Farewell, "Hair of fire"! Rahan's passage to the realm of shadows will be terrifying! All around the torture place, large red ants were swarming. Their circle tightened. Innumerable, the “Beasts-that-eat” attacked his face. No! No! As he screamed in pain, some rushed into his mouth! It was then that other men appeared. Quickly! Free this unfortunate man! Quickly! Chase away the “Eating Beasts”! Quickly! While the tide of ants ebbed before the torch fire, the son of Crao was released. Rahan did not know that the "Tamas" were sacred. He killed one to defend himself. And the hunters, to punish him, delivered him to the “Beasts-who-gnaw!” Page Five. You had the misfortune of meeting Wramm, the cruelest hunter of the cave clan. In other times, this clan and ours clashed constantly! Kill those from the forest! Kill! Kill! But one day Haika, the leader of those of the caves, and his daughter Maoni, lost their way in the swamps. Haika was swallowed up by the "Mud-that-devours”. Maoni was saved by her people, but her face had been eaten by the “Beasts-that-gnaw”! This face was so horrible that she now hid it under a hood of skin! Wramm had hoped to succeed Haika, but the cave clan chose the sweet Maoni, the faceless girl, as its leader! And the forest clan could only rejoice at this choice! Page Six. Because Maoni is good and loyal! Thanks to her, our clans live in peace! Where does the cave clan live? Rahan must take back his knife from Wramm! Wramm is dangerous! Beware of him. Rahan will take back his knife! Along with the necklace of claws left by Crao, the ivory weapon was Rahan's most precious possession! Look! The “Beasts-that-gnaw” have spared “Hair-of-Fire”! What? What!? Wramm's astonishment was very short. Wramm will kill you! With your own knife! The son of fierce ages dodged the first assault of the colossus. Ra-ha-ha! Page Seven. But was knocked down at the end of the second! The ivory blade was about to plunge into his chest. When. Stop Wramm! You must remember that I forbade all fighting between "Those Who Walk Upright"! What did this hunter do? He killed a big “Tama”! He is an ally of the beasts that ate your face, Maoni! He must die! Rahan had never seen a “Tama” before. He did not know. He killed to protect his life! Maoni Believes Rahan! She asks the clan to welcome him like a brother! Why does a leader as generous as you hide his face? Because it is too horrible! By designating me as leader, the clan swore that only those who brought me a bouquet of water lilies could see it! That is impossible. Page Eight. Since these water lilies grow in the middle of the marsh, everyone who tried to approach them had to back away from the “Stinging Beasts.” The venom of these “beasts” makes the body swell and sets the blood on fire! Some died! Rahan will bring you the pink flowers, Maoni! Ha-ha-ha! So you think you're a god!? Well go, Rahan, go. The land of shadows awaits you! Rahan is so sure he will return that he leaves you his knife Wramm! No, Rahan! Do not do that! Why risk your life? Because you deserve pink flowers, Maoni! The son of Crao disappeared under the foliage. No one saw him smear his face, torso and limbs with the juice of the “Sun Fruits”. Poor Maoni! Her face must be scary! But her heart is so generous! Page Nine. When the cave clan saw him again he was already in the middle of the swamp. The mists were dissipating. They could not see the myriads of mosquitoes. But they guessed they were there. Harassing the hunter called “Hair of Fire”. And the "biting beasts", in fact, swirled in clouds around the son of Crao. Who was now tearing off the marvelous pink flowers. And the cloud of mosquitoes surrounded him. Escorting him on the way home! After the “beasts-that-gnaw”, it is the “beasts-that-bite” who spare this demon! The cloud dissipated under the dry breeze coming from the mainland. Under her skin hood Maoni sighed. He succeeded. I must respect clan law. I have to show him. My face! Page Ten. When the son of Crao approached Maoni, Wramm could not control his rage. Die, All who have come to violate our laws! The thick armful of damp leaves saved Rahan. This time, Wramm the brute deserves to be punished! Wramm had the impression that lightning, choosing its target, was opening his stomach. Argh! Ra-ha-ha! Rahan did not violate any of our rules! He brought back the pink water lilies. He therefore has the right to see what remains of the face of Maoni, the daughter of Haika the cheif! A little later. Get out of the cave! Get out! May my face not haunt the nights of those who knew not how to bring the offering of pink water lilies! Page Eleven. As Rahan climbed the steps, the hunters respectfully slipped away. When Rahan has revealed to yours the secret of “Sun Fruits.” They could too, go and pick the pink flowers and earn the right to see your face, Maoni! The son of Crao placed the offering at the feet of Maoni. Keep your secret, Rahan! The clan has obeyed me from the day I was disfigured by the “Eating-Beasts.” I have got them to live in peace with those in the forest! If mine saw what you are about to see, their respect for me would disappear. The war with the other clans would perhaps resume. Maoni slowly raised her hood. And the emotion, the stupefaction, petrified the son of Crao. My people must never know, Rahan! Swear to me not to reveal my secret! Page Twelve. The face of Maoni was the purest, the most beautiful that anyone could see! Over time, my wounds healed themselves! But if the clan knew that I recovered my former appearance. I would lose my authority! Wramm would lead the hunters on the evil paths of war! Rahan will never betray your secret Maoni! Never! Never! During his long stay among this clan, the son of Crao kept his word. But he often had to lie. Maoni's face? A horrible thing Wramm! Bare bones. Bitten lips. Eyes without lids. When he consulted his knife before leaving for new horizons, Wramm himself seemed to regret his departure. You taught us so many things! And Rahan must teach them to others. And the son of wild ages bid farewell to those of the caves. He knew that he would never forget the alert face of Maoni, this young girl who sacrificed her beauty and her youth for the sole happiness of her own! Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html

Rahan. Episode Seventy. By Roger Lecureux, drawn by Andre Cheret. The spirits of the night. The son of Crao had already seen mammoth cemeteries but the one he had just discovered was more impressive than all of the others. What mysterious instinct drives the “Two-tooths” to come and die in the same place? Suddenly! Crack! Ohh! The shock was very violent Argh. Rahan will not be able to run for a while! His leg was sore, but it was just a strained muscle. Page Two. It was with a limp that he approached the extraordinary tangle of carcasses eaten away by the rains and the winds. There was a sickening odor of rotting flesh floating there. Here, the bones had been crushed under the rocks that had been spat out by the volcanoes. Elsewhere, a lava flow had charred them. A fine dust of sand and bone ashes accumulated in the crevasses in the cracked ground. The son of Crao suddenly felt that he was being observed. And he saw the hyenas following him at a distance. He hated these disgusting beasts. You dare not attack Rahan, you corpse eaters. You wait for him to fall! The pack was indeed watching for the collapse of the man, whom they felt was handicapped. As Rahan had just jumped a small crevasse his bruised leg gave way. And. Argh! Page Three. He collapsed, falling flat on his back! With wild growls, the hyenas turned towards this prey, which they had at their mercy. Rahan is not dead yet! Back “Corpse Eaters!” The ivory blade cut the most daring of the attackers. And it cut the throat of their successor! Ra-ha-ha! A blow to the flank of the third had such a jolt, that the son of Crao felt his knife escape! Oh! But he no longer had anything to fear from the snarling beasts who left him to tear their fellow creatures to shreds! Back! Rahan wants his knife! Page Four. His ivory knife was still stuck in the side of the beast that the pack was fighting over, at the edge of a narrow crevice. Back! Back! Back! His disgust and anger were such that Rahan no longer felt the pain. Argh! And the Hyenas cowardly abandoned a fight that had became too difficult! The son of Crao returned to the rift to find the beast dead and. Oh! His knife, which had detached itself from the flesh, had disappeared! He saw it at the bottom of the crevasse, more than three meters deep, stuck in the bone powder. Inaccessible! Rahan needs a branch. Or a line. Shortly after, he had his first failure. The ivory weapon slipped on the fork and fell flat! It no longer offered a hold. Page Five. To the loop of the lasso that Rahan tried in vain to slip around the handle! Will Rahan have to abandon his knife!? This thought of losing his weapon forever was intolerable to him, but suddenly. The fork cannot grip the knife! Neither can the lasso! But both together!? Once again, Rahan's spirit of deduction worked wonders. Maintaining the slip knot, and using the forked hook. He was able to pass the loop around the weapon, gently tightening the loop. Which was impossible without the fork! Ra-ha-ha! He could recover his ivory knife! And his clamor of victory thundered on the cemetery of the “Two-teeth.” Page Six. He happily sheathed it when a long trumpet sound rose up. The “Two teeth” walks like Rahan! A young mammoth was walking, helplessly. He hesitated to place one of his hind legs on the ground. Since we have the same illness, we are brothers! Let Rahan come near you, "Two-tooth"! He might be able to do something for you! The mammoth stood still. Leaning on the carcasses of his ancestors. He did not flinch when the son of Crao revealed his heavy paw. A spear flint! In a moment you will feel better than Rahan! Extracting the spear point was easy. You are cured, "Two-tooth"! And now what are you going to do? Charge Rahan? Page Seven. The young pachyderm, relieved of the pain, observed the man for a moment. You do not charge? Rahan did not know that the "Two-Tooths" could be grateful! The mammoth fled, almost light on his feet. Jostling the bones where he had perhaps thought he would come to die. The son of Crao was happy. Even happier that the pain was finally going away from his leg. Before the moon comes, Rahan will be far away! He will have a sweet night! Rahan could not have known how tormented and fantastic this night would be. It all started with the hunters who emerged from the forest, surrounding him with a circle of hatred. Do not kill the enemy with the "Hair of Fire"! Capture him alive! We will sacrifice him to the moon! Page Eight. Assailed by a group of men, he resisted fiercely. But. Zlang! Argh! When he regains his senses, he noticed that he had been left with his knife. Rahan is not an enemy. He does not want to. Silence “Hair of Fire!” All those who do not belong to our clan are enemies! The son of Crao's rope was pulled unceremoniously. To the hunters' camp. Page Nine. When our mother the moon shines on the top of the great mountain we will offer her your life! He was firmly attached to a long flat rock, undoubtedly the altar where these moon worshipers sacrificed their captives! The clan leader harangued his people. Makawa will kill "Fire Hair" himself! May Mother Moon thank us by recalling to her of the “Spirits-of-the-Night”! What were these “Night Spirits” that these men seemed to fear? Rahan will never know! These bonds are far too strong for him to break! Welcome to our territory, “Mother-moon”! Your sons beg you once again to scare away the spirits of the night! In the rapidly darkening sky the moon appeared. In a moment, Rahan will join the “Territory of Shadows”! The moon was gliding across the sky, slowly approaching the top of the great mountain. Page Ten. When it shone like a crown at the tip of the mountain, Makawa approached. Your impure blood will not stain our weapons! Makawa will kill you with your own knife! Makawa offers you the life of “Hair of Fire,” “Mother-Moon”! The chief's hand closed on the ivory handle. Nothing could save the son of the fierce ages! He drew the knife. Brandished it to strike and. Screamed in fear! “Hair-of-Fire” is a spirit of the night! The blade was giving off a strange green light! Terrified, Makawa dropped the weapon and retreated towards his people who, in panic, were fleeing in all directions. Pardon “Mother-Moon!” Pardon! What a strange thing! Where does this power come from? Astonished, Rahan observed the blade which shone like a glowworm! Page Eleven. Unable to explain this miracle, he contorted himself to bring the weapon closer to his bonds, but his efforts were in vain. And his helplessness reassured the “Worshipers of the Moon.” A true “spirit-of-the-night” could be freed! His weapon is that of a "Night-Spirit.” But he is not a spirit! Let us kill him! The son of fierce ages, his throat tight with anguish, saw the hunters approach with their spears raised. Suddenly! If you kill this stranger, we will make you pay for his death! The clamors had resounded behind them. The warning reverberated into the night! Page Twelve. It was panic again! The spirits of the night! The Spirits of the night! And Rahan believed he saw ghostly greenish beings. Luminous as the blade of his cutlass, approaching the altar! Their axes cut through the bonds. Makawa and his people are savages! Flee this territory, brother! Only we can survive it! Run away and good luck! The son of Crao had no time to thank his saviors. The phosphorescent group was already moving away. And “were extinguished” in the dense thickets of the forest. Rahan has often seen strange things, but nothing more astonishing than these "Luminous Men"! Page thirteen. And you, faithful knife!? Did you never shine like that on other nights? As he had just stroked the blade with his fingertips. Rahan exclaimed. His fingers, too, glowed in the dark! Oh! Rahan Understands! It is the dust that glows. The dust of the “Two-Teeth”! He saw his knife again at the bottom of the crevasse, stuck in the bone ashes. Was not that the origin of the mysterious phenomenon? Perhaps the Night Spirits are just simple hunters who coat their bodies with this powder!? Rahan wants to know! The son of wild ages only returned to the mammoth cemetery in the early morning. The hyenas had been devoured. The vine with which he had recovered his weapon was still there. Page Fourteen. It allowed him to take some mysterious bone powder from the bottom of the rift. With which he carefully coated his torso, his limbs and his face. Why does the dust of the “Two-tooths” only shine in the darkness? Rahan could not know, he would never know, that natural and complex chemical phenomena had transformed this bone ash into the "Phosphor." He impatiently awaited the return of the night. When Makawa and his clan found him by chance. “Fire-hair” Is Not a “Spirit”! This time he will not escape us! Oh! Cornered against the rocky wall, the son of Crao could no longer escape! The first lances, thrown from afar, narrowly missed him. Zlang! Page Fifteen. When they are closer, they will not miss Rahan! Oh! Zlang! Zlang! Schtok! The “Two-Teeth”! The young mammoth he had come to the aid of was furiously charging at the "Moon Worshipers." Who had to face it! Taking advantage of this unexpected diversion, Rahan set off towards the forest. Brave “Two-tooth”! You gave your life to save Rahan's! His body riddled with spears, the young pachyderm moved away. He collapsed on his knees, and got up again. Would he have time to reach the mammoth cemetery? Rahan hoped so. Makawa and his wild pack immediately resumed their manhunt. They had seen the fugitive take refuge in the kingdom of the “Four-Hands” Page Sixteen. They pursued relentlessly, screaming with hatred as soon as they caught a glimpse of Rahan moving from line to line. Kill! Kill! And for the son of Crao it was suddenly a tragedy. The forest ended there! The tree into which he had thrown himself with a fantastic leap. Was the last! Unable to turn back he found himself on this isolated tree. At the mercy of the pack. Projectiles were already whistling from all sides! And the most daring climbed the trunk. Rahan hates killing "Those-Who-Walk-Upright." But he will be forced to defend his life. But this fight that Rahan feared so much did not take place. Cries of terror rose in the twilight. “Hair of fire” is a “night-spirit”! Flee! Run away! Page Seventeen. High above, in the shadow of the foliage, the son of Crao stood in a greenish halo! In an instant, he had become a “Luminous man”! A “Spirit-of-the-night”! It was a stampede. Mother Moon will never forgive us for chasing a spirit! Let us run away! Flee! Rahan was coming down from his refuge when the thickets parted in front of a few men of light. We are happy to see you alive, brother! When we heard the cries of these savages, we feared for you! It is the "Powder-that-Lights-At-Night" that saved Rahan! Yes brother! It is thanks to it that we survive in this territory! Makawa and his wild beasts think that we are "Envoys of the Moon" and "Spirits of the Night"! They fear us, and flee from us! Page Eighteen. The powder is the only way to protect us from these demons! Since you have discovered our secret, I hope you will not betray us brother! Rahan is always faithful. And he hopes that you will convince Makawa and his people not to behave like hyenas! Farewell, brothers! Rahan cannot wait to leave this territory! When the Son of Crao crossed the river, the greenish fluorescence stretched in his wake. He regained his appearance! It was rare that he did not fight bad deeds and actions himself. But he knew that the "Men of light" had no need of him. Arriving on the other bank, he saluted them one last time then left. Rahan will never forget that he too was a “Spirit-of-the-night”! But why? Why? In these fierce times, nature preserved its secrets! It was only tens of thousands of years later that man would discover phosphor, and its properties. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749320/pdf/jcp-26-4-224.pdf https://rumble.com/v3t4yzj-index-of-science.-music-by-dan-vasc.html Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy. An average quality review by Chiara Vidoni, Laboratory of Molecular Pathology, University oriental pasta, Novara, Italy. Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of calorie intake, is gaining attention as a potential adjuvant intervention for preventing and, or fighting cancer. Several forms of energy reduction intake, which include caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow cancer progression. Additional anti-cancer approaches under investigation rely on the use of nutraceuticals known as “Caloric Restriction Mimetics” that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing caloric intake have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient, energy intake experience improved outcomes from chemo and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed. Key Words. Ketogenic diet, Warburg effect, Caloric restriction mimetics, Tumor microenvironment, Drug therapy. Introduction. Calorie restriction (CR) consists of a 20 to 40 percent reduction of the average daily caloric intake without incurring malnutrition or deprivation of essential nutrients. It encompasses the restriction of specific hyper caloric nutrients, which can be substituted with others, that are metabolized with less production of energy. Mammals undergo a metabolic adaptation in response to food restriction. The circulating glucose concentration is the first biomarker to decline under CR condition, which results in the utilization of stored glycogen as a main energy source. Once the glycogen stocks are depleted, the organism utilizes glycerol and fatty acids mobilized from the adipose tissue, and thus ketone bodies become the main fuel. CR has a huge impact on promoting longevity by delaying the severity and the onset of inflammatory and several age-related diseases including obesity, cardiovascular, neurodegenerative and ophthalmic disorders, and cancer. Such pleiotropic effects rely on several mechanisms, although the principal common denominator is the ability of CR to dampen the oxidative stress and inflammation. Aging is one of the major risk factors favoring the development of many cancer types. Epidemiological studies reveal that five out of six cancer-related deaths occur in patients aged 60 years and older. The continuous exposure to carcinogenic factors, which leads to the accumulation of mutations and epimutations in cancer-sensitive genes surely accounts for the increased risk of cancer development with aging. Additional contributors are: The progressive decline of the immune surveillance, the efficiency of DNA repair and of autophagy. The dysregulation of the inflammatory process. The increased production of reactive oxygen species (ROS). Increased levels of circulating insulin and Many other hormones promoting cell growth, and other factors. CR may arrest and slow-down age-related decline of cellular protective systems, especially by improving autophagy and dampening inflammation and ROS production, as well as reducing circulating growth hormones, and this could result in reduced risk of cancer. Preclinical and preliminary clinical data support the view that reducing calorie intake as well as periodic fasting or dietary restriction, in which intake of macronutrients is limited with no reduction in total calories, has the potential to prevent and treat cancer. Typically, in a CR or dietary restriction regimen, carbohydrates, the main source of energy in the regular diet, are reduced and replaced partially or nearly completely, as in the ketogenic diet, by fat. Indeed, reducing sugar intake seems to be a good strategy to fight cancer, given that cancer cells use glucose as the main fuel. Likewise providing ketones as an alternative energy source may limit cancer growth because cancer cells do not efficiently harness ketones for their anabolism. Here, we describe the cellular and molecular mechanisms underlying the pathophysiological effects of calorie and nutrient restrictions and review the scientific proofs of their beneficial effects in preventing cancer onset and progression as well as in improving the anti-cancer therapeutic effects. We also discuss the anti-cancer effects of drugs and nutraceuticals with proven caloric restriction mimetic (CRM) activity. Finally, we present the clinical trials currently investigating the efficacy of caloric restriction dietary regimens as an adjuvant therapy in anti-tumor treatment. Molecular and cellular effects of calorie restriction at a glance. For a long time, the beneficial impact of CR was regarded merely as the result of the passive effect of nutrient limitation and of a slow metabolism. It is now recognized that the organismal effects of CR are actively regulated processes aiming to reduce oxidative stress, and that CR triggers a robust defense program involving multiple metabolic pathways in which nutrient sensors are centrally positioned in such regulation. However, the effects of CR depend on multiple factors such as individual characteristics and the dose and timing of CR. The metabolic adaptations to CR include: (1) A decrease in growth factors and production of anabolic hormones. (2) An upregulation of anti-oxidant systems, which in turn decreases free radical-induced DNA damage. (3) A downregulation of pro-inflammatory cytokines and an increase in circulating levels of corticosteroids, ghrelin and adiponectin, collectively resulting in the reduction of inflammation, and (4) A delay of aging-associated deterioration of host immune surveillance. More in detail, many of the benefits exerted by CR are associated with the upregulation of genes promoting DNA repair, for example, genes belonging to the base excision repair pathway, the removal of damaged cells through apoptosis, autophagy, stress response and anti-oxidant defense, in parallel with the downregulation of pro-inflammatory genes and of energy metabolism pathways. Particularly, autophagy represents the primary stress response to calorie and nutrient restrictions. This process is in fact regulated mainly by two pathways that sense the lack of energy sources and ATP production in the cell, via the AMP-activated kinase (AMPK) and hexokinase 2 (HK2) mTOR complex 1 (mTORC1) pathway, and the lack of growth factors and of amino acids, via the protein kinase B (AKT)-mTORC1 pathway, Figure 1. Autophagy, herewith referring to macro autophagy, consists in the p62, SQSTM1-mediated entrapment of cellular components, such as protein aggregates, membranes, and mitochondria (mitophagy) along with portions of cytoplasm, within a double-membrane organelle named the auto phagosome that upon fusion with the lysosome determines the degradation of those components. This process is regulated by several signaling pathways and autophagy-related (ATG) proteins that also include oncogene products and tumor suppressors, which explains why this process is dysregulated in cancer. Under metabolic stress conditions such as those determined by the lack of nutrients, amino acids, glucose, and of hormones and growth factors, autophagy is upregulated to provide energy and substrates from degradation of redundant cell components. As illustrated in Figure 1: (1) Amino acids, especially, methionine, leucine and arginine, directly activate mTORC1, the mechanistic target of rapamycin complex 1, which then inhibits the axis Unc-51 like autophagy activating kinase 1 complex 1 (ULKC1)-phosphatidylinositol 3-kinase catalytic subunit type 3 (PI3KC3)-BECLIN-1 that positively triggers autophagy. (2) The presence of growth factors and hormones elicits the activation of mTORC1 via the PI3KC1-AKT pathway thus resulting also in inhibition of autophagy. (3) Soon after entry, glucose is phosphorylated to glucose-6-phosphate (G6P) by HK2, and this prevents HK2 from interacting and inhibiting mTORC1, and this results in inhibition of autophagy as well. Therefore, autophagy is maximally induced when all these nutrients and growth factors are absent in the tumor microenvironment (TME), as for instance that occurs during starvation. Upregulation of autophagy in cancer cells may have several beneficial outcomes in terms of improved DNA repair efficiency, improved TME, reduced growth and migration, invasive ability. Calorie restriction and cancer progression. From a molecular point of view, several signaling pathways collaborate and cross-talk to control carcinogenesis under CR conditions. To date, the major effectors known to be responsible for the CR-mediated anti-cancer activity include insulin-like growth factor-1 (IGF-1), phosphatidylinositol-3-kinase, PI3K, AKT, mTOR, the Sirtuin family proteins, Aldolase A (ALDOA), DNA-dependent protein kinase, DNA-PK, p53, NF-kappa B and AMPK signaling pathways. However, further studies aiming to characterize the molecular mechanisms by which CR mediates its cancer inhibitory effects are essential for development of new drugs and therapeutic regimens to prevent tumor initiation and, or interrupt tumor promotion and progression. CR can also modulate epigenetic changes, particularly DNA methylation, histone modifications, chromatin remodeling and generation of microRNA, which regulate the expression of genes involved in those processes responsible for CR anti-cancer activity. Notably, CR has been shown to have a wide impact not only on cancer cells but even on TME by allowing enhanced drug delivery, by decreasing the availability of substrate and growth factors for cancer cells, and by reducing inflammation. Tumor vascularization represents one of the most crucial steps in cancer progression by ensuring nutrients, soluble factors and oxygen to reach the tumor mass. CR has been capable of counteracting this aspect by hampering the secretion of pro-angiogenic factors such as VEGF, factor eight, interleukin-6, IL-6, TNF-alpha, plasminogen activator inhibitor-1, PAI-1, and others. Consequently, tumor neo-vascularization was delayed or even arrested as demonstrated by the reduction in the size, number and density of blood vessels in the CR-fed mice in comparison with the trends observed in ad libitum-fed ones. Additionally, CR can shape the tumor immune microenvironment by specifically decreasing the number of tumor associated macrophages, increasing the formation of a reservoir of CD8 plus cytotoxic T cells and memory T cells while negatively modulating immunosuppressive Treg cells’ activity and immunosuppressive cytokine levels. Other pivotal players in the TME are the cancer-associated fibroblasts. CAF’s, that by releasing onco metabolites, growth factors, inflammatory cytokines and proteolytic enzymes cooperate in the establishment of a malignant liaison between the stroma and cancer parenchymal cells. The evolution of tumor fibrosis, that originates from cancerous lesions, causes an excessive deposition of extracellular matrix and, as a consequence, damaged epithelial cells produce a large amount of pro-inflammatory and pro-fibrotic cytokines, leading to more and more aggravated deposition of collagen and fibrotic tissue. In this context, CR can elicit an anti-fibrotic effect by downregulating TGF-Beta signaling, that normally promotes the phenotypic conversion of normal fibroblasts in CAFs. In this respect, a highly dense and viscous stroma prevents the cells of the immune system to target the tumor, thus making it much more resistant. By preventing fibrosis, CR may facilitate the interaction of immune cells with cancer. The remodeling of the TME mediated by CR is schematically represented in Figure 2. Benefits of caloric restriction in anti-cancer therapy. To date, chemotherapy is one of the main therapeutic strategies for the treatment of several malignancies. However, this approach causes many side effects, such as cardio, neuro, haematological toxicity, nausea, gastrointestinal symptoms, fatigue, weakness, hair loss and stomatitis, that can negatively affect the cancer patients’ quality of life and cause discontinuity of the therapy. Disappointingly, most of the drugs used to manage the symptoms of toxicities may themselves have significant adverse effects. Although most of the available studies regarding CR in anti-cancer therapy are still in the pre-clinical phase, CR appears to be a promising approach to modulate the chemotherapy induced side effects while enhancing the efficacy of the treatment. Reduction of adverse effects would improve the quality of life and potentially reduce the costs of hospitalization as well as the use of drugs, for example anti-emetics, antibiotics. In detail, CR can induce healthy cells to invest their energy in reparation and maintenance pathways rather than cell proliferation. This effect promotes an increased resistance of normal cells to chemotherapeutic drugs known as “differential stress resistance”. On the other hand, cancer cells bearing mutations in oncogenes, for example, IGF-1R, Ras, AKT and and the mTOR pathways, that cause constitutive activation of proliferation pathways in external growth factor-independent manner, and onco suppressor genes, for example, p53, p16 and Rb, that cause insensitivity to growth-inhibitory signals, are not prone to adapt to fasting conditions and continue to proliferate at a high rate. This results in an enhanced sensitization of cancer cells to chemotherapy-induced apoptosis while protecting normal cells from such effect, leading to the so called “differential stress sensitization”. Several reports indicate that fasting potently triggers autophagy, both in normal cells and cancer cells, to recycle critical components and produce energy. The upregulation induction of autophagy before chemotherapy may protect benign cells by providing an alternative mechanism to remove damaged macromolecules and organelles, particularly when the proteasomal degradation pathway is saturated. However, autophagy may also play a pro-survival role in some cancer cells. On the other hand, over activation of autophagy may lead to what is referred to as autophagy-associated cell death. Given the complex role of autophagy in tumor biology, which is strictly dependent on the context and the stage of malignancy, further studies are needed to dissect the balance between benefits and side effects related to CR-induced upregulation of autophagy. Even though CR displays numerous benefits in anti-cancer therapy, the real applicability of fasting regimens in the clinical practice could be limited to a small subset of cancer patients, as some potential risks may be associated with this approach, such as malnutrition, cachexia and sarcopenia, that are strongly associated with chemotherapy-related toxicity, reduced response to cancer treatment, low quality of life and a worse overall prognosis. Another concern is related to the anti-inflammatory effect of CR that could be disadvantageous for those patients that experience immunodeficiency due to cancer progression and, or as a consequence of repeated chemotherapy treatments. Therefore, more tolerable adjuvant regimens should be developed. In this perspective, fasting-mimicking dietary interventions as well as CRM’s, that will be discussed more in detail in the next section, may represent a more feasible therapeutic approach to circumvent these limitations. Overall, the global impact of CR and CRM’s on the anti-cancer therapy is illustrated in Figure 3. Caloric restriction Mimetics. An alternative therapeutic strategy that extends life expectancy and improves health markers, while reducing the development of several age-related diseases, including cancer, involves the use of the pharmacological group of compounds known as CRM’s. These compounds act, either through direct interaction with signaling molecules or via epigenetic mechanisms, those pathways that are triggered when energy intake is reduced, yet in the presence of adequate nutrition. Many CRM’s are bioactive food components able to elicit anti-proliferative, pro-apoptotic and anti-metastatic effects, avoiding a fasting regimen that could not be tolerated by the cancer patient. The family of polyphenol substances are all a good source of potential CRM’s, since they have a wide range of biological activities, including anti-oxidant, anti inflammatory, anti-carcinogenic and epigenetic modulation activities. They include phenolic acids and derivatives, flavonoids, stilbenes, and coumarins. CRM’s modulate energy and nutrient-sensing pathway impinging on many biological mechanisms, including activation of autophagy, enhancement of insulin sensitivity, inhibition of oxidative stress and inflammation, and modulation of glucose metabolism. The molecular targets of CR involve sirtuins, acetyl-CoA, activated AMP protein kinase, insulin, and mTOR. CRM’s in clinical practice. We will focus on the beneficial effects of the most relevant and promising CRM’s, summarized in Table 1, both FDA approved and not yet approved, and will illustrate their potential clinical applications as new effective anti-cancer strategies. Resveratrol. Resveratrol, 3, 5, 4 tri hydroxyl stilbene, RV, is a natural stilbene compound present in vegetables and fruits in general, but especially abundant in grapes. RV acts as a CRM as well as a protein restriction mimetic. RV has pleiotropic beneficial effects not limited to cancer, but even to metabolic syndromes and neurodegenerative diseases. The tumor suppressive effects of RV on manifestation of malignant phenotype of cancer cells involve the repression of the drug resistance and metastatic ability, counteracting hypoxia, inhibition of inflammation and oxidative stress, and so on. In details, RV reverts cell invasion, which is promoted by high generation of ROS through activation of the Hedgehog pathway. Cumulative studies have illustrated the impressive anti-inflammatory properties of RV. In vivo experiments showed that mice treated with RV exhibit low levels of pro-inflammatory cytokines like TNF-alpha, IL-6, IL-1 and IL-8, typical biomarkers of the inflammation. Further, RV increases the number of T cells, specifically natural killer and CD8+ T cytotoxic cells, implementing anti-cancer immune surveillance. Another anti-inflammatory property mediated by RV is the suppression of the NF-kappa B pathway and of TNF alpha induced cancer cell migration and invasion. Additionally, RV can block tumor development by targeting cytochrome p-450 enzymes able to activate pro-carcinogenesis factors. Furthermore, RV positively impacts to expand lifespan as an epigenetic modulator, specifically through the activation of sirtuin deacetylases (SIRT1) and autophagy mediated via AMPK pathway. Besides limiting glucose uptake and reverting the inflammatory phenotype of CAF’s, RV is a potent autophagy inducer. Many preclinical and clinical trials in different types of cancer, for example, breast, colon, and prostate, support its anti-cancer effects. Although RV has many anti-carcinogenic properties, its poor bioavailability limits its clinical use. Nevertheless, there is evidence that RV, either alone or in combination with other agents, is active. Therefore, an alternative strategy is to modify the RV structure for improving its bioavailability and reducing its toxicity. Nowadays, it is clear that RV is a fascinating adjunctive cancer treatment when associated with standard chemotherapeutic agents, but there is still the necessity to define the optimal conditions to ameliorate the delivery and the efficiency. Table 1. Overview of the ongoing clinical trials with caloric restriction mimetics, CRM’s. The table reports the CRM’s that are employed in ongoing clinical trials in cancer patients. The table elaborated with data extracted from the clinical trials dot gov site. Curcumin. Curcumin is a polyphenol compound, FDA-approved, for CRM properties that has caught the attention of many researchers. It is the main bioactive compound isolated from the rhizomes of Curcuma longa (Turmeric). Several investigations have revealed the multitude of biochemical and biological activities of curcumin with therapeutic potential, including anti-inflammatory, anti-oxidant, anti-cancer and anti androgenic effects. Particularly remarkable is its anti-cancer activity exerted through induction of apoptosis, inhibition of cell proliferation and of tumor invasion, and downregulation of NF-kappa B, COX-2, and STAT3. Furthermore, curcumin counteracts the Warburg effect, meaning, the aerobic glycolysis occurring in cancer cells) via the suppression of pyruvate kinase M2 (PKM2). Additionally, curcumin suppresses the PI3K, Akt, mTOR pathway (by decreasing Akt and mTOR phosphorylation in parallel with PTEN upregulation) thus promoting cell death in cancer cells. Of note, curcumin also abrogates CAF-induced aggressiveness of cancer cells through the inhibition of the mTOR, HIF-1 alpha signaling. The anti-carcinogenic property of curcumin is well-documented in several types of cancer, which makes it a promising co-adjuvant agent in cancer therapy. Metformin. Metformin (dimethylbiguanide hydrochloride) is a derivative of natural biguanidines isolated from the French lilac, Galega officinalis, a plant used for the treatment of type 2 diabetes and metabolic syndrome since the nineteen sixties. Metformin administration is not yet certified as adjuvant of anti-cancer therapy. Mechanistically, it suppresses hepatic gluconeogenesis and decreases insulin levels thus acting as a hypoglycemic drug. This effect is attributed to the activation of energy sensor AMPK via the repression of the mitochondrial electron transport chain complex One, thus leading to the inhibition of mTORC1. For this reason, this molecule is associated with prolonged lifespan, promotion of autophagy, and suppression of oxidative stress and inflammation. As epigenetic modulator, metformin inhibits class two HDAC’s, while stimulates class three HDAC SIRT1 activity. Another important physiological action of metformin involves the immune system. This compound can modulate lymphocyte differentiation during the aging process, promoting CD8 plus memory T cell differentiation, and simultaneously reducing the expression of several pro-inflammatory cytokines. The latter aspect could represent a relevant opportunity to counteract the development of immune evasion within the TME. Taken together, metformin has crucial functions in modulating energy metabolism, while its capacity in retarding or contrasting cancer progression is less addressed. In addition, recent clinical trials are also testing its anti-cancer activity, especially in colon, breast, ovarian, prostate and lung tumors, however, further investigations are needed. Spermidine. Spermidine is a polyamine naturally found in a variety of foods, including wheat germ, soybean, mushrooms, and mature cheese. Further, it is produced by the intestinal microbiota. The effects of this polyamine include extending the lifespan in many model organisms, an effect correlated to induction of autophagy and inhibition of acetyltransferase activity. Moreover, spermidine stimulates AMPK, while it limits the mTORC1 activity. Predominantly, spermidine is able to stimulate mitophagy in both in vitro and in vivo assays, sustaining its capability to slow down the aging process and to sustain tissue renewal. Another molecular mechanism underlying the cancer preventive action of spermidine involves the competition of spermidine with acetyl-CoA for EP300 binding which may contribute to a reduced cancer-related mortality in patients. The inhibition of acetyl transferase EP300 triggers autophagy by the deacetylation of many ATG genes. Furthermore, spermidine, through autophagy activation, can also improve anti-cancer immune surveillance. To explore and support the spermidine administration as adjuvant anti cancer treatment, more clinical trials are needed. Hydroxycitrate Hydroxycitrate (HC) or hydroxycitric acid (HCA) is a CRM present in tropical plants as Garcinia cambogia and Hibiscus sabdariffa. It is widely used as a weight-loss drug in obese patients, but it also possesses anti-cancer activity. A HC’s peculiarity is its ability to block acetyl-CoA synthesis by inhibiting the enzyme ATP citrate lyase, thus representing an innovative approach to target cancer metabolism. This compound enhances autophagy flux, since it reduces lysine acetylation of cellular proteins. It has been found that the treatment of HC promotes the depletion of regulatory T cells from the tumor, improving immunosuppressive ability and counteracting lung cancer progression. Based on these premises, further synthetic agents, namely acetyl-CoA inhibitors, have been proposed as CRM’s: perhexiline maleate is now used in the clinical practice as an anti-anginal agent with cardioprotective and anti-tumor effects. Halofuginone. Halofuginone (HF) is a synthetic derivative of febrifugine, a natural quinazolinone alkaloid found in the plant Dichroa febrifuga Lour. It is known for its anti-protozoal activity and it is used as an anti-malarial agent in traditional Chinese medicine. Its activity includes inducing amino acid starvation response (AAR) in cancer cells in parallel with the concomitant activation of autophagy. Accordingly, the molecular explanation for its action is that HF inactivates mTORC1 by causing its detachment from the lysosomes and its degradation in proteasome, while promoting the nuclear translocation of the ATG transcription factor TFEB. Furthermore, HF shows its anti-inflammatory propriety by inhibiting the differentiation of inflammatory Th17 cells, an effect clearly linked to induction of AAR. More significantly, HF is a well-known inhibitor of collagen type I synthesis due to the repression of the TGF-Beta pathway. HF also prevents keloid fibrosis by reducing the deposition of ECM and decreasing the proliferation and migration of TGF-Beta activated myofibroblasts. In agreement with this, HF has found clinical application as a therapeutic agent in fibrotic disease and in some types of malignancies, such as lung and bladder cancer. In this respect, further clinical trials are needed to validate the anti-fibrotic property of HF in a wide range of tumors. Rapamycin. Rapamycin, also known as sirolimus, is a macrolide compound that was first isolated in 1975 from the bacterium Streptomyces hygroscopicus, found in the soil of Easter Island. Rapamycin is the most promising CRM with an anti-cancer activity, and its efficacy has been addressed in various clinical trials. Its molecular mechanism entails the inhibition of mTOR, a major regulator of cell proliferation and protein synthesis, by binding the protein FKBP12. Since rapamycin is an inhibitor of mTOR, this CRM promotes autophagy. Consequently, sirolimus provokes the deregulation of mTOR downstream effectors resulting in a prolonged lifespan and in a healthier metabolism. Additionally, this macrolide mediates immunosuppressive effects by controlling survival and proliferation of regulatory T-cells. Because of its side effects, including risk of cataracts, insulin-resistance and increased infections, the search for analogues of rapamycin, called rapalogs, occurred, which resulted for example, in NVP-BEZ235, OSI-027, and RapaLink 1. Everolimus, which belongs to the first-generation of rapalogs, was certified for the treatment of hormone receptor-positive, HER2, neu-negative advanced breast cancer, whereas temsirolimus, first-generation drug, was identified as a therapeutic agent in metastatic renal cell carcinoma. Currently the anti-cancer activity of rapamycin and rapalogs is under investigation in several clinical trials, opening several possibilities for innovative anti-cancer treatments. To sum up, see Table 1, it is well established that CRM’s can mimic the actions of CR, or rather delay aging and extend the patients longevity in parallel with improvement of physiological function and the reduction of the risk of many chronic diseases. This results in the avoidance of many side effects that occur with CR, together with better patient compliance. Nevertheless, even CRM’s-based therapeutic approaches show some limitations. For instance, many of them have not been investigated in a sufficient number of clinical trials, for example HF, HC, spermidine, to guarantee the safety and the feasibility of their applications. Moreover, some CRM’s fail to extend lifespan to the same degree as CR, suggesting that CR might suppress distinct mechanisms that are partially targeted by CRM’s. Accordingly, innovative clinical protocols for the employment of CRM’s are under investigation. Recently, the anti-tumor effects of everolimus combined with metformin have been examined. This combination results in an improvement of clonogenicity suppression, cancer cell death and inhibition of mTOR signaling. Therefore, combining different CRM’s could synergize their anti-cancer activities and achieve health benefits. Additionally, to escalate CRM’s effectiveness, it is possible to combine these substances with non-CRM compounds or with nutritional approaches, as CR, intermittent fasting and physical exercise. In this respect, HC, rapamycin and metformin, in association with standard chemotherapeutic drugs, are already being applied as anti-cancer therapies. Finally, there is a relation between CRM’s and the “personalized medicine”, which is the targeting of specific molecular pathways and cancer types with these compounds. The employment of HC and spermidine in the fight against lung metastases through the use of aerosolization is an innovative, efficient and non-invasive way to deliver CRM’s to the lungs. This method possesses several advantages. First of all, it guarantees a higher local concentration of CRM in a particular tissue and, secondly, it limits the arise of systemic adverse effects. Hence, many researchers have pointed out the existence of specificity of certain CRM’s for a precise cancer type. For example, RV is commonly used in breast cancer therapy in conjunction with chemotherapy. Altogether, new clinical trials need to be undertaken to define how these compounds could become a real “personalized target therapy”, making these mimetics into an effective and adjunctive weapon to fight the battle against cancer. Concluding remarks and perspectives. Cancer cells have a high affinity for glucose and amino acids, glutamine, methionine, leucine, arginine, and others, and need growth factors for cell proliferation and cell motility. Thus, starving cancer cells is an appealing strategy to halt cancer growth and metastatic spread. It has been hypothesized that a low energy diet could influence tumor progression and prognosis. Indeed, preclinical and preliminary clinical studies have confirmed that fasting has potential benefits by improving the effectiveness of chemotherapy while attenuating the toxic side effects, by protecting normal tissues from DNA damage, by reducing the inflammation in the TME, by restoring anti-tumor autophagy and apoptosis, and by favoring the immune response. All in all, available data suggest that a regimen with very-low-carbohydrate and low-protein intake, substituted by a relatively high-fat intake, may benefit cancer patients in terms of overall survival and, or progression free survival. However, patients may not tolerate such a CR diet for prolonged time. Therefore, an intermittent fasting regimen has been proposed as alternative, whose beneficial effects also appear promising though controversial in preclinical settings. Intermittent Fasting will require further elucidation in controlled clinical trials. An interesting alternative is represented by compounds known as CRM’s that can mimic the caloric, energic restriction condition while allowing an adequate supplementation of nutrients. These CRM’s elicit their action by triggering anti-cancer biochemical pathways through direct interaction with targeted signaling molecules and, or via epigenetic regulation of the expression of relevant regulators. It is likely that CRM’s activity is influenced by the genetic background and the TME context of the tumor. Therefore, understanding the molecular mechanisms underpinning the effects of such CRMs is mandatory for harnessing their adjuvant benefits in the frame of personalized cancer therapy. Acknowledgments, conflicts of interest, orcid and 125 references.

https://www.nature.com/articles/srep12115 https://rumble.com/v3t4yzj-index-of-science.-music-by-dan-vasc.html Fasting activates macro-autophagy in neurons of an Alzheimer’s disease mouse model, but it is insufficient to degrade amyloid-beta. Xigui Chen, Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Japan, and others. We developed a new technique to observe macro autophagy in the brain in vivo, and examined whether fasting induced macro-autophagy in neurons, and how the induction was different between Alzheimer’s disease (AD) model and control mice. Lentivirus for EGFP-LC3 injected into the brain successfully visualized auto-phagosome in living neurons by two-photon microscopy. The time-lapse imaging revealed that fasting increased the number, size and signal intensity of auto-phagosome in neurons. In AD model mice, these parameters of auto-phagosome were higher at the basal levels before starvation, and increased more rapidly by fasting than in control mice. However, the metabolism of exogenous labeled A Beta evaluated by the new technique suggested that the activated macro-autophagy was insufficient to degrade the intracellular A Beta increased by enhanced uptake from extracellular space after fasting. Ordinary immunohistochemistry also revealed that fasting increased intracellular accumulation of endogenous A Beta, triggered cell dysfunction but mostly did not decrease extracellular A Beta accumulation. Moreover, we unexpectedly discovered a circadian rhythm of basal level of macro autophagy. These results revealed new aspects of neuronal autophagy in normal, AD states and indicated usefulness of our method for evaluating autophagy functions in vivo. Autophagy, especially macro-autophagy mediated by auto phagosomes, has been implicated in various neurodegenerative diseases including AD. Ultrastructural analysis of postmortem human AD brains revealed increased auto phagosomes in dystrophic neurites. Macro autophagy was also suggested to be a pathway of generating amyloid beta (A Beta) in the cytoplasm. Meanwhile autophagy-related genes were induced in autopsy brains of AD patients and auto phagosomes were co-localized not only with A Beta in AD but also with a-synuclein and tau aggregation in autopsy brains of Parkinson’s disease and frontotemporal lobar degeneration, suggesting that misfolded disease proteins might generally induce autophagy. Some neurodegenerative diseases have more direct relationships to autophagy. Familial Parkinson’s disease causative proteins, PARK2, Parkin and PARK6, PINK1 act as indicators of functionally abnormal mitochondria to induce mitophagy. Hereditary spastic paraparesis type 15 are linked to mutations of the SPG15 gene that promotes autophagosome maturation. Mutations of an adaptor protein for selective autophagy, p62 are associated with amyotrophic lateral sclerosis, ALS. In vivo analysis of autophagy after nutritional starvation was performed in a pioneering work by Mizushima, Ohsumi and their colleagues with LC3-GFP transgenic mice, but induction of macro-autophagy was not detected in the brain tissues after fixation. Meanwhile, it was reported thereafter that inhibition of m TOR induced autophagy and ameliorated poly-glutamine disease pathology. Moreover, autophagic response of neurons might be conditional. In contrast to inducible autophagy, constitutive autophagy is established to protect neurons in vivo from neurodegeneration through clearance of ubiquitinated proteins. The discrepancy awaits further analysis with a new technique to observe living neurons to settle the issue of in vivo. Results. A new method of in vivo imaging of macro autophagy in the brain of living animals based on two-photon microscopy. To visualize auto phagic vacuoles in living neurons in the brain, we generated lentiviral vector expressing EGFP-LC3. We injected 5 micro liters of lentiviral vector, titer 5 million vector genomes per milliliter, into retrosplenial dysgranular cortex (RSD) or cerebellar cortex. Twenty days after injection the mice were investigated by two-photon microscopy, FV1000 MPE2, Olympus, Japan, with the thin skull method as described in Methods. In both areas, clustered EGFP-positive vesicles and dispersed fine EGFP-positive dots were observed, Figure 1a. Especially in the cerebellar cortex, the vesicles with high intensities were clustered in a narrow area of 10 to 20 micron diameter, suggesting that they correspond to the cell body of Purkinje cells aligned in a single layer, Figure 1a, Supplementary Figure 1. In reconstructed images of the cerebellum, EGFP-LC3 vesicles were also aligned in the main dendrite of Purkinje cells, Supplementary Figure 1. To verify that such clusters of EGFP-LC3 vesicles actually corresponded to the cell body of Purkinje cells, we used double transgenic mice, loxP-flanked STOP cassette Td Tomato by Ptf1a-promoter-Cre, that express red fluorescent protein in GABAergic Purkinje cells in the cerebellum. Infected lentiviral vector actually expressed EGFP-LC3 protein in Purkinje cells, a part of granule cells, but not in Td Tomato positive GABAergic neurons in molecular cell layer, see Supplementary Figure 2. To verify the expression of EGFP-LC3 in cortical neurons, we performed immunohistochemistry with anti-NeuN or GFAP antibody and examined co-localization of non-stained native EGFP-LC3 with a cell-specific marker, Figure 1b. The result revealed EGFP-LC3 vesicles, dots were distributed in NeuN-positive neurons, Figure 1b. GFAP positive astrocytes might also possess EGFP-LC3-positive dots, while the signals were weak in comparison to neuronal EGFP-LC3 vesicles, Figure 1b. On the other hand, infection of AAV-EGFP generated diffuse intracellular signals of EGFP, Figure 1c, supporting that the EGFP-LC3 vesicles were not the artificial self-aggregates of EGFP as reported. Moreover, we found by confocal microscopy that a part of the EGFP-LC3 vesicles was co-stained with a lysosome marker, LAMP2A in brain tissues, indicating that these EGFP-LC3 vesicles were actually fused with lysosomes, Figure 1d. Starvation-dependent induction and circadian rhythm of macro autophagy in neurons. Since these results supported usefulness of two-photon microscopic observation of EGFP-LC3 for evaluation of macro autophagy, we applied the technique to answer the questions: 1) Whether fasting treatment induces macro autophagy in neurons and 2) How the auto phagic response is different between 5XFAD mice, one of the severest mouse AD models that firstly shows A Beta deposition at 3 months of age, and the background mice, C57BL, 6 times SJL, Figure 2. We firstly examined the effect of fasting treatment on body weight and blood glucose, and confirmed that 5XFAD and background mice showed similar responses to fasting in these parameters, Supplementary Figure 3. In this experiment, 20 days after injection of EGFP-LC3 lentivirus, the mice were fasted and supplied only with water for 48 hours, Figure 2a. Two-photon microscopic observation was performed at 0, 6, 12, 24 and 48 hour time points during fasting, Figure 2a. Using the vessels as markers, the position of observation was strictly controlled, Supplementary Figure 4. Before analyzing the effect of fasting, we needed to test whether auto phagosome formation possesses a circadian rhythm, Supplementary Figure 5, because it had not been investigated previously. Unexpectedly, our live imaging of the brain revealed that the number, volume, and signal intensity per cell of the EGFP-LC3 vesicles changed in a circadian rhythm pattern, Supplementary Figure 5. All the parameters increased during daytime (light) and decreased in nighttime, dark. Interestingly, however, the parameters started to decrease around 4 PM when mice do not eat much, Supplementary Figure 5, suggesting that the circadian rhythm genes might affect auto phagosome formation independently of feeding behavior. However, the question whether circadian rhythm genes affect auto phagosome formation through or not through feeding behavior is an open question requiring further investigation. Therefore we started the observation strictly at the same time points to evaluate the response of autophagosome to the fasting treatment, Figure 2a, b. Two photon microscopy images, 100 micron by 100 micron by 100 micron volume, were obtained from four groups of mice. The number, signal intensity and volume of EGFP-LC3 vesicles were quantified and their mean and SD were calculated, Figure 2c. More than five mice were analyzed in each group of 5XFAD fasting, 5XFAD non-fasting, Wt fasting and Wt non-fasting mice, respectively, Figure 2c. Detailed methods for acquiring these parameters are described in the Methods section. The time-lapse live imaging revealed that basal levels of EGFP-LC3 vesicles were higher in 5XFAD mice at the number, intensity, and total volume of vesicles per cell but not the average size of puncta, Figure 2c. In addition, when these values were corrected by the basal values in each mouse group, the increasing ratio was also higher in 5XFAD mice, Figure 2c. We also employed an ordinary immune-histo-chemistry method with postmortem brains of 5XFAD mice after fasting treatment to detect endogenous LC3 vesicles. In this analysis, sensitivity of the endogenous LC3 detection was far lower than that of AAV-EGFP-LC3 by our new method, and it was hard to evaluate the number of macro auto phagosome strictly. However, the result of LC3 signals still suggested induction of macro auto phagosome after fasting, which was generally observed across multiple brain regions, Figure 2d. Figure 1. In vivo imaging of macro autophagy in neurons. (a) EGFP-LC3 lentivirus was injected into the cerebellar cortex (left panel) and retrosplenial dysgranular cortex (RSD, right panel) of wild type mice (C57BL, 6 by SJL) at 3 months of age. Twenty days later, EGFP-LC3 signals were directly observed by two photon microscopy. The EGFP-positive vesicles were distributed in a group as if they were auto phagosomes in a cell. (b) The brain tissues of wild type mice injected with EGFP-LC3 lentivirus were immunostained with anti-NeuN and GFAP antibodies. EGFP-LC3 vesicles surrounded NeuN-positive neuronal nuclei, yellow arrows, indicating that they were auto phagosomes in neurons. Such distributions of EGFP-LC3 were not found in GFAP-positive astrocytes, white arrowhead, suggesting that most EGFP-LC3 vesicles were located in neurons. EGFP-LC3 was directly observed without immunostaining in these experiments. (c) Two-photon microscopic observation of the RSD region of AAV-EGFP-injected wild type and 5XFAD mice at 3 months. Both genotypes of mice showed homogeneous signals of EGFP in cells, supporting the specificity of EGFP-LC3 signals. (d) Colocalization of a part of EGFP-LC3 vesicles with LAMP2A in RSD region of 5XFAD mice at 3 months. Figure 2. In vivo imaging of auto phagosome in AD model and control mice. (a) Experimental protocol of the in vivo time-lapse imaging to test the effect of fasting on auto phagosome formation. (b) Time-lapse imaging of EGFP-LC3 vesicles was performed at a similar region of AD model and control mice at 3 months with or without fasting. The signal intensities were higher in 5XFAD mice than control mice before fasting. Fasting induced the increase of signal intensities in both genotypes, while the induction was more prominent in 5XFAD mice. (c) Quantitative analyses of the chronological changes of EGFP-LC3 vesicles with or without fasting. In mean signal intensity per cell, mean vesicle number per cell, and mean vesicle volume per cell, the values were higher in 5XFAD mice than control mice. Some of these values were also increased more remarkably in 5XFAD mice than control mice. The mean volume of the vesicles was not changed so remarkably. More information is included in the text of the paper. Effect of starvation-induced macroautophagy on extracellular and intracellular A Beta accumulation. Finally, we tested whether induced auto phagosome was really effective for degradation of A Beta because it was reported previously that AD-asscociated mutation of presenilin-1 impairs autolysosome acidification and cathepsin activation to inhibit proceeding of autophagy processes. Such a dysfunction in macro autophagy might occur in 5XFAD mice and might prevent degradation of the substrates within auto phagosomes after fusion with lysosomes. For this purpose, we injected A Beta labelled with TAMRA into the retrosplenial dysgranular cortex (RSD), the brain area that corresponds to human precuneus, and observed dynamics of A Beta by time-lapse imaging for 2 days from 24 hours after injection, Figure 3a. The experiment might mimic over-secretion of A Beta from hyperactivated neurons in brain regions composing the default mode neural network. First we found that injected A Beta was taken up into neurons within 24 hours after injection, Figure 3b. Importantly, the amount of A Beta (red vesicle) in neurons was obviously higher in 5XFAD mice, Figure 3b,c. The increase of intracellular A Beta could be explained by increased uptake of extracellular A Beta by endocytosis. Analysis of the yellow vesicle volume per cell that reflects secondary lysosome, the fused vesicle of endosome and autophagosome, revealed that the amount of secondary lysosome increased in neurons during the time of fasting whereas in which A Beta remained undegraded, Figure 3c. The increase of such “residual body” containing A Beta was observed both in wild type and 5XFAD mice, while the extent of increase was more remarkable in 5XFAD mice, Figure 3c. Figure 3. Endocytosis and auto phagosome-dependent degradation of A Beta by cortical neurons. (a) Experimental protocol of the chronological in vivo imaging to test A Beta uptake and degradation in the cortical neurons is shown. (b) Time lapse imaging of TAMRA Beta amyloid (upper panels) and TAMRA Beta amyloid plus EGFP-LC3 vesicles (lower panels) at 24, 0, 48, 24, 60, 36, and 72, 48, hours after injection of TAMRA Beta amyloid. Interaction between endosomes (red) and auto phagosomes (green) were observed chronologically. (c) Quantitative analyses of the chronological changes of endosomes, TAMRA Beta amyloidpositive vesicles, left graph, and secondary lysosomes, TAMRA Beta amyloid and EGFP-LC3 double positive vesicles, right graph, with or without fasting. More information in the text of the paper. Figure 4. Fasting treatment does not affect extracellular A Beta accumulation. (a) Images of A Beta at various brain regions of 5XFAD mice with or without fasting at 3 months. DAB satin was used to visualize the antibody reaction. No obvious difference was detected in intracellular and extracellular A Beta accumulation between fasting (minus) and fasting (plus) groups at all brain regions. Abbreviations. RSD, retrosplenial dysgranular cortex. FC, frontal cortex. LSV, ventral part of lateral septal nucleus. VM, ventromedial thalamic nucleus. PnC, caudal pontine reticular nucleus. OB, olfactory bulb. Sub, subiculum. CA1, hippocampus CA1. CA2, hippocampus CA2. CA3, hippocampus CA3. DG, dentate gyrus. Cbm, cerebellum. (b) Images of A Beta visualized by fluorescent secondary antibody at various brain regions of 5XFAD mice with or without fasting at 3 months. No obvious difference was detected in intracellular and extracellular A Beta accumulation between fasting (minus) and fasting (plus) groups at all brain regions. (c) DAB staining of sagittal sections revealed that extracellular A Beta accumulation was decreased in visual cortex, arrows. For the comparison of the effect of fasting treatment on A Beta accumulation across different regions of the brain, we employed a method using the post-fixed brain samples of 5XFAD mice at 3 months taking the advantage of the pathological stage. In this case we observed the effect of fasting on accumulation of endogenous A Beta of 5XFAD mice instead of exogenous A Beta TAMRA. The DAB and fluorescence immunostainings with anti-A Beta antibody revealed no significant difference of extracellular A Beta accumulation between non-fasting and fasting groups of 5XFAD mice in most brain regions, Figure 4a,b. However, we detected a tendency that extracellular A Beta accumulation was decreased in visual cortex in fasting groups of 5XFAD mice, Figure 4c. Intracellular A Beta accumulation was also confirmed across different brain regions as we reported previously. Also unexpectedly, we observed that intracellular A Beta accumulation accompanies blurring or fading-out of DAPI or NeuN stains of the nuclei of neurons, Figure 5a,b. This suggested that a certain type of cell death was induced by intracellular A Beta accumulation and that extracellular plaque formation might be triggered by the seed of A Beta foci of ghost neurons, the residual intracellular A Beta accumulation of dead neurons. Indeed, we often observed various images supporting the progression from intracellular to extracellular A Beta aggregates, Figure 5c, and queer ballooning’s of the cytoplasm and apoptoic changes of the nuclei in intracellular A Beta positive cells, Figure 5d. Hence, we categorized such types of cells with intracellular A Beta accumulation into three groups, vital cells with clear nuclear margin with DAPI stains (Group A); dying cells with blurred or faint DAPI nuclear stains (Group B); and dead cells with the defect of DAPI nuclear shape (Group C), Figure 5a. Quantitative analysis revealed that the total cell number of neurons with intracellular A Beta accumulation was increased by fasting treatment generally in all brain regions, Figure 5e. Quantification of each group revealed that fasting treatment induced a shift from A to C generally in all regions of the brain, Figure 5e. These results were consistent with the hypothesis that intracellular A Beta accumulation triggers the cell death and that plaque formation is seeded by the ghost of intracellular A Beta accumulation, whereas this hypothesis should be examined more extensively by employing additional methods in the future. Figure 5. Intracellular A Beta accumulation was affected by fasting. (a) Various forms of intracellular A Beta accumulation observed in the cortex of 5XFAD mice at 3 months. Accumulation of intracellular A Beta often accompanied with blurring or fading out of the nuclei, thus the were aligned with hypothetical progression of the cell pathology. Intracellular A Beta positive cells with intact nuclei, with abnormal nuclei, and with no nuclei are classified to group A, B and C, respectively. (b) Co-staining of NeuN and A Beta revealed that neurons are the cells possessing intracellular A Beta accumulation. (c) Hypothetical progression of extracellular A Beta aggregates from the seed of intracellular A Beta accumulation is shown with representative images in RSD of 5XFAD mice at 3 months. White arrows suggest the defect of dead neurons. Yellow arrows suggested an enlarged nucleus with abnormal DAPI stains of the nucleus. (d) Abnormal ballooning of cells with intracellular A Beta accumulation suggesting atypical cell death. (e) Quantitative analysis of the number of group A, B and C cells at various brain regions in fasting and non-fasting 5XFAD mice at 3 months. P-values for comparison in each group or total cell numbers between fasting and non-fasting were calculated by Welch’s test. Discussion. Our study firstly proved that macro autophagy was actually induced by starvation in mouse neurons in vivo. This finding was consistent with a previous result with post-mortem analysis of GFP-LC3 transgenic mice after fasting. The GFP-LC3 transgenic mice were starved for 24 or 48 hours, perfused and fixed. After killing the mice, the authors of the previous study sampled the brain tissues and observed the GFP-LC3 fluorescence. Compared with their method, our technique has an advantage to directly observe the change of macro autophagy in the brain of living animals but not of dead animals. On the other hand, the protocol used in this study was limited to observation at one or several restricted regions of the brain. However, since our AAV vector is also applicable for systemic delivery by intravenous injection, it might be possible to overcome the limitation of our method in the future. The finding in this study that fasting induces macro autophagy basically supports previous results showing that activation of macro autophagy by chemicals or vectors ameliorated the pathology of neurodegenerative diseases in various animal models. In addition we unexpectedly discovered circadian rhythm of neuronal macro autophagy in vivo. The circadian rhythm might be interesting if we consider it with the previous finding that A Beta secretion is reduced during the sleep. These results would collectively contribute to understanding of the significance of autophagy in the brain. Our results also suggested even though autophagy was activated in 5XFAD mice under starvation, the intracellular degradation of A Beta was still insufficient to compensate the increased uptake of A Beta from extracellular space, Figure 3. This idea was further supported by immunohistochemistry of 5XFAD mice, showing that fasting treatment enhanced intracellular accumulation of endogenous A Beta, Figure 5. Moreover, fasting did not largely affect extracellular accumulation of endogenous A Beta in 5XFAD mice, Figure 4a,b. If this is the case in human AD pathology, such enhanced uptake of A Beta by calorie restriction could be harmful for neuronal function if the intracellular A Beta triggers abnormal signaling cascades. Supporting this hypothesis, we observed an increased number of neurons with intracellular A Beta that lost viability after fasting treatment, Figure 5. However, it is also of note that we had injected a high amount, concentration of A Beta to visualize the metabolism in vivo and that the expression level of A Beta in the 5XFAD mice was significantly higher than in human AD patients. Therefore, starvation–activated macro autophagy might still ameliorate the A Beta pathology if A Beta concentration in extracellular space is not so high. In that case, induction of A Beta uptake by starvation might reduce the extracellular A Beta and the intracellular A Beta could be degraded at a relatively low level by activated macro autophagy. Then, the resultant decrease of extracellular A Beta might also rescue the synaptic transmission. The critical point of concentration of the two hypotheses needs further investigation. Collectively, the balance among secretion, endocytosis and degradation of A Beta should play a pivotal role in initiation and progression of human AD pathology. Therefore nutritional condition and circadian rhythm, which may be influenced by our life style, are considered to be intriguing factors for AD. In conclusion, this study revealed that nutritional starvation induces macro autophagy in neurons but the induction is insufficient to degrade a high amount of A Beta in AD-associated pathological condition. Technical sections, including Methods, AD model mice and the Generation of lentiviral vectors. The Titration of viral vectors, Injection of viral vectors and fluorescence of beta amyloid. In vivo imaging with two photon microscopy, the fasting treatment of mice and Immunohistochemistry. The Positioning of the image fields, Statistics, Ethics, and 25 References. Acknowledgments, Author Contributions, and Additional Information.

Scanned by Highroller. Proofed by Aunti. Made prettier by use of EBook Design Group Stylesheet. Reformatted for machine speech PukeOnAPlate2023. Under The Yoke by SM Stirling. CHAPTER ONE. Enlargement of our standard lines in domestic, supervisory and recreational Items for the intending settler in the new territories. Our Agency has had agents on hand for every auction of choice items; stock your kitchens and servants' quarters from the best hotels and restaurants of Europe. And while Settlement Directorate issue may do for field-hands and machine tenders, when it comes to the strawbosses, interpreters and drivers you will need for your plantation or enterprise, our breaking-and-training establishments are unmatched for price and quality. Why go to the expense of importing your serf cadre from the dregs of the Police Zone? And amusement? From the snowy blond of Sweden to the olive of Italy, the fruits of conquest are yours to pluck. From peasants to aristocrats, from the illiterate to the ballerinas and university students of Paris, wench or prettybuck, your fantasy is our reality. Whether your desire is sjambok-broken docility or a wild Finn you can tame yourself. Stevenson and de Verre has it! Chemo-conditioning and polygraph testing ensure unmatched reliability for our product, reared in and tailored to local languages and custom, from Seoul to Lisbon! Don't waste precious time and capital training your own, consult our brochures, and contact your local representative for further information. Advertising flier of Stevenson and de Verre. Labor Agents, included in: Settler Information Kit Number three. Settlement Directorate, European Area, 1948 edition. LYON, PROVINCE OF BURGUNDIA REGIONAL HQ. SECURITY DIRECTORATE DETENTION CENTER Seventeen. APRIL, 1947. "Pater Noster, qui est in caelis." "Shut up, slut-bitch!" The guard raked her hard-rubber truncheon along the bars in frustration, then stalked off down the corridor. Sister Marya Sokolowska lowered her head and fought to recapture the Presence; a futile effort, it could not be forced. Enough, prayer is more than feelings, she chided herself, while habit droned the sonorous Latin words and told the beads of her rosary. The words were a discipline in themselves; faith was a matter of the intellectual will more than subjective sentiment. And the others relied on her: even Chantal Lefarge the communist over in the corner was joining in; it helped remind them they were human beings and not animals-with-numbers, that they were a community, linked one with the other. Something easy to forget in the ten-by-twelve brick cube of cell 10-27, under the Domination of the Draka. Though she was the only Pole here, and the only religious. Covertly, her eyes followed the guard as far as the grill-door would allow. The building had not been designed as a prison; the Draka had taken it over when Lyons fell, back in forty five. Before then. A school, perhaps, or some sort of offices. Then the Security Directorate had come, and cordoned off as many square blocks of the city as need dictated; knocked doors and built walkways between buildings, surrounded the whole with razor-wire and machine-gun towers, put in bars and control-doors. It was a warren now, brick and concrete, burlap and straw ticking, the ever-present ammonia stink of disinfectant. Lights that were never dimmed, endless noise. The tramp-trampclank of chain gangs driven in lockstep to messhalls or to their work, maintaining and extending the prison-complex. Far-off shouts and screams, or someone in the cell across the corridor waking shrieking from a nightmare. Mornings were worst: that was the hour for executions, in the courtyard below their cell. The metal grille blocked vision but not sound; they could hear the footsteps, sometimes pleading or whimpering, once or twice cracked voices attempting the Marseillaise, then the rapid chattering of automatic weapons and rounds thumping into the earth berm piled against their block's wall. The nun finished the prayer and came to her feet, putting solemnity aside and smiling at the others. Together they rolled the thin straw-stuffed pallets up against the walls, each folding her single cotton blanket on top and placing the cup and pan in the regulation positions. There was nothing else to do; it was forbidden to sleep or sit after the morning siren. Conversation was possible, if you were careful and very quiet, a matter of gesture and brief elliptical phrases, and it helped break the terrible sameness of each day. Newcomers brought in fresh tidings from the world outside, and bits of gossip passed from hand to hand, on work details or at the mess hall, not as elaborate as she had expected, there were too many informers and turnover was too high. This was a holding and processing center, not a real prison; a place to sit and wait until they took you away. Terrible rumors about what lay beyond: factories, labor camps, bordellos, medical experiments such as the Germans had done during the Nazi years. But no real information. For herself, it was not so bad; she had much time to meditate, and the others to help, and what came after would be the will of God, Who would give her strength enough to meet it, if no more. Marya crossed herself and moved a careful half-pace closer to the bars. Good, the guard had gone around the corner. She was just a trusty, a prisoner like the rest of them, with no key to open cell doors. She could mark an individual or a whole cell down and inform the real guards, the Security bulls and retired Janissaries who ran Block D, Female Section. That could mean flogging or electroshock or sweatbox for all of them, you never knew. But the guard would be reluctant to do that; it was unwise to have more contact with the bulls than you had to. A prayer was not enough provocation; a real racket might be, because then she would be in danger of losing her position and being thrown back into a holding pen, which meant being quietly strangled one night. Seven to one was bad odds. God forgive them all, Marya thought. For them too the Savior died. She herself would probably get nothing more than a whack across the kidneys with the rubber truncheon at mess call. Not for the first time, she reflected that Central Detention was like being inside a machine. Not a particularly efficient one, more like an early steam engine that gasped and wheezed and leaked around its gaskets, shuddering with loose fittings and friction. But it used the Domination's cheapest fuel, human life, and it was simple and rugged and did its work with a minimum of attention; she had been here six months and rarely even saw the serf guards and clerks who did the routine management, much less one of the Citizencaste aristocracy of the Domination. There was an iron chung-chung from the landing down at the south end of the corridor; the main door to Block D, two stories up the open stairwell. A sudden hush caught the cells along the narrow passageway, an absence of noise that had been too faint for conscious attention, then a rustle as the inmates sprang to stand by their bedrolls. The nun moved to her own and assumed the proper posture, feet together, head bowed, hands by sides. She could feel the sweat prickle out on her palms, wiped them hurriedly down the coarse cotton sack-dress that prisoners were issued. Suddenly the familiar roughness itched against her skin, and she forced her toes to stop their anxious writhing in the sisal-and-wood clogs. A whimper. Therese; she had never been strong, or quite right in the head since they brought her and Chantal in. A slight girl, dark and too thin, who never spoke and slept badly. The nun had had medical training, but it was nothing physical; the abuse that had made the elder Lefarge sister strong with hate had broken something in Therese. Perhaps it could never be healed, and certainly not here. Eyes met across the cell, and someone coughed to cover the quick squeeze of the shoulder and whisper of comfort that was all they had to offer. Pauvre petite, Marya thought; then with desperation: much too early for the bulls to be down looking for amusement. And they had never picked cell 10-27. Holy Mary, mother of God, please. The guard pelted down the corridor and dropped to her knees by the stairs from the landing. Marya's bedroll was nearest the door; she could see boots descending the pierced-steel treads. Three sets, composition-soled leather with quick-release hooks rather than eyes for the lacings. Draka military issue, the forward pair black and the other two camouflage-mottled. Quickly, she flicked her eyes back to her toes. A Citizen! Could they have found out? Silently she willed the boots to pace by, on down the corridor. Not praying, because this could only mean bad trouble and the only words her heart could speak would be: somebody else, anyone but me. Marya swallowed convulsively, thick saliva blocking her throat. Even Our Lord asked that the cup pass from him. But he had not wished it on anyone else. Nor would she. The lock made its smooth metal sound of oiled steel and the cell door swung open. She could feel the breeze of it, smell leather and cloth, gun-oil and a man's cologne. "Bow, you sluts!" the guard barked, hovering nervously in the corridor. The eight inmates of cell 10-27 put palms to eyes and bent at the waist. "Up, stand up." A man's voice, cool and amused, speaking French with a soft slurred accent. "Present, wenches." Marya jerked erect and bent her head back to show the serf identity-code tattooed behind her left ear, one hand holding back the long ashblond hair that might have covered it. The position gave her a good look at the three men. Their armed presence crowded the cell, even though there was room in plenty with the inmates braced to attention. Two were common soldiers, Janissaries from the Domination's subject-race legions with shaven skulls and serf-numbers on their own necks. Big men, young, thick heavy-muscled shoulders and necks and arms under their mottled uniforms. Both carried automatic rifles; ugly, squared-off things with folding stocks and snail-shaped drum magazines; there were heavy fighting-knives in their boots, stick-grenades clipped to their harness, long machete-like bushknives slung over their backs. Dark men, with blunt features and tight-curled hair and skins the color of old oiled wood; Africans, from the heartlands of the continent where the Domination began. Their people had been under the Yoke for generations, and the Draka favored them for such work; they looked at the women with indifferent contempt and casual desire. The third was an officer, a Citizen. In the black tunic and trousers of garrison uniform, with a peaked cap folded and thrust through his shoulderstrap; Marya understood just enough of the Domination's military insignia to know he was a Merarch, roughly a colonel. A tall man, leopard to the Janissaries' bull strength. Tanned aquiline features, pale gray eyes, brown hair streaked with a lighter color, a single gold hoop-earring. No more than thirty, with white scar-lines on his hands and face, one deep enough to leave a V in his left cheekbone. A machine-pistol rested in an elaborate holster along his thigh, but it was the weapon in his hand that drew her eye. A steel rod as thick as a man's thumb with a rubber-bound hilt, tapering along its meter length to the brass button on its tip; a cable ran from the hilt to the battery-casing at his belt. An electroprod. The tip came towards her face. Sweat prickled out along her upper lip as she fought against the need to flinch. Marya knew what it could do; the 'prod was worse than a whip, as bad as the sweatbox. The Draka used it to control crowds; the threat was usually as effective as an automatic weapon, and less wasteful. Too many times and you could start having fits. Applied to the head it could cause convulsions, loss of memory, change you inside. She closed her eyes. Metal touched her chin. Nothing. Not activated. She opened her eyes, and the Draka nodded with approval. "Spirited," he said. "Sound off, wench." "Marya seven-three-E-S-four-two-two, Master," she recited, fighting off a flush of hatred that left her knees weak, on the verge of trembling. She would not show it, not when it might be mistaken for fear. The man in black flipped open a small leather-bound notebook with his left hand. "Ssssa; 34, literate, languages French, German, English, Polish."He raised an eyebrow. "Quite a scholar. Advanced accounting. Ah, category 3m73, religious cadre, that would account for it." The electroprod clicked against the crucifix and rosary that hung through the cloth tie of her sack-dress. Made from scraps of wood, silently at night beneath her blanket. "Nun?" "I am a Sister of the Order of Saint Cyril, Master." The Draka flicked the steel rod against her hip, hard enough to sting. "You were. Now you're 73ES422, wench." He read further, pursed a lip. "Suspicion of unauthorized education? Ah, that was six months ago; Security must have been dithering whether to pop you off or send you to the Yanks with the Pope and the rest." He shook his head and made a tsk sound between his teeth. "Headhunters, typical." Marya felt herself pale. "The. The Holy Father has been exiled?" Two more cuts, harder this time. "Master," she added. He turned without answering, scanning the others. "You," he pointed. "Chantal nine-seven-E-F-five-seven-eight, Master." Marya could see the film of sweat on the other woman's face, and knew it was rage, not terror. Calm, keep calm, she thought. Suicide is a mortal sin. The Draka stepped over and looked her up and down, smiling slightly. She had dark-Mediterranean good looks, long black hair and a heart-shaped face, a full-curved body under the coarse issue gown. "At ease," he said, and the inmates straightened and dropped their eyes again; the officer chuckled as he watched the dark woman glaring at his boots and consulted the notebook. "Twenty years, literate, numerate, French and English. Ex-bookkeeper, member of the Communist Party." He caught the hem of her gown on the end of the electroprod and raised it to waist height, and murmured in his own tongue: "Not bad haunches, but these Latins run to fat young." Marya understood him, with difficulty; the English her Order had taught her was the standard British form. The Domination's core territory in Africa below Capricorn had been settled by Loyalist refugees from the American Revolution, speakers of an archaic eighteenth-century southern dialect, and it had mutated heavily in the generations since. He paused, let the cloth fall, tapped the steel rod thoughtfully against one boot. "Shuck down, wenches," he said after a moment. There was a quick rustle of cloth as the inmates stripped; the prison gowns were simple cotton sacks with holes for arms and heads. Marya undid her belt, pulled the garment over her head, folded it atop her bedroll, slipped off the briefs that were the only undergarment and folded them in turn, stepped out of the clogs and stood in the inspection posture, hands linked behind the head and eyes forward. The dank chill of the place seemed suddenly greater, raising the gooseflesh on shoulders and thighs, making her wish she could hug herself and run her palms down her arms. When she had been arrested, it was only chance that the secret school was not in session and the children gone. All unauthorized education was forbidden, under penalty of death; they would have penned her and the children together in the room and tossed in a grenade. Alone, she would have died there and then if any evidence had been found. Two of the mothers had been with her, and there was no room in the police van; the green-uniformed Security Directorate officer had drawn her pistol and shot them both through the head as they knelt, to save the trouble of calling in for a larger vehicle. And inside Central Detention there had been no interrogation, no torture; only the cell and the endless monotony spiced by fear, until she realized that her gesture of defiance was not even worth investigating. There had been a speech for her batch of new inmates. Very brief: "This is a bad place, serfs, but it can always be worse. We ask little from the living, only obedience; from the dead, nothing." Beside her Therese was weeping silently, slow fat tears squeezing out from under closed lids and running down her face, dripping from her chin onto her breasts. Most of the others were expressionless, a few preening under the dispassionate gaze; the Draka nodded and turned to the guard. "This one and that one," he said, flicking the prod toward Marya and Chantal. "Put the restraints on them." Marya's stomach lurched as the guard's rough hands turned her around and pulled her arms behind her back. The ring-and-chain bonds clanked, fastening thumbs and wrists and elbows in a straining posture that (breed the shoulders back; you could walk in them if you were careful, but they were as effective as a hobble when it came to running. Not that there was anywhere to run; and anything at all might be waiting beyond the iron door. Cell 10-27 was a bad place; of cold and fear and a monotony that was worse than either, grinding down your mind and spirit. Now it seemed a haven. The one thing you could be certain of in the Domination was that there was always someplace worse. The guard shoved the two women roughly toward the door of the cell. Marya staggered, turned and bowed awkwardly. "Master," she said. "Our things?" "You won't be back, wench," the Draka said, stretching. The Janissaries chuckled; one reached out and grabbed the weeping Therese by the breast, pinching and twisting. She folded about the grip in a futile shrimp-curl of protection, mouth quivering as she sobbed. "Yo" be needin' us'n, suh?" he said. "Mebbeso we-uns stay here fo' whaal?" The officer laughed, and Marya could feel Chantal quivering behind her. Therese was her younger sister; they had been swept up together for curfewviolation. Distributing leaflets, probably, but they had been clean when the patrol caught them and might have gotten off with a light flogging if Chantal had not attacked the squadleader when he started to rape Therese. The nun forced herself between the other woman and the soldiers, pushing her back against the bars, hearing the quick panting breath of adrenaline-overload in her ear and a low guttural sound that was almost a growl. Madness to attack three armed men with hands bound, but a berserker does not count the odds. Even worse madness if by some freak she could hurt one of their captors; that would mean impalement, a slow day's dying standing astride a sharpened stake rammed up the anus. And not just for her; the Draka believed in collective punishment, to give everyone a motive for restraining the wilder spirits. Innocents would die beside her. The Draka laughed again, reaching out and playfully rapping the Janissary across the knuckles with the electroprod. "Na, no rough work with Security's property," he said. "Besides, I know you lads; once you had your pants down you wouldn't notice even if one of the others pulled the pin on a grenade and shoved it where the sun don't shine. Then think of the paperwork I'd have to do." The dark soldier released the woman and saluted. His officer returned the gesture, then grinned and clapped him on the shoulder. "But no reason you shouldn't hit the Rest Center until we're due; consider yourselves off-duty until." He looked at his watch "Twenty-hundred hours. Report to the depot then. Off you go; I think I can handle the wild French wenches alone." "Yaz, suh!" the serf soldiers chorused. Their clenched right fists snapped smartly to their chests before they wheeled and left. It had been half a year since Marya last saw the main door of Block D; not since the night of her arrest, when she had been kicked through still bruised and dazed from the standard working-over with rubber hoses that all new inmates received. And she was nearly the oldest inhabitant; the others came and went, swept in off the streets for some offense too petty to merit an immediate bullet, processed through and vanishing to places unknown. A few found the courage to call farewell as they climbed the pierced-steel treads. Behind them came Therese's voice, thin and reedy: "Chantal, don't leave me, come back, please." Then the welded panels clanged shut, and they were outside. A serf clerk at a desk-kiosk, a saffron-skinned slant-eyed woman in neat coveralls who bowed as she took the papers the Draka handed her. More corridors, more cells; the electroprod tapped her on the shoulder, left, right, pointing to crossings. A harder jab to Chantal's lower back, just over the kidneys. She gasped, stumbled, would have turned her head to glare if the aching strain of the restraints had not prevented. "Walk more humble, wench," the Draka said softly. "Through there, I think." A men's section, hairy faces crowding close to the bars and glittering eyes, silent and intent, others who looked at her with pity, or away. The nun felt herself flushing under that hopeless hunger, forced herself not to shrink back towards the sound of the Draka's bootheels. Courtyards, and she began to shiver as a thin drizzle of cold rain fell slick on her skin. Cobblestones, a brief glimpse to a road outside as a convoy of steam-trucks chuffed in with a new load of detainees, ragged figures clutching bundles and children as the guards chivied them into ranks for processing. Overhead, huge and silent, a dirigible was passing, its lights disappearing northward. Then they were in an office complex. Soft diffused lighting instead of the harsh naked bulbs, warmth, rain beating against sound windows of frosted glass. Incredulous, her feet felt carpet beneath, soft and deep; somewhere a teleprinter was chuttering, and the homey familiarity of the office-sound brought sudden inexplicable tears prickling under her lids. She was conscious of her nakedness again; not in shame or modesty, but as vulnerability. Most of those she saw were serfs as well, but they were neatly clad in pressed overalls and good shoes, clipboards and files in their hands as they strode purposefully down the aisles or sat at desks working, typing, filling the air with a clatter of abacuses and adding-machines. Their eyes flicked over her and away, and she could see herself in them: nude and wet and muddy-footed, rat-tails of wet hair clinging to her shoulders, arms locked behind her. Livestock, beneath contempt to these born-serf bureaucrats, the selected elite who occupied the management positions just below the Draka aristocracy. "Hope these'un're house-broken," a voice said, and others chuckled. Her ears burned, and Chantal beside her stiffened and glared. The man behind them evoked more interest: deferential bows, and curiosity. Marya saw a few other Citizens, through the open doors of offices or walking in their bubbles of social space, crowds parting for them; but those men and women were in the olive-green of the Security Directorate, not War Directorate black. The freefolk grew more numerous as they climbed stairs and at the last an elevator to the upper level. There was no bustle here; empty corridor with wide-spaced doors, wood paneling replacing the institutional-bile paint of the lower levels. Names and mysterious number-letter codes on brass plates: "Morrison: infl. 77A Relig. delation." "Carruthers: alloc. IOF Labor." A larger door still, unmarked, at the end of a hallway. "Through," the Draka said, tapping them again on the backs of their necks with the prod. Hesitantly, Marya stepped closer. The dark oak panel slid aside with a soft shusssh, and she stepped through, blinking with astonishment. She had been six months in prison; before that six years in war-crippled cities, on the roads of Europe, in refugee centers and tenements. For a moment she lost herslf in wonder. The room was large, a lounge-office fifteen meters by twenty. Two walls were floor-to-ceiling tinted glass, a view over the tumbled rooftops of Lyon down to the choppy surface of the Rhone, iron-gray under a sky the color of a wet knife blade. The other walls were murals in the Draka style, hot tawny savannah and herds of zebra beneath a copper sun. A huge desk of some unfamiliar glossy-russet wood occupied one corner, with a sparse scattering of files, intercom, telephone, closed-circuit television monitor. The floor was covered in Isfahan carpets, the furniture soft chairs around a cluster of low brass tables on filigree stands, Arab work. The remains of a light meal were scattered on one, meats and cheeses, fruit and bread, coffee warming over a spirit-lamp with little pots of sugar and cream. Marya felt her nostrils flaring and mouth filling. The prison fodder was abundant and adequate; porridge laced with fish and soya meal, hardtack, raw vegetables. Bland, bland; after months of it, years on scrimping wartime rations, the smell of the good food was intolerable. She was used to austerity, would not have chosen a religious vocation if comfort were essential to her, but she could feel her skin drinking in the softness and warmth, eyes flooding with the color and brightness. To feel something besides harsh cloth and stone, to see something that pleased the eye and was not ugly and hurtful. The Draka officer's hand rested on her shoulder, forcing her to her knees beside Chantal. Inwardly, she shook herself as she bowed her head and glanced upward through the lashes; a prisoner could not afford the luxury of distraction. Focus on the people, she thought. Study them. Know those with power. Knowledge was the only defense of the weak. There were five others in the room. A man behind the desk; Security uniform, high rank. In his forties but athletic, short, with dark curly hair, blue eyes, tanned pug face and a cigarette in an ivory holder. In the lounger. Marya blinked. The woman lolling there was the first Draka she had ever seen not in some type of uniform; she was wearing low tooled boots, loose burgundy trousers, a long blouse-shirt over a stomach that showed the seventh month of pregnancy. Somehow that seemed unnatural, shocking. Of course Draka had to be born like other folk, but. Tall, hawk-faced, hair a mixture of brown and gold that gave the effect of burnished bronze, one hand holding a cup. A massive thumb-ring, long fingers. And beside her a girl of perhaps ten years in a thick silk tunic, playing with a long needle-pointed knife. The nun frowned, glanced covertly from one face to another. There were two servants, in dark elegant liveries; one knelt in a corner and played softly on a stringed instrument, the other was a middle-aged black woman standing by the child, probably a nurse. Forget them for a moment; there was something about the Draka. All the Citizens she had seen had a certain look, of course: hard sculpted faces, gymnast's physique, the studied grace that came of long training. Even the girl had none of the coltish awkwardness usual on the verge of adolescence; her hands moved the blade with relaxed precision, spinning it up and snapping it closed again around the hilt without looking down. But there was something more. Ah, a family likeness. Pale eyes and long limbs and sharp-featured eaglenosed high-cheeked faces; the pregnant woman might be the sister of the officer who had fetched Marya from the cell. She licked her lips, waiting. "Gudrun, yo' said you were old enough to carry a weapon; don't fiddle with it." The woman's voice. Soft, rather husky. The child pouted, flushed and pulled up the hem of her tunic to slide the blade into a sheath on her leg. The blush was very evident under pale freckled skin, copper hair; there were dark circles under her eyes. The pregnant woman worked her fingers and spoke to the man behind the desk. "An' yes, Strategos Vashon, I've been known to do outlines for mural work; the Klimt workshops have a few in their standard offer book. Not takin' commissions right now, though, what with everythin'." She transfered her attention to the two prisoners. "So, Andrew, these two are the best yo' could do?" The voice stirred a memory, elusive; darkness and pain, dust and the hotmetal stink of engines. It slipped away as she tried to grasp at it. The Draka who had brought the women from their cell snapped his fingers for coffee, sinking into one of the chairs with a grateful sigh and hooking the electroprod onto his belt. "More difficult than the manual workers, sister dear, yo' wanted them spirited and intelligent. Troublemakers, in other words. That, these are; healthy sound stock, as well." The woman shifted, sighed, rested one hand on her belly and held out the other. "The tag," she said, and her brother tossed a strip of metal; her hand picked it out of the air with a hard fast slap. "Yasmin." The girl in the corner laid down her mandolin and rose to take the key. "Take the restraints offn them." Marya kept her head bent as the serf approached, knelt behind the two inmates. A crisp sound of linen and silk, a smell of scented soap, a soft hand on her arm. "These-heah on way too tight." The girl's voice was harder to understand than the Draka's had been, the same soft drawl but a more extreme dialect. "It gowin hurt." Metal clicked. Thumbs first, then wrists, then the painful stretch of elbows drawn together behind the shoulderblades. The fetters had been a burning ache; agony lanced through muscles and tendons, throbbing as circulation returned. Then relief through the fading pain, almost as hard to bear; involuntary tears starred her lashes, breaking the light into rainbows that flickered like kaleidoscopes as she blinked, as her hands fell trembling to the rough surface of the carpet. She heard Chantal's hoarse grunt, and the metal of the restraints clanking as the serf-girl folded them. When the dark woman spoke it was in a whisper, barely audible and spoken downward into the rug so as not to carry. "Be brave, mah sistahs. Tings bettah soon." Yasmin rose, laid the restraints on a table with a bow and returned to her instrument, strumming a faint wandering tune. Endless moments passed, and Marya became aware of the Draka speaking among themselves. "Nice pair of Danes, but I thought you still had that Jewish wench, what was her name." the woman was saying. "Leja." The officer in black worked his shoulders into the cushions and sipped his coffee. "I do, but I'm out of Helsinki in the field, most of the time. No company while I'm gone, too much work for one when I'm back. Besides, she's pregnant again." "Why not have her fixed, for God's sake?" Andrew sighed. "And spoil years of work? She just might not like that, you know; even gratitude has its limits. Why do you think I pulled her out of that Treblinka place when we overran it back in. yes, forty two. Don't roll your eyes, I'm not going to start another boring war story." "You don't have to, I remember the pictures you sent. Fuckin' sick picking her out, too, she couldn't have weighed more than thirty kilos." A grimace. "What happened to the rest of them, anyway?" "Ask our good friend Strategos Vashon here." The squat secret police officer looked up from his desk and leaned back in the swivel-chair, picking up a ball of hard indiarubber. "Nursed them back to health, every one we could," he said; the ball flexed under the rhythmic squeezing of his hand. "Most enthusiastic collaborators we've got, particularly in Germany." Alfred nodded. "And Leja was well worth the trouble, to me; six months an' the bounciest wench yo' could want. Saw she had good bones from the start, an' spirit too." He grinned without opening his eyes, as if savoring a memory, a gaunt expression. "Gave her a knife and she went down a row of SS guards we had tied up, slittin' throats. The two I picked up in Copenhagen, Margrethe and Dagmar, they're just nice little bourgeois muffins, pathetically happy to be out of the ruck and terrified of goin' back." "Why not Finns?" Andrew snorted. "Almighty Thor, no! When I want to commit suicide, I'll do it decent, with a pistol." He opened his eyes and extended a finger at Chantal. "Those Finns're most-all like Leja, or her; hearts of fire. Sieu, they call it. Place won't be safe for a decade. You can tell it by the eyes." He waved his cup toward Chantal. "Speakin' of which, look at that one, sister dear. I didn't save her from a gas chamber. Sure yo' want her 'roundabout the place?" The pregnant woman rested her elbows on the arms of the lounger, placed her palms together, tapped fingers, addressed the inmates. "Look at me, wenches." Gray eyes, impassive. Appraising. "My name is Tanya von Shrakenberg," she said. "Yo' will address me as 'Mistress Tanya", we pronounce it 'Mistis.' This is my daughter Gudrun; you will call her 'Young Mistis Gudrun.' I have bought you out of Central Detention." A smile. "It may interest you to know that your price was roughly the same as a record player's; the tort-bond I had to put up was considerable larger, because yo' two're classified as potential trouble-makers." Her head went to one side. "This is a bad place." Freya's truth, and you've probably heard rumors "bout what might happen when you leave; most of them are true. Breaking rock and shoveling rubble in a chain-gang until you died, most likely. Or worse. You've been very lucky indeed; now you're going to be part of the familia rustica on the plantation my family is establishing west of here. Household serfs; interpreters, bookkeepers. Possibly in positions of responsibility, eventually. Well fed and clothed, not punished unless you break my rules. Which are simple and plainly stated, by the way." She pointed at Chantal, turned the hand palm-up, crooked a finger. "Come and kneel here by me, Chantal." The Frenchwoman shuffled forward on hands and knees, wise enough in the Domination's etiquette not to rise without permission. Tanya cupped a hand beneath her chin, forcing the head up. 'I've read your dossier, wench. You were picked up for curfew-breaking by an Order Police lochos; yo then tried to brain the monitor with a piece of pavin'-stone. Why?" A tighter squeeze. “The truth, Chantal, not what you think I want to hear." "He." A pause. "He tried to rape my sister, she's a child, she's only fourteen, Mistis!" The last word was a hiss. Tanya used her grip on the other's chin to wag her head back and forth. "With the result that you were both raped, repeatedly, then beaten bloody and ended up here, rather than in the factory compound where your family was sent." Another pause. "Have you enjoyed it here? Has your sister? From the report, she's simple-minded now: 'post-traumatic shock syndrome.' How do you think she's goin' to do without you to look after her, here in Central Detention?" Marya could see the hands clenched by Chantal's sides, quivering. The Draka's voice continued: "Have you learned anything from this, Chantal? Besides the fact that the Draka are not humanitarians, that is. "Hearken to the voice of experience, wench. Where are we?" "In, in prison, Mistress." "Beyond that." "France, Mistress." The hand shook her head again. "Wrong. We are in the Province of Burgundia, under the Domination; I am at home, you are an immigrant, ignorant of the laws and customs of the land." A smile. "And a serf, who is new to being a serf. I am a serf-owner, born of seven generations of serfowners; consider who will have the advantage of knowing all the tricks, here. "Now, here's what I'll do. I will buy your sister Therese, as well as you. She will have a room, light work; nobody will hurt her, and I'll even tell the overseers that she's hands-off." Chantal jerked and made a muffled sound. "Or, if you wish, I will have you sent back to her cell and pick someone else. Your choice. Shall I send you back, or not? Now, wench." A whisper. "No, Mistress." "Louder. I can't hear you." "No, Mistress, please." Tanya chuckled and leaned closer. "Now, that's what you should have learned from the incident that brought you here: the difference between courage and recklessness. Not at all the same thing. Tell me, Chantal, do you know what in loco parentis means? Yes? Good; you will be in loco parentis for your sister. Only, for you a special rule will be made; when the parent sins, the child is punished. Understand?" She removed the restraining hand, but Chantal did not move. "Yes, Mistress," she said, in a quiet, conversational tone. "Oh, ho, what a look," Tanya said, keeping her eyes locked with Chantal's. "Andrew was right; a heart of fire, this one. Maybe we'll continue this conversation at greater length, someday." She brought up finger and thumb and flicked the other's nose. "Back." Marya let her breath out in a long shudder, only then conscious of holding it, averting her eyes as the other woman crawled back and sank on her heels by the nun's side, panting as if from a sprint. The sight was disquieting; the nun felt a flush of shame rising from breasts to cheeks and bent her head, letting the pale curtain of her hair hide her face and silently cursing the milkpale skin her Slavic ancestors had left her. The war, the Soviet and Nazi occupations, the long flight westward before the Draka had been chaos, random death, hunger, sickness, running through the cold wet squalor of the refugee centers. Soldiers and police, prison and camps she understood; even the Draka occupation had been merely a harsher version. This was not a matter of armies and bureaucracies, however brutal; it was a ritual of submission rawly personal, as much a matter of calm everyday routine to her new owners as eating a meal. Oh, I understand the psychology of it, she thought; hers had been a teaching Order, and a progressive one. It was still something out of the ancient world, come to impossible life around her. Tanya turned to her daughter, stroking her hair. "You've been patient, darlin'; now tell me, what do yo' think of these two." "Well." the child frowned and wrinkled her nose. "They seem sort of, well, uppish. Sort of. um, shouldn't you punish them, mother?" Tanya laughed, and tousled the girl's hair. "Cudrun, sweetlin', school can teach any number of useful things. But handlin' serfs is like." She pursed her lips and tapped one thumb on her chin. "Like dancing; has to be passed on, one practitioner to the next. There's never a set answer, not on an individual scale. What did the Romans call their slaves?" Cudrun's frown relaxed; that was much easier. "Instrumentum vocale, mother. The tool that speaks." "A wise people. But always remember, the tool that speaks is also the tool that thinks, and believes. Watch." She turned her attention back to the two kneeling figures. Fascinated, Marya observed the change sweep over her face; less a matter of expression than of some indefinable shadow behind the eyes, warmth vanishing until frosted silver looked out at her human chattel. "You, yo' were a nun, eh?" "Yes, I am, Mistress." "Were. Now, if 'n I told you to sweep the floor, would you do it?" "Yes, Mistress." "If I gave you Gudrun's knife an' told you to cut Chantal's throat, would you?" There was a silent pause. "The truth, wench: don't try lyin' to me." Marya moistened her lips. "No, Mistress." "Ah." The Draka smiled. "And if I told you to jump out the window?" "No, Mistis." At the Draka's arched brows: "Suicide is a mortal sin." The Draka woman laughed softly. "And if I told you that if you didn't, I'd kill Chantal here?" Marya opened her mouth, hesitated, shook her head. "More difficult, eh?" Tanya chuckled and nodded to her daughter. "Remember this; there is always some order that won't be obeyed. Either don't give it, or be prepared to kill. Human bein's are like horses, born wild but with a capacity fo' domestication. These are old fo' breakin', so it'll be difficult." She turned to the serf-girl with the mandolin. "Yasmin," she continued, writing and tearing a leaf from a pocketnotebook. "Here. There's a Stevenson and deVerre office on the ground level. Take them down and see to them, there's a good wench. Light cuffs, clothin', tell them the basics. We'll come down when yo're finished." Yasmin covered her instrument in a velvet case and pattered over to them, signalling them to rise. Tanya levered herself to her feet and approached also, stopping them for a moment with a lifted finger, paused. "You two are mine now," she continued; neither of the women lifted their eyes from the carpet. "All your choices are gone, except one. Obedience, life. Disobedience, death. That one we can never take from you." Another pause. "But yo've already made it, no?" She shrugged. "I am your fate, then. Yo've decided to spend life under the Yoke; so remember, there's no point kickin' and buckin'. Be good serfs, an' my family will be good masters. Resist, and yo' suffer." CHAPTER TWO. To defeat an enemy, we must understand him. National myths, and their modem equivalent, propaganda, are perhaps inevitable, certainly useful, but they must not be allowed to blind us to objective reality. Take, for example, the belief, common even among some historians, that the Loyalist refugees who settled the then Crown Colony of Drakia in the seventeen eighties had a secret master plan of world conquest already set out. And that a hidden cabal of Draka aristocrats has been implementing it ever since. Nonsense: a transference to the past of present patterns, as ridiculous as a historical novel showing an 18th-century Englishwoman deliberately seeking a suntan. What is the reality? As usual, a process of cultural evolution that combined blind chance with conscious decisions, many of those falling victim to the Law of Unintended Consequences. The leaders of the proto-Draka were migrants from the slave societies of the Caribbean and the American South; but their subjects were not the uprooted, demoralized fragments delivered by the slavers of the Middle Passage. Little is known of the pre-conquest cultures of Africa, the Draka shattered them too thoroughly, but the evidence suggests strong, militarily formidable peoples. Breaking them, and keeping them broken, produced an overwhelmingly warlike culture with a built-in bias towards expansion; the ideologues and philosophers. Carlyle. Gobineau. Nietzsche. Naldorssen. Merely produced an ideology for a society eager to cast off the increasingly alien ethos of liberal rationalism. The Orate aristocracy needed a world-view and belief system which would make them comfortable with what they were, and ordinary social evolution produced it. Such developments cannot be forced: they must spring organically from the human environment. The failed attempt in the eighteen nineties to revive Nordic paganism is an example, producing nothing but a new type of Draka profanity. But the belief system that did arise among the lords of the Domination then took on a life of its own, becoming cause as well as effect. The Mind of the Draka: a Military-Cultural Analysis Monograph delivered by Commodore Aguilar Emaldo, US. Naval War College. Manila. Eleventh Alliance Strategic Studies Conference Subic Bay. DRAKA FORCES BASE NORDKAPPEN JUNE 12, 1947. Oh-two hundred hours. It was very quiet in the screen room of the electro-detection center, quiet, and dark. There was the underlying whir of the fans, click and hum of relays, a low murmur now and then from one of the operators or floor-officers. Most of the stations in the long bunker were switched off and under dust-covers, and the projac map on the north wall was dimmed. The air smelled of tobacco and green concrete and stale coffee and heating-duct, a tired night-watch odor. The controllers bent over the faint green glow of their screens, faces corpsesallow in the cathode-tube light, insectile beneath headsets and eye-filters, motionless except for minute adjustments to the instruments; they were in Citizen Force undress uniform, black trousers and boots and dove-gray shortsleeved shirts. Operator-first Dickson Milhouse leaned back and stretched, sighed and waved his cup in the air to attract the attention of the serf with the refreshment cart; the pedestal chair creaked as he yawned. Nightwatch sent you to sleep with sheer boredom, and when you came right down to it there was nothing very complicated about holding down a screen. Work for the Auxiliaries, really, except that it still had the cachet of high technology and novelty and so was reserved for Citizen personnel. He rubbed his eyes. Nordkappen Base outside was just as boring. Morale Section tried hard, films and sports and amateur theatricals, and there was always the bordello, but there was just nothing to do here at the northern tip of what had once been Norway; they all had assault-rifles clipped to the top rails of the workstations, but that was merely War Zone regulations. There was still guerrilla activity in much of the territory overrun during the Eurasian War, Europe, Russia, eastern China, but here there was no native population at all, since the Lapps were run out. No game animals to speak of, not by African standards; the long summer days were a novelty that soon wore off, and as for winter. He shuddered. The winters here were nothing someone born under the peaks of Mt. Kenia could have believed. Oh, well, you can always sit on a rock and watch the construction work, he thought sourly. This was an important base, watching the shortest greatcircle route connecting western Eurasia and North America, and tensions were already high between the Domination and the Yankee-run Alliance for Democracy. Dirigibles over the Pole, submarines under the ice, round the clock work here, everything from barracks and mess halls to industrial-size fuel cells and electrodetector towers; many of the installations were burn before reading secret. His eyes fell back on the glowing green surface. He blinked, glanced away and back. Equipment malfunction? No, too definite. Suddenly he was no longer tired, nor bored at all. His finger flicked a relay, and the amber light clicked on above his workstation. "Let me see it." The floor-officer leaned over him, her fingers tapping the key-pad beside the screen. "Bring it up, two." A pause. "And again, two." Her thumb punched down on the red button. An alarm klaxon began to wail. "Definitely a bogey," the floor-officer said. Merarch Labushange grunted in reply, hitching at the uniform trousers that were all he had had time to don; sweat glistened in the tangled hair of his chest, amid several purple bite-marks. He was a short man for a Draka, uglyhandsome in the Mediterranean style, black curly hair, blue jowls, body the shape of a brick and thick arms and legs knotted with muscle. "Estimate height and speed," he grunted, rubbing at red-rimmed eyes. The operator hid a smile behind a cough as he worked the calculator; the commander's new German wench was supposed to be costing him sleep. The results clicking up drove camp gossip from his mind. "Estimate. Estimate Mach 2.2 at 36,000 meters, Merarch." There was a rustle from the other stations, a turning cut short by the floorofficer's glare. Silence, until the operator began another check of the console. "Forget it," the Merarch said. "It's genuine." "But sir, Mach 2?" the operator said, a cold feeling seeping up from his gut. The Domination had flown its first supersonic jet only a few months ago, and this was nearly half again as fast. "The Fritz got manned rocket-planes to well over Mach 1, just before the end," the commander said absently, lost in thought. Of course, those had been one-off experiments, air-launched from bombers and not capable of more than a few minutes of powered flight, but. "The Yankees must have been workin' hard, produced a surprise. Afterwards they can claim it was a glitch in our equipment, or little green men from Mars." He grinned like a shark. "Trouble is, we have some surprises too, an' they can scarcely object to our usin' 'em, on somethin' that don't officially exist." He glanced around the dim-lit room, and his smile widened. "Of course, it could be headed this way with an atomic." He strode briskly to the commander's dais, sank into the chair and keyed the communicator. "Alert, codes Timbuktoo, Asmara, Zebra. Get me." Echoing, thundering, the darkness of the B-30's cargo pod shook around Captain Fred Kustaa, toning through muscle and bone with subsonic disharmonies. He was strapped almost flat in the crash-couch, imprisoned in the pressure-suit and helmet, packed about with gel-filled bags to absorb the bruising punishment of the experimental craft's passage through the upper atmosphere. Outside the titanium-alloy skin would be glowing, the edges of the huge square ramjet intakes turning cherry-red as air compressed toward the density of steel. It was the helpless feeling that was hardest to take, he decided, not the physical danger. He had been a combat soldier in the Pacific before he transferred to the OSS in forty-four, and God knew liaison work with the Draka in Europe in the last year of the War had been no picnic, but this. Experimental, he thought. Everything's too fucking experimental for my taste. Donovan should have tried the submarines first. Hell, Murmansk wasn't more than a few weeks on foot through the forest to Finland, although it would be a bit difficult to carry the contents of the cargo pod on his back. The aircraft lurched and banked, and his stomach surged again; he concentrated on dragging in another breath through the rubber-tasting facemask. Vomiting inside it would be highly unpleasant and possibly fatal. About as maneuverable as a locomotive, had been the test-pilot's words; too little was known about airflow at these speeds. Kustaa did not understand the B-30, he would not have been risked over enemy territory if he did, but even just looking at it from the outside was enough to know it was leadingedge work. It didn't even look like an airplane, it looked like a flattened dart pasted on top of two rectangular boxes. "Merde." The pilot's voice, Emile Chretien; Kustaa recognized the thick Quebec-French accent. He spoke a little of the patois himself, there were plenty of habitants scattered among the Finnish-Americans of his home in the Upper Peninsula. "Electrodetection, high-powered scanners." Kustaa winced. Well, that had been one reason for this mission, to find out for sure just how good the Domination's new Northern Lights Chain was. The dark pressed against his eyes, and he used it to paint maps; their course from the Greenland base, over the Arctic toward darkened Europe. His imagination refused to stop, and he saw more; saw the alert going out below, to bases in Sweden and Norway, alarm-klaxons ringing out over concrete and barracks, flight-suited pilots scrambling to their stations. The blue flare of jets lighting the predawn as the stubby delta shapes of the Draka Sharkclass fighters rolled onto the launch paths. The B-30 was supposed to be immune to interception; the Domination had the physical plant of the German ramjet research projects, but the U.S. had managed to smuggle out most of the actual scientists and the crucial liquidhydrogen results. The aircraft lurched again, shook as if the wings were going to peel away at the roots, stooped. One of the Pacific Aircraft researchers had said something about eventually flying right into outer space if they could lick the problem of combustion in a supersonic airstream; damned long-hairs had no sense of need-to-know, shouldn't have been talking like that in a canteen. "Tabernac'! Another ray guidance beam, something's coming up after us!" Of course, he reminded himself, the U.S. hadn't gotten all the German scientists; some had stayed, captives or those who had taken the Domination's offer of Citizen status for themselves and their immediate families. And the Draka army's Technical Section had good ideas too, sometimes; it was propaganda that they stole all their inventions. "Positive detection. fille d' un putain, three of them; not manned, not at those speeds. They're closing on us, they must be riding the beam. Hold on, Captain, I'm dropping chaff and taking evasive action." You mean this battering about wasn't evasive action? Kustaa thought plaintively. This was as bad as going down the tunnels after the Nips, back on Sumatra in forty three, pushing the flamethrower ahead into the cramped mudsmelling blackness. Japanese, Captain, Japanese, he reminded himself. Part of the Alliance for Democracy now, they'd be associate signatories to the Rio Pact as soon as Halleck and the Army of Occupation got through restructuring. Couldn't call the little yellow bastards monkey-men anymore. His mind skipped, nerves jumping in obedience to a fight-flight reflex that was pumping him full of adrenaline. And all I can do is sweat, he thought wryly. He could feel it trickling down his flanks, smell the rankness and taste salt on his upper lip. Think, he commanded himself. You're not an animal driven by instinct, think. Unmanned antiaircraft missiles, a typical Draka brute-force solution. Crude engines would be enough, if they were intended to burn out after a single use. The U.S., he corrected himself mentally, the Alliance, didn't have guidance systems small and rugged enough for a missile like that, although they would soon, so the Domination wouldn't either; they were years behind in electronics. But they could put the tracking and electro detection on the ground, just a passive receptor-steering system on the missile itself, that and a big simple two-stage drive and a warhead. Christ have mercy, I hope it isn't an atomic, he thought. Probably not, they were still rare and mostly reserved for strategic use, but the Draka would be willing to explode one over a populated area. Populated by serfs, that is. Jets and atomic bombs built by slaves, he thought. Insane. The Domination was madness come to earth; he shivered, remembering his liaison-work with the Draka army, during the misbegotten period of joint action against Hitler. Gray faces of the Belgian farmers as they prepared to drive their tractors out over the minefields. And the sick wet noises of the one who had refused, seated on an impaling-stake cut out of the little forest; his feet had scuffed around and around as he tried to rise off the rough wood sunk a foot deep into his gut, and blood and shit dribbled down the bark. Some of the Draka dug in at the treeline had laughed, at him or at the explosions and screams in the plowed field ahead. The B-30 went thump, absurdly like an autosteamer going over a bump at speed, and the sensation was repeated. That would be the strips of foil being ejected, hopefully to baffle the Draka electrodetectors. Acceleration slammed him down and to the side; they were climbing and banking, and metal groaned around him as the big aircraft was stressed to ten-tenths of its capacity. "Still locked on. Merde, Coming up on target. Prepare for ejection. Captain." The pilot's voice was full of a tense calm; Air Force tradition, cando, wild blue yonder. His heart lurched, and his mind refused to believe the time had gone so fast, so fast; it was like the wait between boarding the landing-craft and the moment the ramp went down on the beach. Kustaa wished he could spit out the gummy saliva filling his mouth, as he had running waist-deep through the surf in a landing-zone. Some men did that, some were silent and some shrieked wordlessly, a few shouted the traditional gung-ho and a surprising number pissed their pants or shat themselves; you never saw that in the papers, but only a recruit was surprised at it. Damn, start out a Gyrene and end up a paratrooper, he thought. "Acknowledged." His circuit was locked open, had to be with his hands strapped down, but there was no point in distracting Emile. "Ten seconds from. Mark." There was no point in bracing himself, the harness was as like a womb as the technicians could make it. Nine, he counted to himself. He had married in forty one, right after the Nips had attacked Hawaii; they had planned to wait until he finished the engineering course, but being a Marine private was a high-risk occupation. Aino had spent the war years in San Diego working in a shipyard. They had bought one of the new suburban ranch-style bungalows that started springing up around L.A. right after the Armistice. Eight. The sweating dreams had been bad, waking screaming as the bunker door opened and the calcinated body of the Japanese soldier dropped out onto him, knocking him down in an obscene embrace with their faces an inch apart; Aino had held him and asked no questions, even when it woke little Maila. Seven. She hadn't wanted him to continue with the OSS, especially not when it meant moving back East to New York; the capital was no place to raise a family. She had seen to the sale of the home where she had expected to live the rest of her life, doggedly settled into the Long Island brownstone, entertained his co-workers on awkward evenings when nobody could talk shop and long silences fell. Six. They had been out to a movie, a Civil-War epic called President Douglas; the newsreel had been a political piece, film of a serf-auction in Archona. The usual sensational stuff lifted from the Domination's news services, no routine shots of black factory-hands here, ABS-Path way knew their audience found injustice more titillating spiced with sex and inflicted on white people. A showing of high-cost European concubines in heels and jewelry and nothing else, parading down an elevated walkway; the American film-editors had inserted black rectangles to keep the Catholic Decency League happy. The shabby refugee beside her had stood and begun screaming, pointing at the screen. "Mein Gott, Christina, Christina!" Still screaming, climbing over the seats with clawed hands outstretched towards the smiling blond image standing hand-on-hip. He was screaming as the attendants carried him away. Five. Kustaa's wife had not objected to his volunteering for secret duty after that. He dreamed of the bunker less, now; but sometimes it was the refugee who stumbled through the steel-plate door in the nightmare, and the face was his own. Four. It was not getting agents into Europe that was the trouble, it was moving them around, harder each month as more and more of the population vanished into pens and compounds. The Domination had leaned on its "allies" to reveal their Resistance contacts during the War, and had been politely refused. Some of the networks still survived, incredibly, but they were useful mostly for small stuff, escape-conduits and microfilm. Virtually impossible to move in equipment, except a few microscopic loads by submarine on wilderness coasts. Three. His tongue touched the false tooth at the back of his mouth; melodrama, bad Hollywood, but he knew too much. It was lousy tradecraft, sending him in multiply tasked. There were too many contact-names and dates and codes in his head, but what was the alternative? Besides, they needed a survey, an overview of what was going on. If only they could get deep-cover agents into the Security Directorate! It was easy enough to slip in agents posing as Europeans or Chinese, it would be years before a billion individuals could be necked and registered, but every Citizen's identity was established from birth and there were only forty million of them. Two. Of course, the Draka had probably slipped hundreds through with the vast flood of refugees that had poured across the English channel in the last days of the War, when the Domination's armies were driving for the Atlantic. More would come through with every boatload of escapees, probably many sleepers under deep cover, it was long-term planning and the Draka thought that way, but what could you do? One. He had seen his daughter take her first steps on his last leave; Aino had looked up, and as their eyes met, Impact. Blackness. A yell of satisfaction filled the electrodetection center of Nordkappen Base. The third missile's trajectory intersected the American aircraft's flightpath, and the sound rose to a howl; fell away to a disgusted mutter as it winked out and the blip of the intruder re-emerged. Merarch Labushange ground out another half-smoked cigarette; an attendant had brought his shirt and tunic, but the rims of his eyes were still a bloodshot red. He rose in disgust, then checked. "Wait a minute," he muttered. Then: "Cross-patch on that; increase resolution." He leaned forward to watch one screen, then another; swiveled to view a third that received its input from an automatic station in the mountains to the south. "She's shedding something," he said quietly. "Increase resolution again, maximum. Look!" His finger stabbed out. Half a dozen traces were spreading out from the veering curve of the American aircraft. Smaller, much smaller, curving and falling. "Is she breaking up?" the floor officer said hopefully, cradling her coffeecup. Labushange shook his head. "At that speed? It'd be over by now. Lose aerodynamic stability at Mach 2 and you'd be metallic confetti; she's maintaining velocity. Increasin', if anything; and turning north." His head turned to the nearest operator with a gun-turret precision. "Give me a ballistic trajectory on that debris, unguided." The operator frowned, adjusting and calculating; his fingers danced over the controls while his eyes stayed fixed on the hooded green glow of the screen. "Faint, almost as if they were non-metallic. Hum, if'n they don't change direction after they drop below our detection horizon, central Finland, sir." "So, so, oh, clever little Yankees; force us to show our best defenses, get back with the data, 'n drop good things to the worst troublespot in Europe." Labushange closed his eyes and rose on the balls of his feet, biting his lower lip in thought. Then the orders came, spoken with a triphammer beat. "Get me a teleprinter patch; East Baltic H Q, Riga. Route it though to Europe Command in Marseille, and to Castle Tarleton. Copies to Security liaison, all along. Then." Kustaa was unconscious as the pod fell, the flexing snap of deceleration striking like a horse's hoof. It needed no guidance, a ton-weight egg of soft curves and dull, nonreflective coating that would make any but the most sophisticated electrodetector underestimate its size. Plummeting, tumbling, then turning to present its broadest end to the earth as wei

Rahan. The son of the fierce ages. Episode Sixty-Nine. By Roger Lecureux, drawn by Andre Cheret. The weapon of terror. The men who had chased him reappeared between the charred trees and the son of Crao resumed his course. The charred branches cracked under his feet and with each stride he raised a cloud of charred dust. Oh. Perhaps these caves lead to the other side of the hills? The fugitive had a choice, since six caves were available to him! As he rushed towards the one that seemed the largest, a clamor of fear rose behind him. Page Two. And He noticed that his pursuers stood still, as if stunned by a sacrilegious act! Perhaps this cave is sacred to them? In this case, Rahan will be safe from their spears! The clan, intoning a funeral chant, in fact withdrew. The sentences carried by the wind which reached Rahan announced "The imminent death of the hunter with the hair of fire." Strange! They announce the death of Rahan and seem to deplore it! The cave was, in fact, quite small and had no other exit than the entrance. A lava flow had once been stopped by these hills and the cracks in the ground were full of sand the color of "Fruits of the Sun". A white powder fell from the crumbly walls, mixing with the black dust carried by the wind. Hum! Rahan was not the only one to seek refuge here! Page Three. As night fell, the son of Crao heard the rumble of a "Gorak" He is very close! He approaches! The “Gorak” goes wild when we confront him. But his fury falls before a lifeless prey! Lying on his back, Rahan held his breath when the saber-toothed tiger appeared. But his hand tightened firmly on the ivory knife. The big beast approached and smelled the man. When his instinct told him that the life inhabited this body, it was too late for him! Ra-ha-ha! For a moment Rahan thought he had been cowardly. No! In front of a "Gorak" cunning is not cowardly! But more will come if Rahan does not light a fire. Page Four. At the entrance to the cave he cut some dead branches. His fire, he knew, would keep the wild animals away. He had discovered flints on the powdery ground. He made a spark emerge. And it was terrifying! With a sound like an angry volcano the cave seemed to burst! The breath of this fantastic explosion threw the son of fierce ages thirty steps away! Baroom! Page Five. “Hair-of-fire” is still alive! Thick smoke was still escaping from the cave when hunters discovered him. His sacrilege nevertheless deserved death! The shock was so violent that Rahan did not regain consciousness until daybreak. Men surrounded him. We were not pursuing you yesterday. We wanted to tell you how dangerous it is to approach the “thundering caves”! You should not have run away from us "Hair of Fire." Rahan does not understand. He only struck the “Star-Throwing Stones.” And. It was enough to unleash the wrath of the cave! Taiwa, the leader of this clan, related how, one night, his brother had been torn to pieces in another cave. The unfortunate man believed that the light of his torch would chase away evil spirits! Page Six. And yet Arrix had warned him. We never challenge these evil spirits with impunity! "Hair of Fire" should be punished for arousing their anger! Rahan does not believe in "Evil spirits"! Taiwa's brother had a torch to enter the cave. And Rahan made a spark. It is the fire that makes the caves thunder! Rahan will discover why! He will prove to Arrix the sorcerer that evil spirits do not exist! Nothing could have stopped the son of Crao from returning to the mysterious caves. Arrix still spoke of "Sacrilege", but the hunters admired his courage when he entered the one where he had almost died. Of the great charred "Gorak", only a few bones and ashes remained. The smoke and flames had blackened the walls. Page Seven. And Rahan noticed a strange thing. The lava floor was now bare. The flows of yellow sand, the layer of black dust and white powder had disappeared! The “dust of the cave” has burned. And maybe that was the one who thundered!? In these wild times, such an assumption defied understanding. But the son of Crao knew nature was capable of very strange things! An instant later he entered another cave. Here, the yellow streams were numerous, the trails of coal dust were wide. The layer of white powder was thick. Rahan could not know that it was sulfur, and saltpeter. Worried cries erupted when he appeared with the small piles of powder. Hair of Fire provokes the evil spirits. Fear nothing! Rahan thinks it is one of those powders that "Thunders." He wants to know which one! Page Eight. A little later. Stay where you are. Rahan will join you! The son of fierce ages lit fine lines buried in the three powders. And ran towards the hunters. Arrix will know that the “Thundering Caves” are not haunted by “Evil Spirits”! Everyone held their breath. The little flames gnawed at the vines, approaching the small piles. They reached the black powder, then the white, then the yellow. And nothing happened! “Hair of Fire” wants to deceive our clan! Kill him immediately! Arrix-the-witch had triumphed and the hunters stared at the son of Crao with anger. Page Nine. But he did not resign himself so quickly to failure. Wait! The powders may only “Thunder” when mixed! He made a pile of the three powders and lit the vine. Again there was silence. And pointed looks. And suddenly. Ka-Boom! A muffled noise resounded as a high flame rose, which went out almost immediately. The powder had disappeared. Does Arrix still believe in “Evil Spirits”? Rahan was right to believe in the power of powders! That flame had nothing to compare with those of the caves! The caves thunder in such a terrifying way, because the powders are there in large quantities and because they are trapped in there! Rahan will prove it to you! Page Ten. The son of Crao had had a new experience that day. In this bamboo, the three powders should make a loud "Thunder"! Oh! As he had almost spilled the powder, he decided to block the bamboo with a plug of clay. Attention, stay away! This time the explosion was so strong that, although he moved away, he was thrown to the ground by the blast. Ka-boom! Rahan has discovered a wonderful and terrible secret! The “Two-toothed” themselves would flee before these “bamboos that Thunder”! This demonstration definitely chipped away at the authority of Arrix-the-sorcerer. And it was more so in the days that followed. Page Eleven. The son of ages tried new blends. More white powder and less yellow increased the power of the “Thundering Bamboos” “Hair-of-Fire” will soon have more influence over the clan than you do, Taiwa. Since we know the secret of the powders, you should chase him away! Unaware of the sorcerer's intrigues, Rahan continuously experimented with the "bamboos that thunder”. Let us see their effect in the river, brothers! Hum! The water extinguishes the vine! We should protect the embers for a moment. Just a little moment. That morning he imagined a cover to protect the fuse of the explosive. And the result was astonishing. Page Twelve. A spray rose and dozens of fish came floating to the surface. When game becomes scarce, the river will feed the clan! A dull rumble in the mountain, suddenly interrupted the "Fishing." An avalanche! Quickly Rahan, To the big cave! There always the clan takes refuge! Large rocks were moving down the slope, dragging others down in their fall, creating a torrent of granite. And the avalanche stopped as suddenly as it had begun. We will never see ours again! Beyond the deserted village, the entrance to the large cavern was blocked by huge rocks. Taiwa. Arrix. Our women, Our children. All will die in the belly of the mountain! Page thirteen. No! The “Bamboos that Thunder” will save them! In the black gap of an interstice he threw some “Bamboos.” Then he plunged the torch into it. Run away! Flee! Baroom! He had barely rejoined his companions when the explosion shook the landslide. Rocks were still crumbling. But a breach had been made A gateway to life! Taiwa and Arrix appeared first. Then the hunters. Then the women and children. The night that followed was a night of celebration. But it was disturbed by a harangue from Arrix. Do not forget, my brothers, that the “Thundering Bamboos” give us “Almighty power”! Page Fourteen. We will be able, thanks to them, to decimate those of the Green Valley and seize their territory, which is so full of game! Arrix is more disgusting than a monster! Thundering Powder" should not be used against "Those Who Walk Upright"! The sorcerer roared. Your tongue chatters too much "Hair of Fire"! Our young warriors will snatch it from you! As an eddy stirred in the hunters, the son of Crao jumped towards the fire, a "Thundering Bamboo" in his hand. Rahan awaits your young warriors, Arrix! Calm returned, but Rahan had a premonition that the ignoble idea of Arrix would permeate into their primitive minds. Rahan had simply wanted to discover the secret of the powders. Page Fifteen. But he does not want their terrifying power to be used against men! Obsessed by his thoughts, he could not sleep. He observed the sleeping village. The hut of Taiwa, and that of the sorcerer. And suddenly. Ooh! Arrix is not sleeping either. But what is he afraid of? Casting worried glances around him, the wizard crawled out of his hut. And the son of fierce ages saw him heading towards the lava flow. Towards the “Thundering Caves”! A moment later he surprised the trickster filling a “Bamboo” with powder. He saw many other "Thundering Bamboos", no doubt prepared the previous nights. Arrix has not abandoned his criminal ideas! Page Sixteen. With these “Sticks” Arrix will impose his law! Taiwa will have to obey him! We will annihilate those of the Green Valley! Blinded by the jet of powder, Rahan backed away. He fell against a stone and lost his balance. Ha-ha-ha! The “Territory of Shadows” awaits you, “Firehair”! Between his powder-covered eyelashes, the son of Crao caught a glimpse of the sorcerer brandishing his spear. His hand instinctively closed around a large flint. Arrix jumped back to avoid the projectile. And. As a fantastic explosion shook the cave, the silhouette of his disjointed body was silhouetted against the dazzling light. Page Seventeen. Other explosions followed. Those of the “Bamboos-that-thunder” accumulated by the sorcerer. Why did Rahan make the cave thunder?! Rahan recounted what he had just seen, what he had just done. The stone-that-throws-stars missed Arrix, but it must have hit the wall to make a spark. So, this cheat prepared “Thundering Bamboos.” Unbeknownst to the clan! And he wanted to lead your people into war! The son of fierce ages was serious. Rahan should not have discovered the secret of the caves! The powder gives too much power to those who have bad thoughts! He looked at the caves. The one where the sorcerer had just died, and which was still smoking. The one where Taiwa's brother had been torn to pieces. The one where he himself had almost died. These three were forever harmless. Page Eighteen. But there were still the others! What are you doing? Rahan rushed towards the village where the fire was still burning. He soon appeared again, with three torches. No one knows if your people, or other hunters, will not one day give in to bad thoughts! But Rahan will not give them the means to decimate themselves! The torch flew towards the giant mouth of a cave. The explosion was still shaking the hill when he threw the other torches into the last two caves. All the powder will burn! The caves will never thunder again, brothers! The explosions. Flames. Smoke. The son of fierce ages seemed to have emerged from an inferno. But this “Devil” only proclaimed words of peace, this precious good of “Those-who-walk-upright,” men. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html

Rahan. Episode Sixty-Eight. By Roger Lecureux, drawn by Andre Cheret. The Captive of the great river. The wind had died down, but Rahan, amazed, noticed that the large skin sail was inflating in the opposite direction to the raft's movement! He understood that this phenomenon was due to the speed of the skiff. That an increasingly rapid current carried him towards the horizon. The force of this current became such that its "rudder" no longer had any effect. The son of Crao could not have known, not yet, that this one, which fed hundreds of rivers, poured its waters into a gigantic gorge. Page Two. The current thus created carried him irresistibly towards these falls, and nothing could stop this race towards death. He saw a rocky island beyond which the lake ended abruptly! A dull growl reached him. If Rahan does not reach this island, it is the "Territory of Shadows" that awaits him! He tried to change the course of his skiff. The latter, helpless, turned on itself and. Glided on the tumultuous flow, and rushed towards the islet that was circled with foam. Ra-ha-ha! Rahan will see the sun set! Page Three. The shock was incredibly violent. The raft broke apart and its trunks disappeared between the rocks whipped by the waves. Entangled under the main sail, the son of Crao managed to free himself. A few trunks remained stuck in the rocks, but most were carried towards the thundering falls, two arrow-shots from the islet. Rahan will not be able to rebuild his raft! The rocks on this side of the islet had been worn and polished by the waves. The others arose from sharp edges. Suddenly. Oh! A killer from the sky! Rahan used this name for the pterodactyl. This one held a very young boar in its beak. Page Four. The bird released its prey and, flapping its wings, fluttered towards the son of Crao. Rahan understands! You do not want to share this refuge with him! Rahan dodged the first peck. His ivory knife was going to strike when. Stop, Man! Do not kill "Arak"! Rahan was frozen in astonishment. An old man was finding it difficult to extricate himself from a fault in the rocks. I am Kaagou. And “Arak” is my companion! Approach. Approach. You are the first man I have seen since my raft, like yours, was shattered on this cursed island! Every time the river carries the dead leaves, I draw a new sign! There were signs that numbered twice the fingers of both hands! Rahan was still just a little man when Kaagou ended up here! Yes! Kaagou and his brothers wanted to know where the big lake ended. Page Five. But the flood carried them away, no doubt like you. Kaagou was luckier than his people, who were swallowed up by the falls! Kaagou had another chance. Being able to treat an injured bird. Since then, “Arak” has remained faithful to him. He is the one who hunts and fishes for Kaagou. And Kaagou will live like this until his last day! Rahan will not remain prisoner of the river! The old man gave a sad smile. Kaagou believed it too, at first. How can you make a skiff on this island without trees!? And how can you swim without being caught by these falls!? Page Six. Any attempt was not only impossible, but also unthinkable. And the days passed. "Arak" brought back enough fish to feed the captives of the river. The vision of distant but inaccessible forests, like the incessant roar of the falls exasperated the son of Crao. Ah! If Rahan could fly like "Arak"! This idea haunted him until the morning when, Do you think “Arak” could take away Rahan!? Rahan is no longer in his right mind! But if he wants to try this madness, Kaagou can only wish him good luck! If Rahan succeeds, Kaakou will be able to abandon these cursed rocks in turn. “Arak” will come and get him! Alas. It will not be so, my son! The large pterodactyl was docile and powerful. The son of fierce ages hung on his legs, and he seemed to rise quite easily. Page Seven. But, very quickly, he showed signs of fatigue. Rahan discovered the staggering spectacle of the falls. Everything beneath him was fantastic. The torrent of water surged to a height he never imagined. The swirls and whirlpools only subsided near the falls. Too far! Return, "Arak", return! You will not be able to go any further! The exhausted pterodactyl was falling almost headlong towards the raging waves! However, he found the strength to regain height and returned, gliding, towards the rocky islet. Rahan cannot blame you, "Arak"! His idea was crazy! A little later. Do you understand that we cannot escape the river? You will have to live here until the end of your days! After Kaagou's death, you will be left with "Arak"! Page Eight. No! No! Rahan will find a way to escape this island! He saw! He now knows that a few stone's throws from the falls, the river becomes peaceful again! The thought of growing old, and then dying on these rocks, captive of the river, was untenable to the son of Crao. But what could he do except feel the claw on his necklace which symbolized “confidence”? As night fell, he felt the urge to light a fire. And he thought of the trunks stuck in the rocks. The trunks were still there, near the skin sail. But the wood, soaked in water, did not catch the sparks of his stones. We will not have a fire, Kaagou. It will be a night like any other! As always, there was the sound of the current in the center of the island. As always, the incessant roar of the falls, the same whistling of the wind. And yet this night was not like the others! Page Nine. Rahan knows how to escape, Kaagou! You will be thrown into the falls, you and these trunks! Trunks, yes! But Rahan will fly to the “Calm Waters!” The skins will bear him better than the wings of "Arak"! The old man thought that his companion had definitely lost his mind. He was wrong. Rahan had dreamed of the wings of "Arak" and the wind inflating the mainsail! The wings. The wind. The ideas had merged to form one! And that was why Kaagou found him, at daybreak, on the side of the islet facing the falls, straddling two trunks. Goodbye Kaagou! If Rahan fails this time again, you will find him in the territory of shadows! Farewell! The wind suddenly swelled the sail that the son of Crao had just released. Page Ten. And, Kaagou-the elder thought he was dreaming. The skin rose and Rahan left the rocks. The wind, adding to the current, carried him away at a crazy speed. Tightly gripping the trunks with his legs, Rahan caught a glimpse of "Arak" who was escorting him. The roar of the falls became deafening. And the abyss opened before him! The trunks suddenly reared up, propelling him into the void. If his sail did not support him it was certain death! Page Eleven. Clinging to the vines, he saw the gulf of water and terrifying swirls rising towards him. The son of Crao fell! But he was falling slowly. Hanging from the sail, he was moving away from the falls! It was an agonizing descent, obliquely above the whirlpools. Ra-ha-ha! The falls thundered in the distance. The current which he was approaching was certainly still formidable, but it had crossed the deadly zone. Carried by the sail, he plowed into the foaming surface and, to regain mastery of his movements, he released the vines. Page Twelve. A powerful swirl turned him around, another drew him towards the depths. But these last manifestations of the river's anger. Could no longer jeopardize the life of a swimmer like Rahan. Rahan knew how to soar like a bird. Now he swims like a fish! The current became less strong, but the shore was still far away. When the son of Crao reached it, his strength abandoned him. He lay down on the sand, and before falling asleep, he thought of old Kaagou who had remained forever a captive to the river! He slept for a very long time because the sun was rising behind the falls, when strange murmurings woke him up. What? What? Page thirteen. Dozens of men, face down, were prostrate around him! They suddenly stopped their prayer. The “God-Who-Flies” is awake! Stand up, brothers! We saw you flying above the "Rumbling Waters"! All night, we prayed for you while waiting for you to wake up! You probably come from the “territory of the Gods”! Our clan is flattered by the honor you do it! Rahan is not a god. He is only the son of Crao, a simple hunter like you! Why are you lying? Our eyes have not deceived us! You had a big wing above your head and you were flying! Our clan would like to see you fly again! Uh!? It is impossible. Page Fourteen. Rahan spoke of the wind. A skin sail. From the height of the falls. Which allowed him to glide. You are making all this up because you refuse to fly in front of us! Do you despise our clan? Be careful “God-that-flies”! Our clan will not hesitate to kill a god who despises it! The hunters, clutching their assegais, had become threatening! Marrak demands that you fly in front of his brothers! If you refuse, their spears will tear your chest open! The son of Crao felt that these men would not hesitate to carry out the execution. But, observing the puny Marrak, he suddenly had an idea. Rahan will fly, But on one condition. Marrak must defeat him in a fair fight! Page Fifteen. If Marrak triumphs, Rahan will fly, otherwise he will not fly! Our clan accepts! Rahan smiled. He knew he was capable of defeating the leader with the first strike! But. Our clan accepts, but Marrak cannot ignore the custom that prohibits the leader from fighting! This is why Ogloo will fight in his name! Rahan's smile froze, the colossus who was approaching was a head taller than him! But he could not refuse without unleashing the hunters. May the “God-Who-Flies” and Ogloo face each other fairly! The fight began and the son of Crao immediately felt that it would turn out badly for him! Ogloo, who engulfed him, had the strength of a large four-hands. Page Sixteen. And he could not loosen his grip. If Rahan loses, they will kill him, so he will not be able to "Fly"! Rahan had unusual strength. But did not Crao-the-sage say “that we always end up meeting someone stronger than ourselves! That day had come! He felt himself torn from the ground and found himself, dazed, five steps from his adversary. Ogloo has won! The “god-who-flies” must keep his promise! The son of fierce ages had only one goal left: Escape as quickly as possible from these men who attributed to him a power that he would never have! The circle of assegais prevented him from doing so. It is understood. Rahan is going to fly, but he has to climb this tree. Page Seventeen. A moment later, he saw beyond the foliage, the course of the great river. Salvation was on this side! A clamor arose when he let himself fall into the void! The god is flying! The god is flying! The son of Crao, in fact, now gave the impression of flying. Fluttering from one vine to another, he moved away into the kingdom of the "Four-Hands". And the hunters followed him. And cheered each of his jumps. The “God-Who-Flies” is leaving! The “God-Who-Flies” is leaving us! No doubt he is angry with the clan. We should not have forced him to fly! Oh! Look! Page Eighteen. High above, Rahan had just abandoned a long vine. His tense body passed like an arrow above the tall thickets. And he dived towards the calm of the river. The clan screamed with joy, convinced that they had been visited by a supernatural being. Rahan could join them. But. They would end up demanding that he fly without the help of the lines! But Rahan is not a bird! Very high in the sky, in fact, hovered a large bird. And the son of Crao thought he recognized "Arak." While the light current carried him away, he thought of everything that the bird had discovered and that his master would never see! He thought of the old man forever captive of the great river, who would continue to engrave a sign in the rock each time he reached the season of dead leaves. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html

doi:10.1038/s43587-020-00013-3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932957/ https://rumble.com/v3t4yzj-index-of-science.-music-by-dan-vasc.html Intermittent and periodic fasting, longevity and disease. Valter Longo, Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, and others. Published in Nature Aging, January 2021, pages 47 to 59. Abstract. Intermittent and periodic fasting, I-F and P-F, respectively, are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. I-F lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have the potential to prevent and treat disease, but their effect on cellular aging and the molecular mechanisms involved are only beginning to be unraveled. Here, we describe the different fasting methods and their effect on longevity in organisms ranging from yeast to humans, linking them to the major nutrient-sensing signaling pathways and focusing on the benefits of the fasting and the refeeding periods. We also discuss both the therapeutic potential and side effects of I-F and PF with a focus on cancer, autoimmunity, neurodegeneration and metabolic and cardiovascular disease. Dietary restriction (D-R) refers to regimens including the reduction of the intake of either calories or of specific components of the diet, such as protein or certain amino acids, and to intermittent and periodic fasting, I-F and PF, respectively, which may or may not require an overall reduction in calorie intake. Instead, calorie restriction (CR), which in most cases involves a chronic reduction in calorie intake by 20 to 40 percent below the standard, extends lifespan and health span in yeast, invertebrates, laboratory rodents and non-human primates. In humans, 15 percent CR reduces markers or risk factors for a range of age-related diseases, including diabetes, cancer and cardiovascular disease, but it also causes side effects, which include a low or very low body mass index (BMI) when applied chronically. Moreover, a chronic CR of 20 to 60 percent in mice can have positive effects on aging and immune function, but can increase susceptibility to certain pathogens, such as the influenza virus and intestinal parasites. Protein restriction (PR) independently of calorie intake also extends lifespan in mice and improves the health of young and middle-age mice and humans, but moderate to severe PR can lead to frailty and,or disease in old mice or individuals over the age of 65. Severe PR, in which calories from proteins are below 5 percent of the total, could also have detrimental effects, including weight loss in younger organisms, as shown in mice. Signaling pathways by which CR and PR extend lifespan include those activated by growth hormone, insulin-like growth factor-1 (IGF-1) and insulin, and involve downstream factors, including phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin complex 1 (mTORC1), protein-kinase A (PKA), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1 alpha, PGC-1 alpha, sirtuins and forkhead transcription factors (FOXOs), that are well established to regulate or affect aging and longevity. Thus, both CR and PR can have strong effects on nutrient signaling pathways and aging, but there is a need to identify novel interventions that optimize health span while minimizing side effects and the burden imposed by chronic dietary interventions. These studies could allow the identification of specific dietary regimens effective in delaying, and even partially reversing, aging and age-related diseases. In this Review, we discuss the role of dietary restriction in aging and disease, with a focus on I-F and PF regimens (Table 1 and Box 1). The use of generic terms like I-F, fasting and even dietary restriction, which include interventions lasting from a few hours to months and represent many dietary compositions and severities of caloric restriction, needs to be limited and replaced by specific terminology referring to a clearly defined intervention so that use can be standardized for the laboratory, the clinic and eventually the public. These intermittent or periodic dietary interventions can promote cell protection and repair as well as the clearance of damaged cells and intracellular components, in part through the modulation of conserved stress-response or nutrient-sensing pathways. Whereas the dietary-restriction field has mostly focused on the benefits of continuous caloric or macronutrient restriction, here we focus both on the importance of much shorter restriction periods and the refeeding and post-refeeding phases, which is accompanied by a regenerative process that is not observed or is much less active during chronic restrictions. We summarize the metabolic and cellular responses triggered by these feeding regimens, their impact on nutrient signaling pathways and their link to age-related diseases. Fasting methods and effects. Common fasting methods. Different fasting regimens (Table 1) can affect metabolism, aging, disease and mortality in simple organisms and mammals. I-F includes various eating patterns; water-only fasting or severely restricted (over 50 percent) calorie intake lasts between 12 and 48 hours, and in most cases is repeated in cycles occurring every day to once per week. There are several types of I-F diets commonly adopted in rodents and human clinical studies: complete water-only fasting that occurs every other day, also called alternate-day fasting, ADF; 70 percent energy restriction every other day; The 5 to 2 diet, which provides between 500 and 700 calories for 2 days per week; And time-restricted feeding (TRF), in which food intake is in most cases restricted to 6 to 12 hours per day. Thus, I-F regimens usually encompass a period in which only water is consumed or calorie intake is very low, which is followed by a normal feeding period that in most cases lasts between 12 and 48 hours. In contrast, PF refers to a prolonged and severely calorie-restricted or water-only fasting period lasting in most cases between 48 hours and 1 week, although several studies have investigated longer fasting periods. Unlike I-F, it can occur at specific intervals or on an as needed basis, but it is usually carried out less than once every 2 weeks and in most cases only a limited number of times per year for periods lasting 2 days or longer in mice or 4 days or longer in humans. There are two major methods of PF: (1) water-only PF25 and (2) a fasting-mimicking diet (FMD), which is a plant-based caloric-restricted diet containing low proteins, low sugars and high unsaturated fats that are able to mimic the effects that water-only fasting has on IGF-1, IGF binding protein 1 (IGFBP-1), ketone bodies and glucose. Metabolic effects of fasting. In most mammals, the liver serves as the main reservoir of glucose, which is stored in the form of glycogen. In humans, depending upon their level of physical activity, 12 to 24 hours of fasting typically results in a decrease in serum glucose and depletion of hepatic glycogen, accompanied by a switch to a metabolic mode in which glucose, fat-derived ketone bodies and free fatty acids are used as energy sources. After hepatic glycogen depletion, lactate, pyruvate, fat-derived glycerol and amino acids account for the gluconeogenesis-dependent generation of approximately 80 grams per day of glucose, which is mostly utilized by the brain. Depending on the severity and length of the restriction, fatty acids are mobilized, leading to an increase in circulating ketone bodies and adiponectin and a lowering of circulating leptin. In humans, the fed-state blood levels of ketone bodies are at or below the limit of detection and reach levels of 0.2 to 0.5 milli Molar within 8 to 12 hours after the onset of fasting, but reach levels between 1 and 2 milli Molar by 48 hours. This metabolic switch occurs more rapidly in rodents, as plasma ketone levels are elevated within 4 to 8 hours after the onset of fasting and reach millimolar levels by 24 hours. Intermittent fasting, metabolism and aging. Intermittent fasting in simple organisms and rodents. I-F affects longevity in multiple organisms. In worms, I-F activates mitochondrial-network plasticity as they are switched between fasted and fed states, which may contribute to longevity extension. Moreover, recent studies in mice show that cycles of fasting lasting from 12 to 72 hours followed by a refeeding period have beneficial effects on longevity, markers for health, stress, metabolic response, age-related diseases and tissue regeneration. Cycles of fasting lasting 48 hours or longer will be covered in more detail in the Effects of periodic fasting and fasting-mimicking diet section. In flies, chronic I-F has failed to extend lifespan, suggesting that flies can be sensitive to a shorter starvation period. In mice, however, I-F can have both neutral or positive effects on lifespan (see following section) and the beneficial effects of D-R on longevity appear to be due, at least in part, to the time-restricted access to food, and therefore to extended daily fasting periods. New studies in flies investigating short-term I-F regimens for only a part of the lifespan followed by a switch to ad libitum feeding at later stages indicate stronger effects on the aging process. Again, more marked effects are observed when the flies are switched back to an ad libitum diet after 30 days of I-F, in agreement with a series of studies in mice, indicating that the refeeding period is as important as the fasting or restricted stage. A number of studies have investigated the effect of I-F on the health and lifespan of rodents. In one of the earliest studies, Goodrick et al, reported an increase of up to 80 percent in the average lifespan of rats maintained on a regimen of ADF, started at 5 weeks of age. Later studies show much smaller effects of ADF, but several of them confirm an extension of median, as well as maximal, lifespan. In addition, longevity in male C57BL, 6J mice subjected to ADF is associated with a delayed onset of lethal neoplastic disorders that typically limit natural lifespan in many mouse strains, but this was achieved without a delay of the aging process, in agreement with earlier studies. Thus, the magnitude of the effects of ADF on longevity in rodents depends upon the species, mouse versus rat, strain and age at regimen initiation, and can range from a small negative effect to as much as an 80 percent lifespan extension. Similarly, it has emerged from a genetic screening that CR can exert positive or even detrimental effects on longevity, depending on genetic variations in different mouse backgrounds. For example, in two different mouse genetic backgrounds A, J and C57BL, 6J, I-F did not extend mean lifespan, and even reduced lifespan, when initiated at 10 months. When initiated at 1.5 months, I-F either increased longevity or had no effect. However, in rodents, I-F enhances cognitive performance, which may be caused in part by its stimulatory effect on synaptic plasticity, improves insulin sensitivity and reduces blood pressure and heart rate. Moreover, 2-month-old male C57BL, 6J mice fed a time-restricted high-fat diet (16-hour daily fasting period), show protection against obesity, hyperinsulinemia, hepatic steatosis and inflammation with improved motor coordination, despite a caloric intake equivalent to that of the group with ad libitum access to a high-fat diet. At the molecular level, TRF in mice affects the energy signaling mediated by c-AMP responsive element binding protein (CREB) and AMPK, the pro growth mTOR pathways and the expression of circadian clock gene. A deep understanding of the type and length of fasting and mechanisms that can maximize longevity effects, as well as of the detrimental effects that may be counterbalancing the positive ones, is required. Fasting may be consistently protective in young and middle-aged laboratory rodents that are affected by cellular damage and aging, which lead to insulin resistance, inflammation, genomic instability and so on, but may have at least some detrimental effects in old or very old animals after they begin to lose weight or become frail. Human studies on intermittent fasting, aging and disease risk factors. A rapidly increasing number of studies have investigated the effects of different I-F regimens produces mild caloric restriction and weight loss in obese adults. A number of trials testing I-F in humans show positive effects on metabolic markers but, together with epidemiological studies, also point to potential side effects, particularly after long-term use. Varady and colleagues showed that ADF in overweight or obese adults with insulin resistance produces a greater reduction in insulin levels and insulin resistance than CR does, despite achieving a similar decrease in body weight. On the other hand, Madeo and colleagues found that either short-term (4 weeks) or long-term (6 months) ADF carried out in healthy middle-aged humans has beneficial effects on metabolic and cardiovascular markers alongside reduced levels of soluble intracellular adhesion molecule-1 (sICAM-1), an age-associated inflammatory marker, low-density lipoprotein (LDL) and the metabolic regulator triiodothyronine. Panda and colleagues, who had shown the beneficial effects of TRF for preventing and treating obesity and metabolic disorders in mice, showed similar cardiometabolic benefits in people with metabolic syndrome who consumed food for only 10 hours daily. TRF prevents excessive body-weight gain, improves sleep, attenuates age and diet-induced deterioration in cardiac performance and improves blood pressure and accumulation of atherogenic lipids. Cienfuegos and colleagues also reported that 4 and 6 hour TRF reduces body weight, insulin resistance and oxidative stress compared with results from non-time-restricted controls, supporting further studies on TRF as a promising intervention for weight loss and cardiometabolic protection. The health effects of I-F are accompanied by weight loss, but how much reduced adiposity affects disease risk factors remains poorly understood. In one trial, 16 healthy participants, aged between 23 and 53 years with a BMI between 20 and 30, assigned to a regimen of ADF for 22 days lost 2.5 percent of their initial weight and 4 percent of their fat mass, with a 57 percent decrease in fasting insulin levels. In two other trials, overweight women, with approximately 100 women in each trial, were assigned to either a 5 to 2 I-F regimen or a 25 percent reduction in daily caloric intake. The women in the two groups lost the same amount of weight during the 6-month period, but those in the group assigned to the 5 to 2 I-F had a greater increase in insulin sensitivity and a larger reduction in waist circumference. However, there are also a number of studies indicating that frequent fasting cycles may not only be difficult to carry out for long periods, but also increase side effects and even mortality. For example, the risk of gallstone disease nearly doubles between women who fast for 8 hours per day and those who fast for over 14 hours per day. Furthermore, skipping breakfast, which is perhaps the most common method adopted to reach a daily 14 to 18 hour daily fasting period, is associated with an increased risk of mortality from cardiovascular and all-cause mortality in the US population. Clearly, epidemiological data are not easy to interpret and the association between long daily fasting periods and increased incidence of disease or mortality could be explained by factors other than the fasting itself. However, until further studies, including randomized clinical studies and additional epidemiological studies, are conducted, the use of this type of daily fasting intervention should be limited to short-term periods and applied to only people with disease for which regular I-F has been demonstrated to be effective. It is also important to gain an understanding of the effect of long daily fasting periods in which dinner is skipped instead of breakfast. In contrast, daily fasting, TRF periods of approximately 12 hours appear to be associated with benefits without known negative effects. Effects of periodic fasting on aging Periodic fasting and fasting-mimicking diet. In contrast to the short and very frequent fasting periods of I-F, PF or FMD last in most cases between 2 and 7 days, 2 to 3 days in mice and 4 to 7 days in humans, and are followed by a high-nourishment refeeding period of at least 1 week. Another major difference from I-F is that PF can be periodic and does not have to be carried out at a specific interval, but can be applied for one or several cycles either as a preventive measure or to treat a specific disease or condition. PF was traditionally carried out in specialized clinics with water-only or very-low-calorie methods, but outside of a clinic, such a regimen can be difficult to maintain and unsafe because it can cause side effects, including malnourishment, rapid weight loss, reduced blood pressure and hypoglycemia, as well as the exacerbation of existing micronutrient deficiencies. These safety concerns and the scarcity of preclinical and clinical data may explain why historically the potential benefits of PF have emerged multiple times within the medical community, but have eventually disappeared and have not been integrated into standard-of-care practices. Thus, FMDs were developed to promote the effects of fasting while standardizing dietary composition, providing nourishment and minimizing the burden and side effects associated with water-only fasting. Notably, these steps are necessary for PF and possibly I-F to move toward approval from the US Food and Drug Administration and standard-of-care applications. The FMD composition, which includes low protein, low sugar and high unsaturated fat, achieves a reduction in IGF-1 and glucose, and an increase in ketone bodies, and IGFBP-1, similar to that caused by water-only fasting in mice. Various versions of the rodent FMD have been utilized, but in most cases, they provide between 10 percent and 50 percent of the normal caloric intake for periods ranging from 2 to 5 days, with the most severe restrictions lasting from 2 to 3 days. A longer regimen with less caloric restriction is also used, which consists of 5 days with a caloric intake ranging from 50 percent on the first day to 30 percent for the rest of the days. Mice undergoing FMD cycles lose about 15 to 20 percent of their body weight, which is recovered upon refeeding. In fact, the severe caloric restriction is compensated by overeating during the refeeding period, resulting in the same or similar caloric intake in the FMD and control groups. Rodent studies on prolonged fasting or fasting-mimicking diet and longevity. Sixteen-month-old female C57BL, 6 mice placed on a periodic 4-day FMD twice per month, alternating with a normal diet, display an 11 percent increase in their median lifespan, in addition to significant weight and visceral-fat loss, without loss of muscle mass. Moreover, FMD cycles reduce tumor incidence by 45 percent and delay tumor development, with most being detected after 26 months of age. FMD cycles that are started at middle age reduce skin inflammation including dermatitis by 50 percent and improve motor coordination along with long and short-term memory. Notably, the FMD cycles also promote changes leading to an immune-system profile in 20.5-month-old mice more similar to that of younger mice, 4 months old, in agreement with the effect of PF on hematopoietic stem cell (HSC)-dependent regeneration of immune cells. In addition, FMD cycles selectively reduce visceral fat without an overall reduction in per-month calorie intake, indicating a potential acceleration in metabolism during the refeeding period. In summary, similarly to the well-established effects of CR, FMD cycles delay the onset and reduce the incidence of age-related diseases, but achieve this with minimal or no long-term reduction in calorie intake and with positive effects on immunity and a targeted reduction in visceral fat. Thus, PF, FMD but potentially also certain D-R, including I-F, may achieve many beneficial effects by mechanisms that are independent of reduced calorie intake. In fact, chronic protein restriction, without calorie restriction, is well established to extend longevity and healthspan. Notably, I-F and PF, similarly to chronic CR, delay disease incidence but also reduce the lifelong portion of animals that develop any type of disease, and particularly cancer. One limitation of studies with PF and I-F is that they have been conducted on only a few mouse strains, and mostly on C57BL6 mice, so we do not yet know whether the health benefits and lifespan increase is not dependent on rodent strain. On the other hand, several of these studies were conducted in both female19 and male mice, and some of them began when the mice were young and others when the mice were already middle aged (16 months), indicating that the health and lifespan benefits of I-F or PF can be achieved when started at middle age. A recent study has shown that there is memory of CR done during early mouse life, and that age-dependent mortality can depend on the nutrition earlier in life. This is another effect of CR, I-F and PF that is poorly understood and could help achieve the goal of maximizing healthspan and longevity with minimal burden. Human studies on prolonged fasting, fasting-mimicking diet and longevity. A study assessed longer periods of fasting in large cohorts that included non-obese participants. In a 1 year observational study, 1,422 non-obese participants aged between 18 and 99 participated in a fasting program consisting of fasting periods of between 4 and 21 days in which they fasted with a daily caloric intake of 200 to 250 kcal accompanied by a moderate-intensity lifestyle program. Significant reductions in weight, abdominal circumference and blood pressure were observed, along with a reduction in blood glucose levels and increase in ketone bodies, proving the fasting-related metabolic switch. However, these effects are detected during the fasting period. Also, a single period of extended fasting with concomitant weight reduction leads to significant, rapid improvement of fatty-liver index in people with or without type 2 diabetes, age greater than or equal to 18 and BMI greater than or equal to 19 kilograms per meter squared by the end of the fasting cycle. However, the long-term effect of this regimen on fatty liver after return to the normal diet is not known. The major limitation of these very severe and prolonged fasting periods is that they must be carried out in a specialized clinic to avoid adverse events. Furthermore, we do not know the long-term effects of the long periods (weeks) of water-only or very-low-calorie fasting on health. In fact, long periods of CR have been associated with a reduction in metabolic rates, which could actually promote, rather than reduce, fat accumulation after the end of the fasting or CR period, which would result in the regain of weight as established in studies involving severe restrictions or fasting lasting 10 days and longer. In addition, multiple cycles of weight loss (ranging between 7 percent and 10 percent) and regain (yo-yo diets) are associated with increased mortality, indicating that long and severe fasting periods could have short-term benefits followed by long-term beneficial as well as detrimental effects. The periodic use of FMD and refeeding cycles was studied to identify interventions to maximize effects against aging and age-related diseases, while minimizing side effects and the burden of frequent restrictions. In a randomized clinical trial with 100 relatively healthy volunteers, FMD cycles lasting 5 days, carried out once per month for 3 months, reduce multiple risk factors for age-related diseases, including diabetes, cancer and cardiovascular disease. These effects include reduced body weight and trunk fat, lowered blood pressure and decreased IGF-1, along with decreased BMI, glucose, triglycerides, cholesterol and C-reactive protein 5 to 7 days after returning to a normal diet in people that displayed elevated levels of these markers at baseline. Notably, the beneficial effects of the FMD on several of these markers, risk factors were maintained for months after subjects returned to a normal diet. These studies underline the potential of PF, FMDs and other types of fasting for extension of not only health span but also youth span, the range of time in which an organism remains youthful, healthy and fully functional. Thus, PF and FMD cycles that alternate with normal refeeding periods appear to be safe in both rodents and humans and to have beneficial effects on disease or disease risk factors when started at middle to old age, 16 months in rodents. Although FMDs appear to be safe, their use should be limited to three times per year in healthy people with normal levels of disease risk factors, until additional and long-term clinical studies demonstrating the safety of more frequent use are carried out. In contrast, the more severe and longer forms of fasting should only be done in a specialized clinic in the presence of medical personnel. How much of the benefit of PF is due to effects on cellular aging and dysfunction versus the effect of weight loss remains unclear and is addressed in the following sections. Because there is a concern that all types of fasting methods may in the long term cause side effects, including those listed earlier, when done too frequently, the beneficial effects of I-F and PF must be weighed against their potential side effects, particularly in healthy or relatively healthy individuals. Both basic and clinical research should focus more on interventions that maximize efficacy against aging and age-related diseases while minimizing side effects and the burden of the intervention, which is usually inversely correlated with long-term compliance. Periodic fasting, intermittent fasting and nutrient signaling pathways. Reduced activity of the nutrient-sensing pathways that regulate aging in yeast, Figure 1), worms and flies can also extend longevity in rodents, Figure 2. Thus, inhibition of the mTOR pathway either pharmacologically with rapamycin or genetically by deletion of the ribosomal S6 kinase 1 (S6K1) extends longevity in mice. In addition, S6K1-mutant mice show a delayed onset of age-related phenotypes, such as bone-matrix loss, immune and motor dysfunction and insulin resistance. The GH IGF-1 axis, acting upstream of mTOR PI3K AKT-1 and PKA signaling, has been intensively studied in mammals because of its effects on the incidence of age-related diseases and lifespan. Indeed, mice lacking the GH receptor binding protein (GHR-BP) display a 40 percent longer average lifespan than that of controls, with reduced tumor incidence. A number of additional studies have shown similar extended lifespans for mice with defects leading to both GH and IGF-1 deficiencies, which are also associated with downregulation of TOR signaling in multiple cell types. Whereas the mTORC1 inhibitor rapamycin increases longevity in wild-type mice, in mice with knocked out growth hormone receptor that have constitutively suppressed mTORC1 and upregulated mTORC2 signaling, it leads to a drastic reduction in mTORC2 in liver, muscle and subcutaneous fat, which in turn causes an elevation of the inflammation marker interleukin-6, reduced numbers of functional immune cells and a shortened lifespan. These results together, with a series of previous studies, indicate that mTORC2 is not as clearly linked to aging as mTORC1 and that its inhibition may even be deleterious. Because carbohydrates and proteins play a central role in growth, it is not surprising that the protein and sugar restriction associated with PF, I-F and CR causes conserved changes in growth factors and nutrient signaling. It is well established that higher protein levels increase IGF-1 levels and that several amino acids are sufficient to promote an increase in the levels of this growth factor in the serum and also in TOR-S6K signaling. For example, methionine regulates the growth hormone (GH)-IGF-1 axis, whereas amino acids including leucine and arginine can activate TOR-S6K signaling. Moreover, the balance of macronutrients, not just their levels, and particularly of protein and carbohydrate can affect lifespan. In the mouse liver, when protein is replaced with carbohydrate, compensatory mechanisms are inhibited and protein uptake is suppressed, leading to mTOR inhibition. Furthermore, the quality of macronutrient, for instance animal versus plant-derived proteins, can influence aging and disease. In fact, high protein intake in adult life (up to age 65) is associated with increased risk of overall mortality and cancer-related death, however this association is attenuated or eliminated when the higher intake of proteins is from plant-derived sources. It has also emerged that amino-acid quality can have an important effect on aging, and in fact an imbalance of branched-chain amino acids compared with other amino acids (high BCAA:non-BCAA ratio) leads to reduced longevity through a mechanism independent of mTOR activation and caused by hyperphagia. Sugars can also activate various pathways including Ras or PKA signaling either through insulin action or by an insulin-independent mechanism of insulin and resulting in reduced antioxidant protection and cellular stress sensitivity. Thus, it is not surprising that GH or GHR-deficient mice and those undergoing I-F or PF, all of which reduce common proaging pathways, share an extended longevity and a major reduction in disease incidence. For example, CR (from 10 percent to 50 percent) reduces IGF-1 and insulin, as well as Tor-S6K signaling, in rodent models. In agreement with mouse studies, in humans CR reduces IGF-1 levels only when protein intake is also restricted, underlining the need to focus both on calorie intake and dietary composition and their effects on nutrient signaling pathways. I-F, including ADF and TRF (8-week fast, 16 hours per day, 16 to 8, also decrease IGF-1, blood glucose and insulin levels while increasing insulin sensitivity and adiponectin levels. PF and FMDs also affect the levels TOR-S6K, IGF-1, insulin and glucose in mice, but these effects are reversed when animals return to the normal diet. Thus, it is likely that a long-lasting reduction of factors including glucose, insulin and IGF-1 caused by CR is not necessary for at least part of the lifespan and healthspan effects. However, in humans, FMD cycles can have long-lasting effects on IGF-1, insulin and glucose, raising the possibility that at least some of the effects of dietary restriction and FMDs on longevity may involve long-term effects on the levels of these factors. Another mechanism that may explain the role of the temporary reduction of these factors on the longevity extension caused by PF is the activation of HSC-based and other regenerative processes discussed later in this Review. Notably, these effects depend on the activation of regenerative processes that begin during fasting periods but are completed after mice return to a normal diet. I-F lasting between 12 and 24 hours can also have effects on IGF-1, IGFBP-1, glucose and ketone bodies, but most of the changes are smaller than those obtained by the longer PF or the chronic CR. For example, in mice, 4 weeks of every-other-day I-F did not elevate ketone bodies but instead caused a reduction in beta-hydroxybutyrate levels and beta-hydroxybutyrate dehydrogenase activity in the mouse liver but not in the cerebral cortex, where levels remained unchanged or enhanced, supporting the importance of further investigating the mechanisms of ketone-body production, release and delivery. However, circulating IGF-1, insulin and glucose were decreased after resistance-trained men (aged 29 to 33 and weighing 85 to 92 kilograms) were placed on a 16 to 8 fast, indicating that I-F can have a positive effect on these factors. Notably, because this I-F period also caused loss of fat mass, it is difficult to establish whether the effects of I-F on insulin and glucose and possibly IGF-1 are mediated by effects on adipose tissue. Importantly, these positive effects in men undergoing the 16 to 8 TRF were also accompanied by negative ones, including an over 20 percent decrease in total testosterone. These results point to the importance of continuing to study both the short-term and long-term molecular changes caused by I-F, PF and CR and to connect them to the positive as well as negative effects on metabolic markers, but also diseases and other conditions. Fasting-refeeding and regeneration. Fasting and refeeding regimens are powerful promoters of stem-cell self-renewal mechanisms and activators of tissue regeneration, in part through inhibition and reactivation of the IGF-1, PKA and mTOR pathways (Figure 3). The PF and FMD regimens can promote a rejuvenation process in tissues, organs and cells through the activation of cell death and autophagy followed by the activation of stem or progenitor cells. Notably, the refeeding period appears to be responsible for a major component of the regeneration process leading to the replacement of senescent or damaged cells with new cells arising from tissue-specific stem cells. Not surprisingly, the effects of short-term fasting and FMD on stem-cell function and regeneration depend on the content of the diet, its effects on different pathways and the timing and duration of the regimen. For example, lifelong CR does not prevent the age-related functional decline of HSCs in mice, whereas short-term fasting periods, as well as FMD regimens followed by refeeding periods, do promote regenerative and rejuvenating effects in the hematopoietic and immune systems. This is a fundamental distinction between cycles of fasting and refeeding compared with chronic dietary interventions, which may have smaller regenerative effects compared to fasting, refeeding by preventing or limiting the regenerative phase which requires high levels of macro and micronutrients and possibly higher calories to support macromolecular synthesis, cellular division and growth and tissue and organ expansion. Stem-cell-based regeneration is stimulated by I-F and PF through nutrient-sensing pathways. The positive effects of fasting have been described in multiple stem-cell types, including muscle stem cells, HSC’s, intestinal stem cells, ISC’s, and neuronal stem cells, NSC’s. The common mechanisms through which fasting affects stem-cell function involve modulation of the amino-acid and glucose-sensing pathways, including IGF-1 TOR PKA, also implicated in longevity regulation. However, the fasting refeeding cycles also affect inflammation and can cause long-lasting epigenetic changes or changes in the stem-cell niche, which could contribute to the biological age of cells and organs. Whether changes in stem-cell function in response to nutrient availability are mediated by epigenetic changes is still unclear, but a few studies have indicated this possibility. For instance, the regulation of NSC proliferation in response to decreased glucose availability is governed by the nutrient sensors CREB and SIRT1, and the effects of CR are accompanied by an increase in histone H3 acetylated at Lys 9 (H3K9Ac). Changes in dietary intake are accompanied by massive changes in chromatin states in several species. On the basis of these studies and on previous results of PF and FMD on tissue regeneration, we speculate that FMD and, or refeeding periods may cause long-lasting epigenetic changes, although further studies are required to test this hypothesis and to understand its possible role in stem-cell maintenance during aging. During aging, a skewing in the lineage of differentiation of HSCs occurs with relatively more myeloid cells being produced than lymphoid cells. This skewing contributes to an age-related impairment of adaptive immunity. PF reduces IGF-1-PKA signaling and promotes HSC self-renewal and long-term repopulation capacity upon serial transplantations and lineage-balanced regeneration of the immune system. Also, four periodic cycles of PF or FMD started at 16 months of age rejuvenate the hematopoietic system, leading to an increased number of white blood cells 1 week after refeeding, and to a partial reversion of the age-dependent lineage skewing. Moreover, FMD cycles can partially revert the age-dependent decline of mesenchymal stem and progenitor cells, thus indicating that they promote proliferation of new stem and progenitor cells in various tissues. Quiescent satellite cells express the transcription factor paired box 7 (Pax-7), and when activated, coexpress Pax-7 and MyoD, the myoblast determination protein, which promotes transcription of muscle-specific target genes and plays a role in muscle differentiation. When they proliferate, they downregulate Pax-7 and differentiate. Interestingly, mice undergoing FMD cycles show increases in Pax-7 and MyoD in muscle tissue, with associated reversal of markers of impaired autophagy. Of note, the boost in protein expression of the regenerative markers was detected during the refeeding period, while no major changes were measured at the end of the fasting period. These results indicate that different systems may activate quiescent stem or progenitor cells at different stages during the fasting and refeeding periods. Notably, in old mice, short-term administration of spermidine, a known CR mimetic, reverses the age-associated defect of autophagy in muscle cells, normally characterized by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress. The molecular mechanism of spermidine action involves the increase of protein deacetylation and autophagy activation through induction of arginine and NO (nitric oxide) metabolism, as well as downregulation of pro inflammatory cytokines in muscle stem cells (satellite cells). In the mouse pancreas, PF and FMD promote a decrease in the numbers of differentiated or committed pancreatic cells, followed by the induction of transitional alpha-to-beta or beta-to-alpha cells that coexpress both alpha (that is, glucagon) and beta (that is, PDX-1 or insulin) cell markers, and finally a major increase in the proliferation and number of insulin-generating beta cells. The metabolic reprogramming caused by the FMD also affects lineage determination in pancreatic islets with increased pluripotency and beta cell reprogramming markers, especially one day after refeeding. Results in human pancreatic islets from healthy donors and people with type 1 diabetes indicate that FMD induces the expression of SOX-2, NGN3 and insulin in part by reducing IGF-1 and inhibiting both mTOR and PKA signaling. Recent work confirms the effect of FMD on pancreatic regeneration and diabetes in a genetic mouse model of type 2 diabetes and also confirms that a FMD promotes reduced blood glucose, increased insulin sensitivity, beta cell proliferation and NGN3 expression. The protein content of this specific FMD formulation was higher (17 percent versus 6 percent), whereas fat was lower (14 percent versus 65 percent), than the content of the Cheng et al, formulation, but the diet was administered for nearly twice as long and was much more calorically restricted (7 days at 30 percent of daily calorie intake). Thus, in the latter study, changes in the key signaling pathways, similar to those caused by the shorter FMD, were likely to be achieved by a longer and more severely restricted period with a less-fasting-mimicking macronutrient ratio. Thus, the beneficial regenerative effects achieved are affected by dietary composition, severity of the calorie restriction and length of the PF or FMD period. In another study, one day of fasting was sufficient to increase ISCs and progenitor activity both in young and old mice by inducing a fatty-acid oxidation program. Interestingly, a recent study carried out in a mouse model of intestinal bowel disease shows that FMD cycles stimulate protective gut microbiota, reduce intestinal inflammation, increase stem-cell number and reverse intestinal pathology. Notably, water-only fasting increases regenerative and reduces inflammatory markers without reversing pathology, supporting the possibility that specific nutrients contained in the FMD, and possibly prebiotic ingredients contained in plant-based foods, can have a crucial impact on microbiota and consequently on the course of the disease. A recent study highlights that dietary macronutrients, in particular carbohydrate and protein, can also be major drivers of microbial response and can reshape microbiome by dictating nitrogen availability to bacteria. Previous studies also indicate that long-term dietary restriction can increase the regenerative capacity of ISCs via an extrinsic mechanism involving reduction of mTORC1 in the niche surrounding Paneth cells, suggesting that the refeeding period is not necessary for ISC activation, although it may enhance or maximize regeneration as indicated in other studies. Taken together, these studies suggest that the mechanisms of regeneration may vary depending on the timing, duration, composition and severity of both the fasting and refeeding diet. However, mechanisms involving IGF-1, TOR and PKA are likely to represent common denominators in the protective and regenerative effects of I-F, PF and CR. Notably, both the inhibition of these signaling proteins and enzymes during the fasting and their activation during the refeeding are likely to be important for the regenerative process. In fact, their role in regeneration during the refeeding period is poorly understood and should be investigated further in multiple tissues. Intermittent fasting, periodic fasting and aging-related diseases. Advancing age is the major risk factor for most major diseases, including cancer, diabetes and neurodegenerative, cardiovascular and immunological diseases. Because I-F, PF and FMD cycles have been shown to slow down and partially reverse cellular aging in rodent models, a number of studies have investigated their potential application to the prevention and treatment of age-related diseases (Table 2). Neurodegeneration. Fasting has been shown to protect neurons and ameliorate cognitive impairment in animal models. A triple transgenic mouse model of Alzheimer’s disease (AD), which expresses familial AD mutations in the beta-amyloid precursor protein (APP), presenilin 1 and Tau, fed either a 40 percent CR or ADF dietary regimen for 1 year starting at 5 months of age, developed reduced cognitive impairment, compared with that in ad libitum-fed control mice. Interestingly, 40 percent CR, but not ADF, reduces the levels of beta amyloid (A Beta) and Tau accumulation in the brains of the AD mice. The intermittent restriction of essential amino acids also protects mice from pathology and cognitive decline in triple transgenic AD mice, suggesting that the protein-restriction component of the fasting plays a key role in its protective effects. The latter study did not detect reduced levels of Abeta after restriction of essential amino acids, although it did observe reduced accumulation of phosphorylated Tau in the hippocampus. This suggests that fasting and protein restriction can protect the nervous system even in the presence of high levels of Abeta, although their effect on the fibrillar versus soluble forms of Abeta remain poorly understood. The mechanism by which fasting protects neurons from degeneration has been linked to increased expression of neurotrophic factors important for neuronal cell growth and stress resistance, including BDNF and FGF2. Studies also suggest important roles for the ketone body beta-hydroxybutyrate and the mitochondrial sirtuin SIRT3 in the neuroprotective mechanism of IF. Ketone bodies may be protective against GABAergic interneurons degeneration through a mechanism dependent on SIRT3, which was shown to reduce anxiety-like behavior and to improve hippocampus-dependent memory in mouse models of AD. A common genetic mouse model for Parkinson’s disease (PD) that overexpresses human alpha-synuclein exhibits progressive accumulation in neurons and shows motor dysfunction and premature death. When these mice were treated with ADF, the autonomic nervous system deficit was reversed, while it was exacerbated even more in mice on a high-fat diet. Bai et al, in a recent study showed that, in response to rapamycin treatment and the consequent inhibition of mTOR, these PD model mice displayed reduced oxidative stress and synaptic damage and an overall improvement of motor function. Hence, ADF cycles have the potential to improve the overall pathology progression. Although it has not been tested with AD mouse models yet, PF or FMD has been shown to increase neural stem cells and increase cognitive performance in normal, old mice. Major issues remaining to be addressed when considering human trials are the burden of fasting every other day and the side effects described earlier, particularly in people with PD or AD, who in most cases will be over age 70. The identification of the specific dietary compositions responsible for neuroprotective and regenerative effects and the description of the mechanisms involved should eventually allow the design and development of fasting-like interventions that are able to protect against neurodegeneration with minimal side effects. Diseases of the immune system. Aging is associated with progressive immune senescence, which is caused in part by the age-dependent impairment of HSC function. This results in a higher ratio of myeloid cells relative to lymphoid cells, accompanied by a decline in common lymphoid progenitors, and ultimately reduced T and B-cell lymphogenesis as well as stem-cell exhaustion and reduced regenerative capacity. Dysfunctional lymphocytes can consequently give rise to immunosuppression or immune senescence, but may also contribute to autoimmune disorders such as asthma, systemic lupus erythematosus, multiple sclerosis (MS) and rheumatoid arthritis. Certain dietary restriction regimens have the potential to prevent and, or reverse age-dependent immune dysfunction by killing or altering autoimmune cells and activating HSC-dependent regeneration. Notably, severe CR (66 percent CR) and 8 weeks of ADF regimen prevent autoimmune encephalomyelitis (EAE) in mice. Although the molecular mechanisms of autoimmune disease suppression are not yet known, these diet regimens have been shown to decrease the amount of circulating T cell and inflammatory cytokines and chemokines. In contrast to the prevention of autoimmunity described above, for the treatment of already-established MS symptoms and pathology, FMD refeeding cycles were shown to attenuate EAE by modulating immune cells and promoting regeneration of oligodendrocyte precursor cells. The FMD cycle increased apoptosis in autoreactive T cells, which are replaced in part by newly generated naive T cells during the refeeding period. Notably, several studies show that fasting and CR can cause both the death and relocalization of different immune-cell populations. In agreement with the rodent study, a clinical trial in humans also reported a reduction in lymphocytes upon FMD intervention and an improvement in quality of life in people with MS. However, larger studies are necessary to determine whether the FMD can reduce multiple sclerosis pathology and progression in people. Cancer. Recently, a series of studies in animal models has shown that PF and FMD lasting two or more days can be as effective as chemotherapy at delaying the progression of a wide range of cancers but, more importantly, can protect normal cells from the toxic effects of chemotherapy while sensitizing cancer cells to the treatment. PF and FMD cycles appear to increase the killing of cancer cells by causing system-wide changes that affect the ability of malignant cells to survive or adapt, which includes a reduction in IGF-1, insulin, glucose, leptin and cytokines, but likely also changes in hundreds of enzymes or pathways. Notably, fasting and FMD are most effective against cancer cells when combined with chemotherapy, radiotherapy, kinase inhibitors, metabolic drugs or hormone therapy. Another important mode of action of cycles of PF or FMDs and refeeding is the activation of the immune surveillance to promote T-cell-dependent killing of cancer cells. These effects of the fasting, FMD on immunity-dependent attack of cancer cells was confirmed by a recent study from Collins et al, showing that mice that underwent severe 50 percent CR for few weeks accumulated memory T cells in the bone marrow, and that caused enhanced protection against infections and tumors. The broad effect of fasting and FMD in decreasing circulating levels of glucose, and IGF-1 and increasing ketone bodies, IGFBP-1 and so on together with the targeted toxicities of standard cancer therapies have the potential to promote major improvements in therapeutic index and cancer or progression-free survival. Diabetes and cardiovascular disease. Both I-F and PF or FMDs can be effective in reducing not only weight, abdominal circumference and body fat, but also risk factors for metabolic syndrome, diabetes and cardiovascular disease. ADF and chronic CR caused similar effects on weight loss, reducing body and abdominal fat and lipids and improving insulin sensitivity in humans. Notably, ADF had stronger effects on high-density lipoprotein (HDL) and LDL than did CR. Another study on people with one or more risk factors for metabolic syndrome compared a 6-month ADF against chronic CR. Both groups experienced a similar decrease in body weight, 8 to 9 kilograms, as well as improvements in blood pressure, triglycerides and HDL (Table 2). In another study, 8 weeks of a 10-hour time-restricted eating decreased body weight (4 kilograms), waist circumference (4 cm), systolic BP (13 millimeters of Mercury) and glucose in people with metabolic syndrome. No significant changes were found in LDL cholesterol, HDL and insulin or insulin resistance (Table 2). For the PF interventions, three monthly cycles of a FMD were effective at reducing risk factors for diabetes and CVD in higher risk people. Independently of initial weight, people underwent a reduction in BMI, although individuals with BMI greater than 30 displayed a greater decrease (Table 2). Significant improvements in total cholesterol, LDL, fasting glucose, C-reactive protein and triglycerides were also observed in people with high levels of these risk factors at baseline (Table 2). In summary, both I-F and PF or FMD’s can cause a wide range of improvements in cardio metabolic risk factors, which are likely to lead to a reduction in diabetes and CVD’s. Additional and larger studies will be important to determine which of these interventions can become standard of care in disease prevention and treatment. Conclusion and future perspectives. I-F and PF or FMD activate ancient programs that promote entry into alternative metabolic modes focused on conserving energy and on protecting the organism while enduring extended periods of food deprivation to optimize survival and reproduction once food becomes available. In fact, it is the refeeding period that has more recently emerged as an equally important process involved in the regeneration, and possibly rejuvenation, of systems, including organs, cells and organelles. In humans, the alternation of fasting and refeeding periods is accompanied by positive effects on risk factors for aging, diabetes, autoimmunity, cardiovascular disease, neurodegeneration and cancer. But not all fasting interventions are equal, and some are associated with smaller beneficial effects as well as side effects, including, in some cases, reduced longevity. The I-F and PF field should expand the investigation of the effects of dietary macronutrient composition, ratio and quality on health span. In fact, lifespan and health span extension can be reached by a specific macronutrient balance, independently of caloric intake. It is also important to identify the mediators of the effects of I-F and PF not only on different types of mammalian cells and organs and on disease, but also on the microorganisms of the digestive system, with a focus on the molecular mechanisms mediating key effects on cellular protection, aging and regeneration. It will not only be important to separate the positive effects of I-F and PF from the adverse effects, but also to match the type and length of I-F and PF with goals including health span extension, the prevention and treatment of specific diseases and weight management. Acknowledgements and 150 References, and three figures. Figure One. Fasting, nutrient signaling and longevity in yeast. Starvation conditions in yeast cause a major lifespan extension mediated in large part by the lack of amino acids and sugars. On one hand, amino-acid restriction causes the inactivation of TOR Pkh S6k signaling; on the other hand, low glucose levels promote reduced activity of the Ras-adenylate cyclase (Cyr1) PKA pathway. Both the amino-acid and the sugar pathways converge on and inactivate the serine threonine kinase Rim 15. This, in turn, contributes to the activation of stress-resistance transcription factors Gis1, which binds to post diauxic shift (PDS) motif, and Msn 2 and Msn 4, orthologs of mammalian early growth response protein 1 (EGR1), which bind to stress-responsive element (STRE) motif. Figure Two. Conserved nutrient-sensing response pathways in worms, flies and mammals. This model summarizes the conserved nutrient-sensing pathways that regulate longevity and stress-response mechanisms in different model organisms. Fasting or calorie restriction reduces the activity of amino acids and glucose signaling pathways through membrane receptors by reducing circulating ligands such as growth factors like mammalian IGF-1. The fasting-inhibited TOR-S6K pathway (labeled in blue) promotes the expression of nuclear transcription factors such as the hypoxia-inducible factor-1 (HIF-1), the FOXA ortholog PHA-4, the nuclear hormone receptors NHR-62 and NHR-49 and the TFEB ortholog HLH-30 (worms), the FOXA nuclear factor (flies) and the increase of the FOXO nuclear factor (mammals). These transcription factors commonly activate antiaging systems and processes, including autophagy and ribosomal biogenesis, stress response and cellular-protection genes, including antioxidant SODs. The RAS-AC-PKA pathway (labeled in green) is also partially conserved between species. Similar to what was observed in yeast, glucose in certain mammalian cells can signal through the PKA pathway and the transcription factor EGR1, the mammalian ortholog of Msn 2, Msn 4 in yeast. In worms, flies and mice, downregulation of TOR S6K signaling has conserved proaging effects. The fasting-dependent effects on longevity in different organisms may also involve sirtuin pathway activation (labeled in orange), the increase in mitochondria respiration and the activation of autophagy. Also, fasting in flies delays the disruption of tri cellular junctions (TCJs), which is linked to improved intestinal barrier integrity and therefore longevity (labeled in gray). Figure Three. Periodic fasting and tissue regeneration and rejuvenation in mice. Periodic fasting or FMD can affect tissue regeneration in multiple systems and organs in mice. a, In bone marrow, PF or FMD drives self-renewal of HSCs and lineage-balance regeneration of the immune system, leading to a lymphoid-biased phenotype. b, PF and FMD increase mesenchymal stem and progenitor cells (MSPCs) in bone marrow. c, PF and FMD increase neurogenesis in brain tissue, represented by increase in doublecortin (DCX) levels in newly generated bromo deoxyuridine (BrdU plus) neurons. d, In muscle tissue, PF or FMD modulates the expression of the pair box protein Pax-7, a stem-cell marker mainly expressed by muscle satellite stem cells, and MyoD, a marker of early muscle differentiation. e, In the pancreas, PF and FMD drive increased expression of early developmental markers, including SOX-17, and of the downstream NGN3 transcription factor, leading to the regeneration of insulin-producing beta cells. f, In intestinal tissue acute one-day-only fasting, PF and FMD increase levels of ISCs and progenitors in part by inducing a fatty-acid oxidation (FAO) program or by modulating gut microbiota.

The Key Role of Mitochondrial Function in Health and Disease. Inigo San-Millan, Department of Human Physiology and Nutrition, University of Colorado, Colorado Springs, and others. https://rumble.com/v3t4yzj-index-of-science.-music-by-dan-vasc.html Source: https://pubmed.ncbi.nlm.nih.gov/37107158/ Abstract. The role of mitochondrial function in health and disease has become increasingly recognized, particularly in the last two decades. Mitochondrial dysfunction as well as disruptions of cellular bioenergetics have been shown to be ubiquitous in some of the most prevalent diseases in our society, such as type 2 diabetes, cardiovascular disease, metabolic syndrome, cancer, and Alzheimer’s disease. However, the etiology and pathogenesis of mitochondrial dysfunction in multiple diseases have yet to be elucidated, making it one of the most significant medical challenges in our history. However, the rapid advances in our knowledge of cellular metabolism coupled with the novel understanding at the molecular and genetic levels show tremendous promise to one day elucidate the mysteries of this ancient organelle in order to treat it therapeutically when needed. Mitochondrial DNA mutations, infections, aging, and a lack of physical activity have been identified to be major players in mitochondrial dysfunction in multiple diseases. This review examines the complexities of mitochondrial function, whose ancient incorporation into eukaryotic cells for energy purposes was key for the survival and creation of new species. Among these complexities, the tightly intertwined bioenergetics derived from the combustion of alimentary substrates and oxygen are necessary for cellular homeostasis, including the production of reactive oxygen species. This review discusses different etiological mechanisms by which mitochondria could become dysregulated, determining the fate of multiple tissues and organs and being a protagonist in the pathogenesis of many non-communicable diseases. Finally, physical activity is a canonical evolutionary characteristic of humans that remains embedded in our genes. The normalization of a lack of physical activity in our modern society has led to the perception that exercise is an “intervention”. However, physical activity remains the modus vivendi engrained in our genes and being sedentary has been the real intervention and collateral effect of modern societies. It is well known that a lack of physical activity leads to mitochondrial dysfunction and, hence, it probably becomes a major etiological factor of many non-communicable diseases affecting modern societies. Since physical activity remains the only stimulus we know that can improve and maintain mitochondrial function, a significant emphasis on exercise promotion should be imperative in order to prevent multiple diseases. Finally, in populations with chronic diseases where mitochondrial dysfunction is involved, an individualized exercise prescription should be crucial for the “metabolic rehabilitation” of many patients. From lessons learned from elite athletes, the perfect human machines, it is possible to translate and apply multiple concepts to the betterment of populations with chronic diseases. Keywords: mitochondrial dysfunction; cellular bioenergetics; diabetes; cardiovascular disease; cancer; Alzheimer’s disease; metabolic flexibility; exercise. One. Introduction. The role of mitochondrial function in health and disease has become increasingly popular, especially in the past two decades. It is known that the dysregulation of mitochondrial function and cellular bioenergetics are hallmarks of many diseases, such as type 2 diabetes, T2D, cardiovascular disease, CVD, metabolic syndrome, cancer, and Alzheimer’s disease, AD. Although mitochondrial dysfunction is ubiquitous to many non-communicable diseases (NCDs), the etiology and pathogenesis of mitochondrial dysfunction remain elusive and the subject of important biomedical research nowadays as one of the most significant medical challenges in our history. The energy production of an individual is based on the metabolic demand and metabolic efficiency during exercise, resting, and fasting and in a postprandial state. Cellular bioenergetics are quite complex and tightly intertwined with the purpose of producing the necessary energy for cellular survival as well as achieving cellular homeostasis. Mitochondria are the main cellular organelles in charge of energy production and play a pivotal role in the control of cellular hemostasis. Under resting conditions, fatty acids and carbohydrates should be successfully transported into mitochondria and be oxidized to Acetyl-CoA for posterior oxidation in the Kreb cycle (tricarboxylic acid cycle (TCA)) and electron transport chain, E-T-C, through oxidative phosphorylation (OXPHOS) in order to synthesize the key energetic compound in the human body (ATP). Mitochondria are also the production site for reactive oxidative species (ROS), which at physiological levels behave as signaling molecules needed for cellular homeostasis. Hence, mitochondrial malfunctions will impact cellular bioenergetics, cellular function, and cellular homeostasis, making mitochondria a key player in health and disease. There are multiple effectors eliciting mitochondrial dysfunction that have been recognized, including mitochondrial DNA mutations, infections, aging, and a lack of physical activity. However, the etiology of mitochondrial dysfunction in the pathogenesis of multiple diseases has yet to be elucidated. The aim of this review is to assemble multiple components involved in the role of mitochondrial function in health and disease, especially some of the most prevalent NCDs in our society. Furthermore, the development of assessments for mitochondrial function in humans appears imperative in order to detect or diagnose mitochondrial dysfunction or decay. If signs of mitochondrial impairment or decay are detected early in life, there could be a significant window of opportunity to intervene in order to prevent diseases or the further deterioration of existing ones as well as improve multiple diseases through enhancing mitochondrial function through lifestyle interventions such as exercise. It has been known for decades that physical activity is probably the only known intervention that can improve mitochondrial function. The “exercise as medicine” concept continues to grow among health professionals as a necessity to prescribe exercise in a personalized and individualized manner, which seems imperative in the decades to come. However, an individualized exercise prescription should be crucial for the “metabolic rehabilitation” of many patients. This task remains a challenge due to the current lack of vertical and horizontal integration of medical systems, including clinicians, multiple providers, exercise specialists, and health care systems, with the proper means and infrastructures. The scientific and individualized approach to training elite athletes has been shown to be quite successful over the last several decades. Hence, the lessons learned from the work done with elite athletes can be an important “template” to apply to populations with chronic diseases in order to prescribe individualized exercise with the goal of improving mitochondrial function, disease, and overall metabolic health. Two. Mitochondria, the Key Aerobic Microbe for Eukaryotic Cell Evolution. Mitochondria originated about 1.5 billion years ago from a prokaryotic origin linked to archae bacterium, “archae” meaning “ancient bacteria”. According to the endosymbiotic hypothesis proposed by Doctor Lynn Margulis in 1967, eukaryotic species evolved from aerobic prokaryotic microbes (mitochondria) that were engulfed by an eukaryotic cell leading to endosymbiosis. In general, through this symbiotic relationship, mitochondria provided aerobic energy to eukaryotic cells in exchange for protection. The ability of mitochondria to conduct aerobic respiration inside the host eukaryotic cell led to a fundamental change in evolution and the origins of hundreds of new genes and proteins, leading to novel metabolic characteristics of eukaryotic cells providing transformational evolutionary advantages to multiple species including animal life. Mitochondria continued to evolve within eukaryotic cells and both entities improved their symbiotic relationship of energy and protection. On the other hand, the Romanian biologist and chemist Eugene Macovschi developed the biostructural theory. According to this theory, living cells possess a related biological structure conferring on them living features through a so called biostructure by which living matter consists of two distinct and interdependent forms: biostructure matter, which is the living matter itself, and coexistent molecular matter, which is a combination of chemicals in non-living matter. The biostructure in cells forms an inseparable unit such that, according to Macovschi, only one uniform cell could be the origin of all forms of life, contradicting the endosymbiosis hypothesis. Today, the cell nucleus contains genes encoding for about 1200 proteins involved in mitochondrial structure, membrane, and mitochondrial DNA (M-T DNA) repair. Nuclear DNA (nuDNA) is the key to a mitochondrion as its genome only contains 37 genes that encode 13 proteins, all of them involved in OXPHOS; hence, the symbiotic relationship with nuDNA. Mitochondria are referred to as the “powerhouses of cells” since they provide the ATP necessary for cellular functions and life. Mitochondria are found in all cells in the body except for red blood cells, which rely on aerobic glycolysis and lactate for proliferation and survival. Although it is commonly thought that mitochondria are individual organelles, in skeletal muscle they probably evolved to become interconnected in a reticulum or a network, most likely penetrating deep into skeletal muscles for increased bioenergetic efficiency. Two. Mitochondrial Bioenergetics Are Complex and Intertwined. The oxidation of multiple fuels occurs within the matrix of mitochondria through the TCA cycle and OXPHOS. Mitochondria oxidize all major substrates derived from macronutrients: pyruvate derived from carbohydrates, fatty acids derived from fat, and amino acids derived from protein. Lactate, the obligatory byproduct of glycolysis, is also a very important fuel for mitochondria and could even be the fuel preferred by most cells. Other metabolites, such as ketone bodies, are also commonly oxidized by mitochondria, especially under stress and fasting conditions. Skeletal muscle comprises the largest organ in the body and is the largest contributor to aerobic capacity through mitochondrial respiration. Hence, skeletal muscle mitochondrial function is crucial for whole-body metabolic function and health. Under normal, healthy conditions, mitochondrial bioenergetics are complex and tightly regulated for cellular homeostasis. In general, pyruvate, fatty acids, and a few amino acids are linked together upon being converted to Acetyl-CoA, which is the first step in the TCA cycle. The final step in the TCA cycle is the production of reducing equivalents of NADH and FADH2, which deliver electrons and hydrogen ions (H plus) to mitochondrial complexes through the electron transport chain, E-T-C, in the inner mitochondrial membrane. These electrons build up a chemical gradient that drives ATP production. Hydrogen ions are pumped out from the mitochondrial matrix into the intermembrane space through mitochondrial complexes (One to Four). The large gradient of protons that accumulate in the intermediate space will force H plus back to the lower gradient in the mitochondrial matrix to generate ATP. Even before oxidation, mitochondrial transport of multiple substrates is of key importance. In general, medium-chain fatty acids (FAs) can freely enter mitochondria, while long chain FAs need to be transported through palmitoyl transferase 1 and 2 (CPT 1, 2) located on the outer and inner mitochondrial membranes, respectively. Fatty acids are converted to Acyl CoA, which through oxidation is converted to Acetyl-CoA for oxidation in the TCA. Pyruvate, on the other hand, is transported across mitochondria by the mitochondrial pyruvate carrier (MPC) and oxidized to Acetyl CoA by pyruvate dehydrogenase (PDH). Therefore, the dysfunction of any of these elements involved in substrate transport across mitochondria can severely disrupt cellular bioenergetics and function. Substrate kinetics and dynamics are also important in cellular bioenergetics. When there is increased glycolytic flux, such as in the case of high-intensity exercise or high CHO ingestion, pyruvate may accumulate even under fully aerobic conditions and have difficulty being transported across mitochondria and oxidized to Acetyl-CoA, leading to its reduction to lactate. This is a ubiquitous process in exercise bioenergetics where PDH and lactate dehydrogenase (LDH) enzyme kinetics as well as MPC transport kinetics are key players. The LDH-A isoform possess a higher affinity for pyruvate, therefore eliciting a higher rate of pyruvate reduction to lactate. Further, in the oxidation of 2 Glyceraldehyde 3 phosphate (G-3-P) to 1, 3 Diphosphoglycerate, NAD plus is reduced to NADH and, under high glycolytic flux, cytosolic NAD plus may be depleted, leading to halted glycolysis and the disruption of the NAD plus, NADH ratio and intracellular redox state. During this stressful cellular event, NAD plus is “rescued” by lactate through the reduction of pyruvate to lactate through LDH-A and the oxidation of NADH to NAD plus for the continuation of glycolysis and the stabilization of the cellular redox state. Furthermore, increased glycolytic flux can lead to the accumulation of Acetyl-CoA, resulting in inhibition of Malonyl Co-A, which inhibits CPT1 and, therefore, fatty acid transport across the mitochondrial membrane. Lactate is a canonical component of cell biology and at the crossroads of cellular bioenergetics and intermediary metabolism. Lactate is the obligatory end product of glycolysis and behaves as a “lacthormone” by possessing multiple endocrine, paracrine, and autocrine properties. Lactate is mainly oxidized in mitochondria through the mitochondrial lactate oxidation complex (mLOC). Poor mitochondrial lactate oxidation could lead to a significant dysregulation of cellular bioenergetics. Both lactate accumulation in the cytosol and exportation to the blood could have significant effects on the regulation of both fat and carbohydrate metabolism, tightly regulating the intermediary metabolism as well as having an intimate relationship with mitochondrial function. Lactatemia decreases the mRNA expression of GLUT 4 in skeletal muscles, therefore decreasing glucose uptake and oxidation. Furthermore, lactate binds to the G protein coupled receptor (GPR81) on adipocytes, which inhibits lipolysis. Moreover, we have recently shown that lactate decreases the activity of both CPT1 and CPT2 in neonatal rat cardio myocytes, disrupts cardiolipin species, increases reactive oxidative species (ROS), and disrupts cellular bioenergetics by decreasing the rate of ATP production. A decrease in lactate and fat oxidation (FATox) by mitochondria, as in the case of T2D or metabolic syndrome, indicates a direct relationship between lactatemia and FATox. Metabolic flexibility is a term that has emerged in the last two decades and continues to evolve due to its involvement in multiple diseases. Mitochondrial flexibility is defined as the ability to respond or adapt to conditional changes in metabolic demand. However, the work in metabolic flexibility probably dates back over a hundred years to the pioneering work by Harris and Benedict, who studied the metabolism of adult males and females, infants, and patients with diabetes. Especially relevant was Benedict’s work in the nineteen twenties and thirties on the basal metabolism of both humans and animals as well as metabolic responses to exercise. Skeletal muscle substrate utilization and bioenergetics are central to metabolic flexibility. Kelly and Mandarino elegantly demonstrated that skeletal muscle is central to the study of mitochondrial function. They observed that individuals with type 2 diabetes (T2D) and obesity showed metabolic inflexibility in postprandial conditions with altered glucose and fat oxidation. Before the innovative studies by Kelly and Mandarino, De Fronzo and colleagues had shown that under eu-glycemic hyper-sinsulinemic clamp conditions, skeletal muscle uptakes and metabolizes about 85 percent of all glucose. Metabolic flexibility and mitochondrial function are closely intertwined as under resting and postprandial conditions both fat and glucose are oxidized in mitochondria via OXPHOS. In summary, mitochondrial bioenergetics are quite complex and the studies continue to show that the disruption of mitochondrial and, in general, cellular bioenergetics is central to the pathogenesis of multiple diseases. The following decade will be decisive in unveiling further crucial aspects of mitochondrial bioenergetics as well as therapeutic targets. Four. Mitochondria, the Main Producers of Reactive Oxygen Species (ROS). Oxygen consumption and reactive oxidative species (ROS) are ubiquitous to mitochondrial respiration. As electrons flow through the E-T-C, an estimated 0.4 to 4 percent of them leak before reaching Complex Four. Hence, mitochondria are considered to be the main generators of ROS and, within mitochondria, Complex One is the main ROS-generating site. Historically, ROS were previously thought to only cause cellular damage. However, it is well known that at physiological levels ROS generation is necessary and highly involved in the regulation of cellular homeostasis, key signaling pathways, cell proliferation, cell differentiation, cell migration, angiogenesis, and increased lifespan. The process by which physiological ROS are involved in cellular homeostasis and signaling has been named “oxidative eustress” and also mitohormesis. Superoxide anions, (Oh two minus) and hydrogen peroxide (H 2 O 2) are the main ROS and cells have specific mechanisms for counteracting excessive ROS production as well as scavenging free radicals through antioxidants such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), and glutathione reductase (GR). When ROS production exceeds the antioxidant capacity, ROS accumulate and can cause multiple cellular disruptions involved in multiple diseases. Excess ROS production by mitochondria can cause damage to M-T DNA, proteins, and lipids, which in turn can disrupt mitochondrial function and cellular homeostasis. Although ROS production and mitochondrial dysfunction are intimately associated in multiple diseases, the mechanisms by which either primary ROS production leads to mitochondrial dysfunction or vice versa need to be elucidated. Could “faulty” mitochondrial function be responsible for excessive ROS production, or could it be the opposite? ROS generation occurs in the mitochondrial inner membrane, which is proximal to the M-T DNA that depends on nu DNA for maintenance and repair. Therefore, the proximity of M-T DNA to the ROS generation site makes M-T DNA more vulnerable to oxidative damage. A primary mitochondrial dysfunction may lead to a further increase in the generation of ROS, leading to exacerbated oxidative stress, which, in turn, may lead to further mitochondrial dysfunction in a self-perpetuating, feed-forward, and vicious cycle. As an example of the mitochondrial dysfunction and ROS balance for cellular homeostasis, deficiencies in the pyruvate dehydrogenase complex (PDC) lead to the accumulation of pyruvate and lactate, which has been shown to increase ROS levels and decrease the antioxidant capacity. On the other hand, lactate is an important signaling molecule as it stimulates a modest amount of ROS production, which elicits an antioxidant response for pro-survival cellular pathways such as PI3K, AKT and endoplasmic reticulum (ER) chaperones. Moreover, different events and external effectors have been shown to elicit mitochondrial ROS generation. Tumor necrosis factor alpha, TNF alpha, an inflammatory mediator, has been associated with increased ROS generation. Several toxic metals, such as mercury, damage M-T DNA and elicit lipid peroxidation as well as the depletion of glutathione, leading to increased ROS generation and further mitochondrial damage. Iron-deficiency anemia can cause a decrease in the activity of Complex four, eliciting a higher level of oxidative stress. In summary, mitochondria are the main site for ROS generation and for an extended period of time it was thought that ROS production was exclusively detrimental to human cells. However, it is well known that ROS act as key signaling molecules necessary for cellular and mitochondrial homeostasis. Nevertheless, an understanding of the exact balance between homeostatic and pathological ROS production remains elusive and is currently an area in which important research efforts are being made. Five. Etiologies of Mitochondrial Dysfunction. It is important to note that the term “mitochondrial dysfunction” might not be completely appropriate. In most cases where the term “mitochondrial dysfunction” is coined, mitochondria still work but not at full or an appropriate level of potential compared with healthy states, hence the term “mitochondrial dysfunction”. However, in many situations, “decreased mitochondrial capacity” or “mitochondrial impairment” could be more appropriate. From genetic mutations to aging, infections, and a lack of physical activity, the etiology of mitochondrial dysfunction, impairment (Figure 1) is multiple and currently an important field of research due to its implications in health and disease. Five point one. Genetic Mutations. As previously mentioned, the mitochondrial genome contains 37 genes that encode for 13 proteins, all of which are involved in OXPHOS. Therefore, any mutation of those 13 genes could result in a significant disruption of mitochondrial function and cellular bioenergetics. The incidence of inherited mitochondrial mutations is considered to be quite rare, 1 in 5000 individuals . Most mutations occurring in M-T DNA are mainly point mutations and deletions. Other mutations occur in the nucleus, including to autosomal recessive, dominant, or X-linked M-T DNA maintenance genes. Most mitochondrial genetic diseases are involved in neurological disorders, including myopathy, ataxia, and neuropathy. It is important to highlight the importance of the relationship between nuDNA and M-T DNA. As part of the ancient “symbiotic pact” of aerobic energy for protection between eukaryotic and prokaryotic cells, nuDNA encodes all the genes necessary for mitochondrial maintenance, repair, and replication. Hence, inherited or acquired mutations of nuDNA can contribute to mitochondrial instability. Unlike germline mutations, somatic mutations evolve over the life cycle of an individual and exposure to endogenous and exogenous mutagens could lead to potential errors in nuDNA repair and replication. The symbiotic genetic relationship between nuDNA and M-T DNA remains largely unexplored and could confer significant insights into the etiology of multiple diseases. Other mutations at the mitochondrial structural level can also affect cardiolipin (CL), which is a phospholipid in the inner mitochondrial membrane that regulates multiple mitochondrial processes and is also involved in mitochondrial dysfunction. As an example, Barth syndrome (BTSH) is a rare X-linked genetic disease caused by a mutation of the tafazzin gene, encoding for phospholipid transacylase, which is necessary for CL remodeling and characterized by cardiomyopathy, skeletal myopathy, and neutropenia. BTSH is a classic example of a disruption to mitochondrial bioenergetics due to genetic mutations, leading to metabolic reprograming in the heart characterized by a significant decrease in the capacity for mitochondrial oxidation of fatty acids and pyruvate (about 40 to 60 percent). Cancer is another important disease characterized by decreased, impaired mitochondrial function. M-T DNA is more susceptible to DNA damage than nuDNA as it has no introns, histones, or non histone proteins and, therefore, it is continually exposed to endogenous and exogenous mutagens, ROS, and different carcinogens. This vulnerability is substantial and in cancer it has been shown that M-T DNA mutations are significantly higher in number than nuDNA mutations. Vogelstein’s group was the first to decode the mitochondrial genome in tumors, where they found M-T DNA mutations in seven out of ten human colorectal cancer cell lines. In a study by H C Lee and colleagues with 20 different types of cancer in 859 patients, 66 percent of those cancers carried at least one somatic M-T DNA mutation. In cancer, the term “mitochondrial dysfunction” refers to a significant mitochondrial impairment leading to aberrant metabolic reprograming of cellular bioenergetics characterized by accelerated glucose uptake and lactate production. It was discovered by the Nobel Laureate Otto Warburg one hundred years ago. Five point two. Aging. The process of aging has been extensively studied over decades if not centuries. Aging is an inescapable biological process characterized by decreased physiological and cellular function across the body. A decrease in mitochondrial capacity has been observed with aging and is already considered a hallmark. Briefly, damaged and aging mitochondria are controlled by the process of mitophagy, which is the internal cellular autophagy of mitochondria. Mitophagy and mitochondrial biogenesis are indispensable to the regeneration of new mitochondria and achieve a balance for mitochondrial health. Mitochondrial fission and fusion are key processes for the regeneration and maintenance of mitochondrial networks, structure, and function. In general, mitochondrial fission splits mitochondria, where the damaged structures of mitochondria are degraded through mitophagy. The healthy fragments of mitochondria are attached together by the fusion process, allowing for the regeneration of mitochondrial structure and function, including normal metabolic bioenergetics. A decrease in the mitochondrial dynamics between fission and fusion is typical of aging processes, including increased fission and decreased fusion, which can lead to metabolic changes resulting in increased glycolysis and the metabolic reprogramming of multiple cells. As part of the aging process and exogenous mutagens, M-T DNA mutations become more frequent and could disrupt mitochondrial dynamics and bioenergetics over time. One particular mitochondrial deletion, M-T DNA4977, accumulates in multiple organs and is highly correlated with increased O2 consumption, which is a sign of increased glycolysis and metabolic reprograming. The GEHA EU project was an ambitious project whose goal was to compare the M-T DNA variability in 2200 nonagenarian Europeans and the same number of younger individuals as a control. The study showed that the association with longevity was only present when M-T DNA OXPHOS complexes co-occurred. It is also well known that, in aging, ROS and mitochondrial dysfunction are highly Interconnected. According to the free radicals theory of aging first proposed by Harman in 1956, the E-T-C’s inside mitochondria produce intracellular ROS that elicit mitochondrial damage and eventually cellular dysfunction. Mitochondrial ROS production can also interfere with mitophagy by disrupting the balance between fusion and fission, promoting the latter and activating intrinsic apoptotic pathway. However, over the last decade the emphasis on ROS production as the underlying mechanism of the pathogenesis of aging has evolved to mitochondrial bioenergetics and turnover, where ROS generation could be a consequence of aging and mitochondrial dysfunction instead of the primary cause of mitochondrial injury. Moreover, aging elicits an accumulation of damaged mitochondria in the brain, leading to a lower degree of metabolic efficiency, producing less ATP, and increasing the production of ROS, which can result in a disruption of cellular bioenergetics triggering neurogenerative disease. Five point three. Infections. Mitochondria play an important role in regulating the immune response to infections as they trigger multiple modulators involved in the innate immune system, including the transcriptional regulation of cytokines, chemokines, and inflammasomes. Multiple bacteria and viruses modulate cellular bioenergetics in order to increase their survival rate and establish a proliferative niche. One main way by which microbes hijack cellular functions is by targeting mitochondria. Bacteria-like listeria mono cytogenes, helicobacter pylori, shigella flexneri, legionella pneumophila, and chlamydia trachomatis cause mitochondrial fragmentation, mainly by increasing fission. Viruses also target mitochondria through different mechanisms. The Hepatitis C virus targets mitochondria by increasing mitophagy. The HIV virus disrupts the mitochondrial fission-fusion balance in the brain by increasing mitochondrial fusion, causing damage to neurons. PB1-F2, an Influenza A protein, is translocated into the mitochondrial inner membrane, disrupting the membrane potential and leading to mitochondrial fragmentation. Of recent importance is the pandemic caused by the SARS-CoV-2 virus. Although still under investigation, it would seem that SARS-CoV-2 also targets mitochondrial function for survival and replication by downregulating OXPHOS, increasing the elongation and overproduction of ROS. Recently, we observed both metabolic and mitochondrial dysregulation in 50 patients infected with SARS-CoV-2 and affected by post-acute sequelae of COVID-19 (PASC), referring to extreme chronic fatigue. About half of these patients had previous comorbidities, but the other half were healthy and moderately active individuals. We observed significant metabolic dysregulation with an extremely poor capacity to oxidize fatty acids and clear lactate compared with individuals with metabolic syndrome, suggesting mitochondrial dysfunction. In a subsequent study deploying metabolomics, we were able to find robust signatures of mitochondrial dysfunction and impaired fatty acid metabolism in PASC. While mitochondrial function is normally restored when infections cease, patients affected by SARS-CoV-2 and suffering from long lasting effects may have a significant and long-lasting alteration to muscle mitochondrial function, which needs to be studied in more depth. Septicemia (sepsis) due to bacterial infection can also cause metabolic and bioenergetics disruptions in multiple organs that can ultimately lead to multi-organ failure and death. Mitochondrial dysfunction in sepsis has attracted an increasing amount of attention over the last decade in order to explain the bioenergetic dysfunction of organ failure characteristic of patients with sepsis. Impaired perfusion early on in the sepsis process, increased ROS generation, hormonal alterations, and altered transcription of mitochondrial genes can significantly affect mitochondrial function during sepsis. Recently, it has been shown that mitochondrial transcription factor A (TFAM), which is key in mitochondrial biogenesis, is significantly decreased in sepsis. Rahmel and colleagues have shown that intramitochondrial TFAM levels were about 80 percent lower compared with controls and accompanied by decreased M-T DNA copy numbers and cellular ATP content. This finding is relevant as many sepsis survivors suffer from “post-sepsis syndrome”, which includes neuropathies, energetic dysfunction, and muscle weakness and wasting. The metabolic derangements in sepsis survivors also include hyperglycemia, which is a risk factor for the development of T2DM post-sepsis and CVD. In summary, although long-term effects of viral or bacterial infections in general are rare, a decrease in mitochondrial function caused by certain infections can elicit significant metabolic dysregulation through mitochondrial dysfunction increasing the risk of metabolism-related diseases. Five point four. Lack of Physical Activity. Physical inactivity has been associated with multiple diseases, including cardiovascular disease, cancer, Alzheimer’s disease, type 2 diabetes, and Parkinson’s disease. In fact, low cardiorespiratory fitness is considered to be responsible for the highest percentage of all attributable fractions for all cause mortality. The effects of a lack of physical activity on mitochondrial function have been known for decades. In 1979, Houston and colleagues found a 24 percent decrease in a mitochondrial function surrogate, succinate dehydrogenase (SDH), after 15 days of detraining in distance runners. Coyle et al, observed that 56 days of detraining elicited a 40 percent decrease in mitochondrial oxidative enzyme levels and a 22 percent increase in lactagenic enzyme lactate dehydrogenase (LDH) levels with increased blood lactate accumulation during exercise. Fritzen et al, found that 4 weeks of detraining in healthy male subjects elicited a decrease of 32 percent in the activity of another mitochondrial function surrogate, citrate synthase (CS), and a 29 to 36 percent decrease in mitochondrial complexes one to four. Houmard and colleagues showed a decrease in CS activity of 25 percent with just 14 days of detraining. Bed studies have contributed significantly to our understanding of the loss of proper mitochondrial function and metabolic flexibility. Alibegovic and colleagues elegantly showed that 9 days of bed rest altered more than 4500 genes and downregulated 34 metabolic pathways mainly associated with mitochondrial biogenesis, function, and OXPHOS. In this study, the most downregulated pathway was OXPHOS (54 percent of all genes involved in OXPHOS were downregulated). Further, bed rest elicited changes in the DNA methylation of the PPARGC1A gene, which encodes for PGC one alpha, a master regulator of mitochondrial biogenesis. In this same study, upon retraining for four weeks, 82 percent of the genetic expression that was altered with bed rest was restored, showing that physical activity restores major losses in genetic expression in a relatively short period of time. Furthermore, bed rest also induces changes in substrate partitioning favoring glycolysis instead of OXPHOS with a decrease of 37 percent in fat oxidation and an increase of 21 percent in CHO in the post-absorptive state. Moreover, bed rest increases insulin resistance, which primarily occurs in skeletal muscle. Finally, as described in Section 7 (vide infra), there are many studies showing that physical activity can efficiently increase mitochondrial function. Hence, the levels of daily physical activity (or the lack thereof) are significantly involved in mitochondrial function, the prevention of multiple diseases, and decreasing the risk of all-cause mortality. Six. The Role of Mitochondrial Function in Multiple Diseases. Six point one. Type 2 Diabetes. Type 2 diabetes has become an unstoppable epidemic affecting millions around the world and in various countries, regardless of their degree of development and sociocultural characteristics. Currently, in the United States alone, about 52 percent of the adult population has either pre or type 2 diabetes. China is experiencing the largest increase in T2DM in the world and Europe is also experiencing a significant increase in T2DM. Other parts of the world, including developing countries such as Cuba and highly developed countries such as the United Arab Emirates, are also being affected by this epidemic. Insulin resistance is the hallmark of T2D and central to its pathogenesis. As previously mentioned, skeletal muscle is central to the study of mitochondrial function and its relationship to the pathogenesis of T2D. Although the mechanisms remain elusive, multiple studies over the last two decades have implicated skeletal muscle mitochondrial dysfunction in the development of insulin resistance (IR). It is widely known that individuals with T2DM and metabolic syndrome are characterized by decreased mitochondrial content in both intermyofibrillar and subsarcolemmal skeletal muscle regions, mitochondrial oxidative enzymes, mitochondrial DNA, transcriptional factors and genes, and overall mitochondrial function. Furthermore, dysregulated muscle bioenergetics are a prevalent feature in individuals with type 2 diabetes, characterized by a poor capacity to oxidize fats and carbohydrates. The decreased capacity to oxidize both FAs and CHO in mitochondria leads to metabolic inflexibility and metabolic reprogramming with increased reliance on cytosolic glycolysis and lactate production to generate ATP. Furthermore, a lack of mitochondrial capacity for fat oxidation may lead to an accumulation of lipids in skeletal muscle adjacent to mitochondria, which is correlated with increased diacylglycerols, sphingolipids, ceramides, and insulin resistance. In individuals with IR, insulin signaling is disrupted, resulting in a decrease in AKT phosphorylation and the translocation of skeletal muscle glucose transporter (GLUT-4) to the sarcolemma, leading to a decrease in glucose uptake. Fernandez and colleagues developed a transgenic mouse model with the dominant-negative insulin-like growth factor one receptor (KR, IG, IR) in skeletal muscle. Expression of KR, IGF, IR abrogated IGF 1 and insulin receptors, resulting in insulin resistance in skeletal muscle. Since skeletal muscle seems to be the tissue with the highest uptake of glucose, De Fronzo and Tipathy as well as Fernendez and colleagues proposed that T2D debuts in skeletal muscle and that muscle insulin resistance is the primary mechanistic event involved in the development of T2D. Six point two. Cardiovascular Disease. The role of mitochondrial dysfunction in cardiovascular disease has been receiving increasing attention in recent years. The heart can suffer from severe metabolic reprograming and mitochondrial dysfunction with a decrease in oxidative capacity, oxidative phosphorylation, and ATP synthesis and an increase in ROS production. The heart is the most oxidative tissue in the body and about 50-70 percent of ATP is synthesized through the beta oxidation of fatty acids with 30 to 40 percent derived from aerobic glycolysis. Consequently, decreased mitochondrial function of the heart could lead to a disruption of the cellular bioenergetics of cardiomyocytes through increased glycolysis as in the case of cardiac hypertrophy and heart failure. Furthermore, it has been shown that cardiomyocytes of patients with coronary artery disease possess 8 to 2000 more M-T DNA deletions than healthy patients, which can significantly alter mitochondrial function and increase ROS production, leading to cellular damage and a dysregulated cellular metabolism. Moreover, even a small increase in glucose metabolism as a result of mitochondrial dysfunction can lead to cardiomyocytes with metabolic inflexibility. Vascular tissue is also affected by mitochondrial dysfunction. M-T DNA mutations and mitochondrial damage have been correlated with atherosclerosis. Specifically, atherosclerotic plaques are characterized by mitochondrial dysfunction and reduced M-T DNA copy numbers. In the process of angiogenesis, vascular endothelial cells (VECs) possess a high degree of metabolic flexibility in order to adapt to the changing microenvironment of sprouting angiogenesis. Although the mitochondrial composition of VECs is only 2 to 6 percent of the cell volume as opposed to 32 percent in cardiac myocytes, a small percentage of the volume of mitochondria in VECs may be key to maintaining their homeostasis. Because of this specific phenotype, VECs rely on glycolysis and lactate for cell proliferation and angiogenesis. In fact, about 99 percent of the glucose is reduced to lactate in VEC’s as lactate is a major regulator of vascular endothelial vascular growth factor (VEGF) and hypoxia-inducible factor HIF 1, which are both key processes in angiogenesis. The remaining ATP synthesis is derived from fatty acids and glutamine via OXPHOS. Although minor, the role of fatty acid oxidation may be of importance to control and balance VEC proliferation as disruptions in VEC bioenergetics could lead to pathophysiological conditions, including atherosclerosis and hypertension. VECs also suffer from senescence associated with intrinsic mitochondrial impairments involving M-T DNA mutations, E-T-C dysfunctions, changes in the fission-fusion balance, excessive ROS production, and decreases in antioxidant capacity. Six point three. Mitochondrial Dysfunction at the Crossroads of the Connection between Type 2 Diabetes and Cardiovascular Disease. The connection between T2D and CVD has received much attention, especially over the last two decades, as a large number of patients with T2D also develop CVD and vice versa. In many cases, this connection has led to the confluence of both diseases into one emerging disease: cardiometabolic disease. At this point, the connection between these two diseases is mainly epidemiological as the mechanisms behind the relationship remain elusive. As a possible hypothesis, a primary mitochondrial dysfunction in skeletal muscle could be important to understanding the connection between both diseases. A significant histological finding pertaining to skeletal fat metabolism occurs in physically fit individuals as well as in individuals with T2D, where both populations show an accumulation of intramuscular triglycerides. This phenomenon is known as the “skeletal muscle lipid paradox” as both physically fit individuals as well as individuals with T2D are characterized by the presence of a “lipid droplet” adjacent to mitochondria. However, the presence of skeletal muscle lipid or intra myocellular lipid (IMCL) content in highly metabolically fit individuals accounts for a significant source of fat oxidation during exercise. On the other hand, in individuals with T2D, this accumulation of fat possesses different metabolic properties and lipid profiles compared with fit individuals. In the case of individuals with T2D, the composition of intramuscular triglycerides is high in ceramides, which belong to a family of lipids consisting of sphingosines, which are bioactive lipid molecules and are involved in skeletal muscle insulin resistance, and mitochondrial dysfunction. Circulating ceramide levels are already considered to be a biomarker of insulin resistance, T2D, and CVD. Further, in the field of CVD research, it is well known that ceramides are key players in the atherosclerotic process. Historically, circulating ceramides have been thought to primarily originate in the liver, where they are packed in lipoprotein particles and transported to different tissues. However, it could be possible that the decrease in mitochondrial fat transport and oxidation in individuals with T2D could lead to chronic muscle lipid accumulation characterized by an increase in the content of ceramides that could be released into the blood and, consequently, contribute to the atherosclerotic process. Furthermore, as a possible cross-talk and transport mechanism, it has been shown that extracellular vesicles, EV’s, can contain ceramides and that skeletal muscle is very active in secreting EV’s. Could the skeletal muscles of people with T2D secrete EVs containing ceramides to the blood in a way that could influence the atherosclerotic process? Could other components of EV’s, mRNA, microRNA, proteins, enzymes, be implicated in the dysregulation of the metabolic function of the endothelial tissue? Although the relationships between CDV and T2D are quite strong, the mechanisms behind the link between these diseases remain elusive and a significant amount of research is needed. Six point four. Alzheimer’s Disease, Is It the Brain’s Diabetes? Over the past two decades, an increasing number of studies have linked T2D to AD and cognitive impairment. It is known that individuals with T2D have a 1 point 5 to 2 fold higher risk of developing CVD compared with people without T2D. Moreover, a study by Janson and colleagues found that 81 percent of patients with AD had either T2D or impaired fasting glucose. The same study showed that individuals with T2D possessed a higher frequency of islet amyloids and a greater extent of islet amyloids compared with control subjects. The hypothesis of beta amyloid plaque as being the main culprit in the etiology of AD has prevailed since the mid nineteen eighties. However, the therapeutic approaches to treating AD by targeting amyloid plaque have proven to be unsuccessful. Consequently, and due to the necessity of developing novel therapies, innovative pathways and approaches to understanding the pathogenesis of AD have emerged. Consequently, research on brain metabolism and bioenergetics has emerged and attracted a significant amount of attention over the last two decades. Glucose and lactate are the main energy substrates for the brain. A metabolic characteristic of patients with AD is diminished cerebral glucose metabolism characterized by a decreased capacity to uptake and oxidize glucose, signaling dysregulated brain bioenergetics. A traditional methodology for studying cerebral glucose metabolism is the use of an 18-F-Fluorodeoxyglucose (18F-FDG) PET scan. Early studies from the 1990s showed decreased glucose metabolism in AD patients despite normal blood flow. Recently, Hammond and Lin proposed that glucose metabolism is a better marker for predicting AD than amyloid or tau. Further, there has been a recent tendency in clinical practice to incorporate 18F-FDG-PET in the diagnosis and progression assessment of AD. The plethora of studies showing decreased cerebral glucose metabolism in patients with AD have led multiple researchers to inevitably explore the role of IR and mitochondrial dysfunction in the pathogenesis of AD. These pronounced novel interests have shown that, indeed, two main metabolic hallmarks of patients with AD are IR and mitochondrial dysfunction. Since IR and mitochondrial dysfunction are also the main hallmarks of T2D, there seems to be a metabolic connection. Hence, novel terminologies such as “type 3 diabetes”, “brain diabetes”, and “end stage type 2” have emerged in efforts to describe the pathogenesis of AD using a metabolism-centric approach. Furthermore, like skeletal muscle, the brain possesses a lactate shuttle key to brain bioenergetics. Although glucose historically has been thought to be the main fuel for the brain, it is now well known that lactate is a key fuel for neurons, possibly the preferred fuel for the brain, and essential for long term memory. In skeletal muscle, the discovery of the lactate shuttle by Doctor George Brooks was instrumental in understanding skeletal muscle glucose and intermediary metabolism. Briefly, lactate is shuttled from fast to slow-twitch muscle fibers, where lactate is oxidized in the mitochondria of slow twitch muscle fibers via the mitochondrial lactate oxidative complex (mLOC) for fuel purposes. Like skeletal muscle, the brain possesses its own lactate shuttle, which is called the “astrocyte neuron lactate shuttle”. Astrocytes play a key metabolic role in glucose metabolism as they receive glucose from the blood as well as store glycogen and break it down to glucose. Glycolysis is the main metabolic pathway for astrocytes, where most of the pyruvate is reduced to the lactate that is exported to neurons for fuel. From lessons learned from skeletal muscle metabolism, it is possible to observe similarities in brain metabolism through intracellular and extracellular lactate dynamics associated with mitochondrial function. While in skeletal muscle lactate is shuttled from fast twitch muscle fibers to the mitochondria of slow twitch fibers, in the brain, lactate is shuttled from astrocytes to neurons, where lactate is oxidized in the mitochondria of neurons via pyruvate oxidation. As a possible hypothesis, a mitochondrial dysfunction in neurons might lead to reduced astrocyte-derived lactate oxidation resulting in decreased pyruvate oxidation and a disruption of neuronal bioenergetics, as is the case with skeletal muscle, which is ultimately limited not only by glucose transport but by pyruvate oxidation. The etiology of mitochondrial dysfunction in AD patients remains largely unknown. Although the mechanisms behind the pathogenesis of AD remain elusive, novel and exciting advances in our understanding of brain metabolism have been made in the last decade, opening the door towards the generation of novel diagnostic methods and therapeutics. Six point five. Cancer. The lack of progress in targeting genes to cure cancer has led to the development of novel areas of research and clinical applications with exciting therapeutic possibilities. These therapies include immunotherapy and targeted therapies, particularly those that use tyrosine kinase inhibitors, TKI’s. Both immunotherapy and TKIs have helped to extend the lives of and even cure disease in, as in the case of immunotherapy, millions of people. Although they have efficacy in only a relatively small number of tumors and people, we can expect that new and more efficient generations of these therapies will be developed. As a result of the necessity of expanding our understanding of cancer, the field of cancer metabolism has experienced a strong renaissance in the last two decades due to the renewed interest in the Warburg Effect. As previously mentioned, in 1923, the German cell physiologist and Nobel Laureate Otto Warburg discovered that cancer cells show accelerated glycolysis and produce significant amounts of lactate. Although cancer cells increase their glucose uptake, they may not oxidize pyruvate correctly in mitochondria, reducing it to lactate. The observation of the significant amount of lactate that accumulates in cancer cells ledWarburg to posit that cancer is an injury to the cellular respiratory system (mitochondria). However, one century ago, DNA and genetic mutations were not known to exist, as DNA was discovered by Watson and Crick in 1953. It is widely recognized that genetic mutations are ubiquitous to cancer, especially the overexpression of genes such as RAS, MYC, and hypoxia inducible factor 1 alpha (HIF-1-alpha) and the loss of function of the tumor suppressor factor TP53, which confers on cancer cells a selective growth advantage for aberrant cell growth and proliferation. Hence, not all types of cancer necessarily possess a mitochondrial dysfunction. As mentioned above, the Warburg Effect is characterized by accelerated glycolysis and increased lactate production, which was probably what struck Warburg the most. According to the “lactagenesis hypothesis”, the exacerbated lactate production due to cancer cells observed by Warburg one hundred years ago could be the explanation for and purpose of the Warburg Effect. According to this hypothesis, lactate could be a major regulator of the main elements involved carcinogenesis: angiogenesis, immune escape, metastasis, and self-sufficient metabolism. Moreover, it has been shown recently that lactate is an onco metabolite capable of regulating histone acetylation as well as the expression of the main genes involved in ER positive breast cancer cells, including RAS, MYC, and HIF 1 alpha. Since lactate is a canonical element in most cancers, the transcendental question is: why is lactate so ubiquitous to cancer metabolism? As Warburg described a century ago, an injury to mitochondria could be one possible answer. The question of whether this injury is due to a genetic etiology, a metabolic dysregulation, or both will be fundamental to answer and even crucial to finally conquering cancer in the next decade. As previously mentioned, it is known that many cancers have some form of mitochondrial impairment, dysfunction that could be attributable to somatic M-T DNA mutations (as already observed by Vogelstein’s laboratory in the late nineteen ninties as well as M-T DNA depletion. Furthermore, other authors have observed direct disruptions of the mitochondrial structure affecting cristae (cristolysis) in glioblastoma multiforme (GBM), which should have devastating consequences for cellular bioenergetics and homeostasis and could possibly be a reason for the high aggressiveness of GBM. Furthermore, as previously mentioned, mitochondria highly depend on nuDNA as it encodes for about 1200 proteins necessary to mitochondrial repair, maintenance, and biogenesis. Hence, any mutation of any of the mitochondrial nuDNA dependent genes could lead to dysregulation of the mitochondrial bioenergetics resulting in metabolic reprogramming through decreased OXPHOS as well as increased glycolysis and lactate production, leading to carcinogenesis. The crucial symbiotic relationship between the cellular nucleus and the mitochondrion dates back about 1.5 billion years and any disruption of this relationship by either external, internal mutagens or epigenetic effectors could lead to severe consequences for cellular homeostasis. Although the enduring symbiotic relations between the nucleus and the mitochondrion remain largely unexplored in cancer, they may provide us with a better understanding of cancer. In summary, the implications of mitochondrial function in some of the most common NCDs are quite prevalent and central to the pathogenesis of these diseases (Figure 2). Furthermore, there is growing evidence of strong relationships between several diseases, where mitochondrial dysfunction could not only be the etiology behind the pathogenesis of these diseases but also a nexus, which, if true, would elevate medical research to horizons never before reached. Undoubtedly, the research that will be conducted the next decade holds much promise. Seven. Exercise, the Only Known “Medicine” for Maintaining and Improving Mitochondrial Function. It has been known for decades that exercise is the best physiological stimulus for improving mitochondrial function in skeletal muscles and possibly other organs. In this regard, we have learned many lessons from elite athletes that can be translated to multiple populations. Well trained athletes possess the highest mitochondrial function of any humans. The typical characteristic of elite endurance athletes is an increased capacity to oxidize fatty acids as well as carbohydrates, making them highly metabolically flexible. Since the late nineteen sixties and early seventies, multiple studies have demonstrated improvements in mitochondrial biogenesis and function after training. Twelve weeks of endurance training, 5 days a week, increased the number of mitochondrial enzymes by 2 fold and the total amount of protein content by 60 percent . Ten weeks of daily endurance training increased the mitochondrial concentration in the gastrocnemius muscle by about 30 percent and 1 hour of cycling for 4 days a week over five months at an intensity of 70 to 90 percent of the VO2max increased the oxidative capacity and glycolytic capacity by 95 and 117 percent, respectively. Exercise can improve mitochondrial health by increasing mitochondrial content, increasing the transcriptional activity of mitochondrial proteins such as PGC 1 alpha, and decreasing ROS production. A 16 week aerobic exercise program as an intervention in both men and women showed an increase in CS and cytochrome c oxidase of 45 and 76 percent, respectively, as well as an increase in the expression of genes involved in mitochondrial biogenesis, such as PGC1a (55 percent), NRF (15 percent), and TFAM (85 percent). Different studies have also used the model of training followed by detraining in order to measure muscle and mitochondrial plasticity and as a stimulus for physical activity and detraining. Moore and colleagues observed an increase of about 38 percent in CS activity in sedentary subjects after 7 weeks of training followed by a decrease of about 25 percent in CS activity and an increase of about 10 percent in the respiratory exchange ratio (RER) after 3 weeks of detraining, reflecting a decrease in mitochondrial oxidative capacity and flexibility. Klausen et al, observed an increase of 30 to 40 percent in SDH and mitochondrial cytochrome c oxidase (COX) after 8 weeks of training, followed by a decrease to basal levels after 8 weeks of detraining. Wibom et al, found an increase of 70 percent in the mitochondrial ATP production rate after 6 weeks of training followed by a decrease to between 12 and 28 percent after 3 weeks of detraining. Regarding the beneficial effects of exercise on mitochondrial function in multiple diseases, there are multiple studies demonstrating the benefits of exercise on mitochondrial function. For example, a 16-week aerobic training program in sedentary, overweight, obese individuals resulted in a significant increase in mitochondria (76 percent) in the myofiber volume accompanied by improvements in insulin resistance that were highly correlated with mitochondrial size and content (r equals 0.88 and 0.72, respectively, p less than 0.01). Toledo and colleagues also showed that diet and weight loss alone are insufficient to stimulate the mitochondrial capacity in skeletal muscle compared with diet plus exercise. In this study, both groups showed similar improvements in insulin resistance but the exercise group was the only one in which improvements in mitochondrial density, cardiolipin content, and E-T-C were observed. The same group of researchers showed that, in individuals with T2D, a moderate-intensity exercise program for 4 months elicited significant increases in mitochondrial density (67 percent), cardiolipin (55 percent), and mitochondrial oxidative enzymes and improved glycemic and metabolic flexibility. In diabetic mice, eight weeks of aerobic exercise significantly improved the expression of mitofusin-2 (Mf2n), which improves fusion, increases the expression of the mitochondrial transcription factor PGC 1 alpha for mitochondrial biogenesis, increases overall mitochondrial respiration, and decreases IR and ROS production. In patients with mitochondrial myopathies, due to M-T DNA mutations, endurance exercise has been shown to elicit significant improvements in mitochondrial function. Taivassalo and colleagues elegantly showed that 14 weeks of endurance training significantly increased the mitochondrial oxidative capacity, with increases in CS activity, about 50 percent), SDH activity (about 40 percent), and Complex four, about 25 percent, and a decrease in blood lactate accumulation (p less than 0.05). In CVD, exercise is known to improve cardiomyocyte, muscle, and platelet mitochondrial biogenesis, the oxidative capacity, and the antioxidant capacity. In patients with chronic heart failure, a six-month exercise program improved the total volume density of mitochondria by 19 percent and the surface density of mitochondrial cristae by 43 percent. Exercise has also been shown to significantly improve OXPHOS in the platelets of patients with stroke and with peripheral artery disease. Furthermore, exercise was shown to inhibit the pathological mitochondrial remodeling in rats with myocardial infarction (MI) by improving mitochondrial fusion and decreasing mitochondrial fission. Furthermore, eight weeks of exercise post-MI improved the mitochondrial O2 consumption, bioenergetics, and oxidative capacity in mice. Exercise can also improve the mitochondrial function and biogenesis in the brain as well as cognitive function, which opens an exciting door of opportunity to further understand the mechanisms behind the pathogenesis of AD and to improve the therapeutics against this disease. Therefore, we should stress the importance of physical activity not just for the prevention of T2D but possibly for mitigating the severity of and risks associated with AD as has already been shown in. In aging, some studies have obtained promising results. Sustained endurance training over time is also quite effective at maintaining mitochondrial function and flexibility in aging populations. Dube et al, showed that the muscle oxidative capacity, metabolic flexibility, and insulin sensitivity in older endurance-trained master athletes, average age 65 years old, were similar to those of young recreational athletes, average age 28 years old. Another recent study comparing the effects of exercise between elderly, average 80 years old, and young, average age 24 years old, cohorts found that 6 weeks of aerobic exercise increased CS activity by 31 percent in elderly individuals and by 45 percent in younger individuals. Complex one, two three and four increased in both groups by between 51 and 163 percent. The study found that both elderly individuals and younger individuals have the capacity to improve their mitochondrial function after 6 weeks of aerobic training. In summary, there are many studies demonstrating the benefits of exercise on mitochondrial function in many types of populations, including populations with chronic diseases. However, if we consider exercise to be a therapy that we can use to improve mitochondrial and metabolic function, it is essential to optimize and individualize the dose and duration of the exercise that is prescribed. Over the last decade, this is an area where we have gained a wealth of knowledge by working with elite athletes to whom prescribing the right training regime is key to improving athletic performance. Translating this knowledge to populations with chronic diseases is a challenge due to the lack of vertical and horizontal integration of medical systems, including clinicians, multiple providers, exercise specialists, and health care systems, with the proper means and infrastructures. However, all stakeholders should (must) be able to materialize this multidisciplinary partnership in order to achieve proper and individualized exercise prescription programs as exercise continues to be the most important intervention that is known to improve mitochondrial function, metabolic flexibility, and, thus, metabolic health. Eight. Assessment of Mitochondrial and Metabolic Function in the Clinical Setting. Historically, the assessment of mitochondrial respiration and function has focused on the measurement of relevant oxidative enzymes involved in OXPHOS. CS and SDH have been traditionally used in multiple studies as surrogates for mitochondrial function and content. More modern technologies have been developed to measure mitochondrial respiration and substrate utilization in skeletal muscle through two predominant techniques: the Oroboros and Seahorse technologies. These modern techniques, as well as the traditional ones, require muscle biopsies or cell cultures, which are not feasible to obtain on a large scale in humans in order to assess mitochondrial function and respiration. Non invasive techniques based on nuclear magnetic resonance (NMR) and magnetic resonance spectroscopy (MRS) techniques have become popular for research purposes as a valid way to assess mitochondrial respiration in vivo. However, the application of these new techniques to the general population would be very costly and infeasible. Recently, we proposed a novel and simple methodology for indirectly measuring mitochondrial function and metabolic flexibility that can be performed on a large scale in an ambulatory manner. Our methodology is based on the combination of measuring fat oxidation through indirect calorimetry using stoichiometric equations and the measurement of blood lactate levels during exercise, both important mitochondrial substrates. The concept is similar to cardiology stress tests where the heart is stressed through exercise in order to measure its activity and detect pathologies. Through our methodology, we use similar protocols with incremental exercise stages in order to stress the mitochondrial capacity and detect changes in mitochondrial and muscle bioenergetics. As shown in Figure 3, during exercise, both fat oxidation and lactate are oxidized in mitochondria as t

Rahan. Episode Sixty-Seven. By Roger Lecureux, drawn by Andre Cheret. The Bird that runs. Horrified, the son of Crao froze when he saw the head on the ground. Because even in those wild times, it was rare for “Those-who-walk-upright” to behead each other! Horror gave way to astonishment when the face came to life. Go on your way, hunter. Gahoa must atone for his faults! Buried, up to his chin, the man must have suffered. But he was not complaining. Rahan will take Gahoa from the earth trap! Page Two. While the knife dug and dug, Gahoa protested. Stop, “Hair of Fire”! You are violating the custom of the Clan! Stop! But the son of Crao did not rest until the victim of torture was freed! Mine will turn their anger against you! Rahan hates seeing “those-who-walk-standing-up” suffer! But what fault did Gahoa commit to deserve such cruel torture? Gahoa was hungry. Very hungry. He ate a sacred egg! It was right for the clan to punish him! But Gahoa would have been freed by sunset! My brothers are fair and loyal! But their anger will be great when they know that you have violated our custom! Run away from here, “Firehair”! Flee our territory! Page Three. And Gahoa himself fled into the thickets, admonishing Rahan who was left to be perplexed. Did Rahan do something wrong? No! Rahan is right! Soon after, the son of wild ages, wandered here and there looking for food, when. Oh! Are these the “Sacred Eggs” that Gahoa spoke about?! The eggs lay in a hollow in the sand, and resembled stones. But they were indeed huge eggs, as big as “fruits of wood.” Eggs like he had never seen! Rahan was holding out his hand when a loud cackle came from behind him. Oh! The strange birds! If they shout like that it means the eggs belong to them! The son of wild ages had never met ostriches before. The silhouette of these birds amazed him. Crao sometimes spoke of "The Running Bird"! Page Four. As he approached, the panicked ostriches scampered away on their long legs, their necks stiff like bamboo. Ha-ha-ha! That is right! These birds do not fly. They run! Then began a merry pursuit. But Rahan means you no harm! He just wants to see you up close. To touch your plumage! Amused, Rahan picked up the pace. His fingers reached out to grip a plumed tail. And. Oh! Rahan begs your pardon, “Bird who runs! A splendid feather, thick and silky, remained in his hand! The ostriches were already far away. The son of Crao returned to the eggs, which a large reptile was contemplating! Rahan discovered the eggs before you, “Boak”! They are his! Page Five. Rahan had always hated snakes. Like this one, that raised its threatening head. Do you hear “Boak”?! Rahan will not let you eat his eggs! The branch whipped him with such violence that his flesh burst! Ra-ha-ha! He recovered heavily, breaking an egg whose contents spilled out. And Rahan exclaimed that the yellow was bigger than his fist! Just one egg could satisfy the hunger of a hunter! Rahan does not believe these eggs are "Sacred". But they will be very precious to him! Cries of men arose in the distance and the son of Crao, grieving more for his "Find" than for himself. Hid the two eggs under a layer of clay. Gahoa has undoubtedly found his own. They are approaching. Page Six. Indeed, Gahoa was accompanied by hunters who searched the thickets. But Rahan, who knew the art of hiding, was not discovered. They could come back. Rahan will leave his eggs in their hiding place! As night fell, he lit a fire by which he intended to watch. But fatigue got the better of him and he did not wake up until dawn. He observed the still warm ashes and. The eggs? Cracked under the effect of the heat, the clay mass revealed the eggs. Which rang curiously under the point of the knife. Rahan remained immobile. Although he expected to find a clear, sticky liquid. He discovered under the thin “skin-of-stone”, another white and firm egg. Page Seven. His delight grew even more when he noticed that he could cut egg slices! Therefore, the “clay” burned in the fire, has this wonderful power! Hum, Rahan has never had an egg this good! He would like to know if “clay-earth” also makes meat or fish better! The son of Crao, shortly after, was lying in wait at the edge of a stream. Trout were swimming in the clear water. Their movements were lively and precise. If a raft had a tail like these fish, Rahan could drive it wherever he wanted! Rahan never missed an opportunity to observe nature. And always took advantage of his observations. But, in the meantime, he spied a superb trout. Page Eight. His hand plunged with incredible suddenness. His fingers grabbed the fish, just behind the gills. Ra-ha-ha! Shortly after, this fish was wrapped in clay and placed on the heated fire. Rahan just has to wait! Playing with the long and soft ostrich feather, the son of Crao observed the clay which slowly cracked, when. You will not escape us “Hair of fire”! By rescuing Gahoa before his time, you challenged us! The hunters who launched themselves were not armed, but numerous. And not only ado you challenge the clan, but you have outraged a "Running Bird"! And you ate a sacred egg! Indignant, the chief pointed to the large feather and the remains of the shell. Page Nine. Then, intrigued, he leaned towards the fire. But what demon are you to eat earth! Rahan does not eat the earth. But what he is cooking inside! With a blow of his knife, Rahan broke the baked earthenware mold. A delicious smell escaped. What? What? The astonishment of these men did not diminish their anger. You know things that our clan does not know “Hair of fire”! But that won't spare you the punishment you deserve! May our law be respected, brothers! Let “Fire Hair” meditate on his faults until the next return of the sun! Ten men rushed forward, which the son of Crao tried to resist. Ra-ha-ha! Page Ten. Although unequal, it was a fair and honest fight. The hunters showed firmness, but not hatred. And Rahan was finally knocked to the ground. His wrists were tied. You are stupid hunters! Rahan hopes you will understand it one day! Other men were already digging a hole, with sticks in their hands. Rahan will suffer the same punishment as Gahoa! Indeed, the son of Crao was pushed into this hole, which was filled again. And if Fear consumes you, you can always beg for the clemency of the clan! Ha-ha-ha! “Hair of Fire” is a prisoner of the earth. Like his fish of the clay! The hunters disappeared, abandoning their captive to the burning fire of the sun. Page Eleven. It was impossible to free himself from the earth trap, and until the end of the day Rahan suffered from thirst. But, at dusk, a man crept towards him. It was Gahoa. Drink, “Fire hair”, drink! Gahoa cannot do anything else for you! And Gahoa disappeared into the darkness. A long night began for the prisoner. A night of anxiety. Rahan is at the mercy of the first beast that passes by! Wild animals were roaming in the forest and suddenly, a panther appeared in the moonlight. She approached. Rahan will join the territory of the shadows. When the feline raised her clawed paw, the son of fierce ages, dominating his fear, did not utter a word that could have excited the beast. He held his breath and closed his eyes. Page Twelve. When he reopened them, the beast, without doubt finding no interest in this lifeless "Thing", was walking away. Rahan has never been so scared! With the day, a new danger was presented, more unexpected but just as worrying. The Birds who run! Very interested, the ostriches surround him. The boldest one gave him a quick peck. Then another. These blows were painful but bearable. Fearful of being harassed with pecks which, sooner or later, would put out his eyes, the son of Crao howled. Ra-ha-ha! And the frightened ostriches scattered around. Had it not been for his situation, this frantic flight would have made Rahan smile. Page thirteen. The hunters reappeared shortly after. The punishment is over "Fire hair"! We will free you! If you wish, you can stay with us! With ardor, the men cleared the earth. Was “Hair of Fire” not afraid? Yes. Rahan was very scared! Our clan loves those who admit their fear! Rahan was pulled out of the hole when a howl of terror rang out. The “Nandouk”! The “Nandouk”! In an instant, it was panic. The hunters were running away from all sides, shouting a word that the son of Crao did not know. And he understood the cause of this fear. A fantastic animal was approaching. Twice as tall as a man, this monstrous bird, like the ostriches, seemed incapable of flight. Its legs were massive, its neck thick and its beak enormous. Page Fourteen. Hoping that this monster would flee like the "Running Birds", Rahan uttered his cry. Back Nandouk! Ra-ha-ha! But the bird, far from fleeing, charged! The son of Crao, his hands still hampered, did not have time to dodge! Ah! A peck of incredible violence threw him to the ground! And the rest was terrifying. The Nandouk jumped around Rahan who was writhing desperately on the ground to avoid the pecks, any one of which could have dis-embowelled him! Ten times this monstrous beak plunged towards him. And he managed to avoid it ten times! Rahan is doomed if he does not manage to get up! Page Fifteen. Between two attacks he managed to stand up. Fleeing was his only chance to survive! Ra-ha-ha! Rahan never imagined that he would one day run away. From A bird! His restrained hands unbalanced his running and the "Nandouk" was already on his heels! A terrible blow to the back threw him to the ground again! Argh! He had an instinctive reaction and his freed hands broke his fall! The monster's blow had broken his Bonds. Ra-ha-ha! He immediately stood up and faced the "Nandouk" which was preparing a new attack. Clutching his faithful ivory knife gave him hope. Page Sixteen. But this hope immediately dissipated. He could not approach to strike. And he refused to throw the cutlass for fear of missing a vital organ and finding himself disarmed. Rahan knows how to triumph over you, “Nandouk”! The son of Crao suddenly rushed towards the forest, pursued by the giant bird. An instant later, he ducked into the branches where the monster could not follow him. But it remained on the lookout under the tree! And Rahan, who was making a strong lasso, did not want anything else. You are going to fly for the first time in your life, "Nandouk"! The bird, which observed the man with its cruel eyes, did not react even when the long loop sprung from the foliage. Page Seventeen. It slipped over her plumage, fell onto the ground, and was ready to snare her enormous legs. And Rahan plunged into the void! Ra-ha-ha! He was finishing tying the vine to a root when the hunters came running. You will no longer have to fear the “Nandouk” brothers! In fact, the monstrous bird was suspended by its legs, and it was now at the mercy of these men. Rahan achieved something that our hunters have wanted for ages! He deserves the “Feather of Bravery”! Plucking an ostrich feather from his loincloth, the chief offered it to the son of Crao. Would Rahan also have the right to eat the sacred eggs? Rahan will have this privilege! But not my brothers! Page Eighteen. Why this interdiction? Because the “Running Birds” are the main food of the clan. If we ate their eggs. There would be no more "little ones", therefore no more "Big ones" and therefore no more eggs! And we would experience famine! Rahan recognized the wisdom of this reasoning. He stayed for some time among these men who now cooked the flesh of the "Running Birds" in clay molds. But Rahan could not integrate into this clan. There was so much left for him to discover! And his knife, that morning, pointed out to him the immense lake. A lake whipped by the wind. A lake where it would be difficult to steer a skiff. And it was then that he thought of the lively trout. Of the trout, and their tails! Page Nineteen. The following days often found him on the lookout. He needed skins to make a sail. And under the amazed eyes of the hunters his boat slowly took shape. To those who cried for a miracle, the son of fierce ages always revealed his secrets. He spoke of trees carried away by the river, which had given him the idea of building platforms. Floating shapes. He spoke of the dead leaves sliding on the trees, which had inspired him with the idea of “skins-pushed by-the-speaking-wind.” Rahan's observations, as we have said, always found an application. So he designed what would be the “tail” of his raft! Page Twenty. And the day of farewells came. Our clan will not forget you “Hair of Fire”! And we want to make you an offering! Men approached, holding out eggs of the “running birds”! They were cooked in the “ground of Clay”! May they allow you to go far away! Very far! Rahan plunged his fork covered with skin into the water. And this “Rudder” was a marvel! The assembled skins swelled in the wind. The raft launched itself away from the shore. Maybe one day Rahan will return, brothers! The raft, docile, obeyed the combined forces of man and the wind! Towards which unknown land was he sailing? The son of fierce ages did not care, still amused as he was by the white escort of the seagulls. Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html

Rahan. Episode Sixty-Six. By Roger Lecureux, drawn by Andre Cheret. The men without heads. The son of Crao could not find wood supple enough to make a bow. So he thought of a blowgun, to kill one of these birds and satisfy his hunger. He had once discovered the effectiveness of this silent weapon. The bank covered with large dry reeds would provide him with one. These reeds had been pierced by insects. One of them escaped from the reed he cut. The beast that stings will find refuge elsewhere! Page Two. Before slipping a long thorn into his blowgun, he crawled towards the screaming birds. When he was within range he blew and. Almost screamed in astonishment. It was not the thorn that had sprung from the weapon, but a strange sound! Intrigued, he started again, and a new sound arose which lasted as long as he blew. To-e-i-ou! How can the “wind-of-cheeks” make music? Stuck in the orifice of the reed, the thorn will only allow a trickle of air to pass through. And Rahan Noticed that the sounds changed depending on whether he was blocking this or that hole! Delighted, he had fun modulating short sounds, then long ones that resembled complaints. This music is softer, prettier than that of the great horns of the hunters of the “two tooth”! Page Three. The son of Crao forgot his hunger. He forgot the birds. He even forgot his knife, which he had left stuck in the ground. This was why he found himself disarmed when three menacing beings burst out of the thicket! “Hair of Fire” will pay with his life for the suffering that his people have made us endure! The rough trio rushed towards Rahan. Who only had time to grab a solid vine. Rahan does not understand your words! But he will not let himself be killed without a fight! The vine whirled, lashing the faces. But Rahan, retreating, was soon cornered against a rock. Page Four. And suddenly, hit in the forehead by a stone, one of the men collapsed! Tock! The other two fled, terrified! "Hair of fire" has a magic weapon! Rahan looked up for the one who had come to his aid. But he saw nothing and heard nothing. However, this stone did not fly by itself! Oh! He perceived the rock, and saw similar stones on it. An explanation was born in his mind. The vine of Rahan whipped this rock. It was the vine, who grabbed the stone and threw it! Placing the loop of the line around a stone, he pulled violently. And. The projectile whirled away! Ra-ha-ha! Page Five. It is a happy day for Rahan! He has discovered the “Music-Reed” and the “Vine that throws Stones”! Attributing the discovery of the flute and the slingshot to the son of Crao would be very daring, but who knows? The man, a few steps away, came back to himself. “Hair-of-fire” is bad like all his people! He almost broke Gagna's skull! Rahan did not want to kill. He does not kill "Those Who Walk Upright"! But why did Gagna and his brothers attack him? They want revenge for having been treated like animals for so long! Rahan had no time to ask any further questions. Who are you, you who allowed us to catch up with this “Headless Man”? I am Rahan, the son of Crao! And Rahan does not understand why you are brutalizing Gagna! The hunters savagely prodded Gagna with their spears. Page Six. But they showed Rahan considerable respect. Rahan should have no pity for those who have no more brains than the "Four Hands"! Come with us to the village. You will be welcomed there like a brother! Rahan's gaze met Gagna's. There he detected despondency and fear. And he decided to follow these hunters who pushed their captive without care. Why do they call Gagna "The man without a Head"? Rahan wants to know! The group was crossing a vast clearing when a hammering sounded. A “Two Nose”! The rhinoceros that charged was a large male, one of those loners that hunters so feared. They scattered around screaming. Page Seven. And Gagna, taking advantage of this moment of panic, rushed towards the forest. May the “Two Nose” punish the bad men! Too busy looking for shelter, the hunters did not care about the fugitive. Look! "Fire-hair" has lost his mind! Look! The son of Crao rushed towards the pachyderm that had just stopped, looking for men with his tiny eyes. Attack, “Two-nose”! Attack Rahan! Rahan knew he could not defeat such a monster. But he had another purpose. To lure him towards the large pit he had just glimpsed. Attack! “Two-nose”! Would you be afraid of Rahan!? The rhinoceros swung its heavy head, observing the man gesticulating in front of him. Its formidable hoofs plowed the ground. Page Eight. And he charged the excited animal, which had only one desire left. To crush, to destroy this agile being who was fleeing him. This way, “Two Nose!” This way! The son of fierce ages made a sudden turn, imitated by the monster. The pit was only a hundred steps away. The hunters, hiding in the thickets, did not understand. Why had “Fire-hair” attracted the anger of “Two-Nose”? The pachyderm was no more than thirty steps from Rahan. Twenty steps. Fifteen steps. Ten steps. Ra-ha-ha-ha! In a fantastic bound, Rahan had just lept from the ground. Page Nine. He barely held on to the other edge of the pit, while the rhinoceros, on its dash, rushed headlong into the improvised trap! The clamor of the hunters greeted the reappearance of the son of Crao. “Fire Hair” has just proven that he is not a “Man without a Head”! Rahan deserves no special credit. The "Two-noses" are as stupid as they are powerful! And, backing up to gain momentum. Rahan re-crossed the wide pit from which the monster would never escape again. Tamud himself would not have had this idea to get rid of a “Two-nose”! Who is Tamud? Page Ten. Tamud is our sorcerer. He knows a hundred things that others do not! He foresees everything! Did Tamud predict that Gagna wouldl escape you? The men did not notice the irony of the son of Crao. Come, brother. Tamud will be happy to welcome a brave hunter! An important village soon appeared. The huts which stood on the banks of the river were high and solid. The Clan that lived there was visibly more evolved than many others. One thing immediately intrigued the son of fierce ages. An enclosure where several dozen men were kept. Enemies of your clan? The “Men without Heads” are not enemies, they are our slaves! Slaves! Rahan doesn't like hearing this word! Page Eleven. Rahan, shortly after, was presented to Tamud, who showed no admiration when the hunters recounted the exploit of "Hair-of-fire". Rahan was fleeing the "Two-nose" and he had the chance to jump this pit! It was neither cunning nor intelligence that guided him but fear! But we saw him provoke the "Two-tooth" and. What your eyes saw does not matter! All that matters is what Tamud thinks! Like many wizards Rahan had known, Tamud was jealous of his authority. Lock up Rahan with the “Headless Men”! The hunters who had witnessed Rahan's exploit hesitated. But others rushed forward. If Tamud is jealous of Rahan why does he not confront him himself!? Page Twelve. The wizard gave a scornful smile. Tamud, who knows how to create fire, who knows how to cut stones, who knows how to make bows and spears, does not lower himself to fight! A moment later, the son of Crao was pushed into the enclosure. Fearful men surrounded him. Are you a “Man without a head” too? Rahan was finally able to learn who these captives were. They all belonged to the swamp clan, a particularly primitive tribe that knew nothing, or almost nothing. We do not know, like the hunters of Tamud, how to make fire from stones. We do not know, like them, how to make weapons that kill from afar. We do not know anything! And that is why Tamud calls you "Headless Men"! And he takes advantage of the ignorance of these unfortunate men to make them his slaves! Page thirteen. Rahan further learned how Tamud forced his captives to build huts. How he treated them like animals to carry out the most arduous work. Some of us occasionally manage to escape the village. But hunters of Tamud almost always catch up with them! You will soon be free! Rahan promises you! He will prove that Tamud is merely a proud and stupid person! Strange things happened that night. There was, first of all, a curious music which rose from the enclosure. When the sorcerer, escorted by hunters entered there, Rahan blew into a bamboo reed. That! So what is this? Page Fourteen. Rahan thought Tamud knew everything? Does Tamud not know that you can make a bamboo sing? Displeased, The Sorcerer withdrew. He was meditating near the big fire when, a little later, some hunters saw him wavering. Ha! Who? Who hit Tamud? Can you not see? It was Rahan who struck Tamud! Supported by the shoulders of the headless men, the son of Crao jumped the enclosure. You lie! How could you have struck me, since you do not have a weapon! Therefore, Tamud does not know how to throw stones from a distance! With this!? Rahan placed a stone on the strip of skin, twirled his "Sling" and released the projectile. He shattered the earthen jar that he had aimed for! Page Fifteen. Tamud was not aware of this weapon? Clearly, there are a lot of things that Tamud does not know! But perhaps Tamud knows, like Rahan, “Crawling on water”? Mockingly, the son of Crao dove into the river. A moment later, he was moving in the water with magnificent ease. The moment of astonishment passed, and then the whole clan cheered him on. Why does Tamud not join Rahan? Does Tamud not know that “Those-who-walk-upright” can also crawl on water? Being ignorant of so many things, could Tamud be a “man without a head”? Kill this demon! Kill him! The wizard screamed in rage. But, as the hunters did not obey his orders, he brandished his own spear. Page Sixteen. This one did not reach Rahan, who had let himself sink. Rahan could flee! But he will not abandon those of the swamp! He returned to the shore to the ovations of the clan. But Tamud rushed towards him, brandishing a sharp flint. And you said that Tamud would not lower himself to fighting! There was not even a fight. The sorcerer, lifted from the ground, was thrown into the black waters! Ra-ha-ha! Agloo! But as he was about to drown, the son of the fierce ages dove to his aid. This was a generous gesture, which definitely won him the trust of the clan. “Hair-of-Fire” knows more things than Tamud! And he is more loyal than Tamud! Page Seventeen. No one opposed him when he opened the door of the enclosure to free the “Headless Men”. Grateful but fearful, they were going to flee. But he kept them there. Stay here, brothers! Rahan will teach you everything he knows! There will be no more difference between you and the hunters of Tamud! In the days that followed, the son of Crao revealed all his knowledge to these men. He taught a thousand things. He spoke of a hundred distant countries and a hundred peoples. Tamud-the-sorcerer, who had lost all authority over the clan, remained prostrate in his hut, meditating on revenge. Tamud will kill “Hair of Fire” this very night! That night, in fact, the sorcerer slipped towards the hut that had been attributed to Rahan. Page Eighteen. This one, plunged into a calm and deep sleep did not hear, and could not hear, as the deceiver approached. But Tamud heard the peaceful breathing of the one he was going to assassinate. The hunters will believe that the evil spirit has come to take the life of “Fire-hair!” A wicked smile creased Tamud's face. Stretched out on the palm litter Rahan was there, at his mercy! He raised his weapon. He took another step. And then, the son of Crao rolled onto his side, narrowly avoiding the terrible blow of the spear! Shouts arose, alerting the hunters! What is going on "Hair of Fire"? Why are you shouting like that? Page Nineteen. And Rahan appeared, throwing the Sorcerer out of the hut. Tamud the coward wanted to kill Rahan! You wanted to take away the life of the one who taught us so much! You are the one who's going to die, Tamud! No! No! Panicked, the sorcerer fled. And the son of fierce ages did not have time to intervene. A spear had stopped the coward! This deceiver could have disemboweled you, “Hair of fire”! Luckily you were not sleeping! If Rahan was sleeping! But Rahan guessed Tamud's bad feelings. He knew that Tamud would try to kill him while he slept. And Rahan had set a trap for him! Come and see. Page Twenty. This vine was stretched across the bottom of the door and tied to Rahan's wrist. Like this. Upon entering the hut, Talmud touched the vine and the shaking woke up Rahan! Oh! Please excuse me for not teaching you this trick yet! The body of the sorcerer was placed in the river at dawn. May peace now reign between our clan and that of the swamps! Thanks to you, there will be no more “headless men”! You will also remember that "Those-who-walk-upright" must not abuse their knowledge, but that they must share it with their brothers! The son of Crao stayed a long, very long time in this village. In fact, he only left when he was certain that all these men had nothing more to learn from Him! Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html

Rahan. The son of the Ferocious ages. Episode Sixty Five. By Roger Lecureux, drawn by Andre Cheret. The Infant Chief. The ground suddenly began to shake and the son of Crao instantly remembered the tragic night of the blue Mountain. The nearby volcano, he knew, would soon vomit its fiery entrails. Abandoning the half-dismembered "Two-horn" he set off in search of a cave. But will Rahan have time to find refuge! Oh! They would do well to imitate Rahan! A few arrow ranges away, hunters and their companions implored the spirits for clemency. They responded to every rumble of the ground with incantations. Page Two. May the good mountain spirits spare our clan! May good spirits appease the anger of the “Great Mountain!” Your pleas are in vain, brothers! “Those-who-walk-upright” must rely only on themselves! Run away while there is still time! Run away! Who are you? What allows you to give us orders? I am Rahan, the son of Crao! Rahan does not give orders, but advice! The man who had just emerged from a strange hut made of mammoth tusks was obviously the clan sorcerer. I have just consulted our chief! He affirms that the “Great Mountain” will calm down and. Your chief is stupid and Rahan is going to tell him so! Sacrilege! “Hair-of-fire” Violates the leader's secret abode! Energetically pushing the wizard aside, Rahan rushed into the hut. Page Three. And astonishment froze him in place. Under the large ivory dome, lying on thick, warm furs, he saw only a very young child. This little man has only seen the green leaf season once! Your chief is not here! Where is he? You just saw him! And those who set eyes on Atara must die! A leader who cannot stand on his feet yet!? Rahan has never seen or heard of such stupidity! “Fire Hair” Despises our revered leader! Kill him! Gahar commands you! The hunters were already rushing forward, brandishing their clubs. The son of Crao repelled the first assault, but his vivacity and strength, although exceptional, did not allow him to confront the pack victoriously. Ra-ha-ha! Page Four. He was out numbered, he was defeated, and mastered. Clubs were going to crush his skull when. Wait! If we deliver him alive to the "Grand-Mountain", like Ogoo-the-Profaner, we will attract the favor of good spirits to the clan! While Gahar-the-sorcerer grabbed his ivory knife, Rahan was firmly tied up Gahar is lying to you! No sacrifice will calm the "Great Mountain"! Some hunters dragged him away from the camp, towards the volcano whose sides were now rumbling dully. They left him there. Rahan was desperately trying to break his bonds when a voice spoke out. We will leave together for the territory of shadows! What? What? Page Five. The fiery slime of the “Grand-mountain” will burn our flesh and bones! A man was lying twenty steps away, also tied up. Who are you? I am Ogoo! Gahar decided that I had to die because I refused to obey the orders he said he had come from little Atara! Rahan does not understand. Ogoo recounted how Raykaa, the clan leader, had died two seasons earlier. But Gahar-the-sorcerer claimed that he still lived in the body of his son, little Atara! With this lie, Gahar imposes his wishes on the clan! No one other than he can approach Atara, who, he claims, relays his father's orders to him! It was because I opposed this deceiver that he demanded my death, claiming, of course, that it was Raukaa who demanded it through the mouth of his son! The rumblings grew louder. The eruption could happen at any moment! Page Six. Neither Ogoo nor Rahan will die! Rahan will untie your bonds! Getting close to Ogoo was difficult for the son of the ferocious ages. To get his wrists free, when the knots resisted, he sheared them with his teeth. Your turn Ogoo! Rid Rahan of these vines! Their hands free, the rest was childishly easy. He was rushing away from the "Gand-Mountain" when the fantastic explosion rang out. Ba-boom! The crest of the volcano was crowned with reddish clouds from which a terrifying geyser of fire and molten rock gushed. In a few seconds it was an inferno. The ground cracked, releasing jets of steam. Rocks rolled down the "Grand-mountain." Others rained down from the sky, from all sides. Page Seven. Yours finally understand that they have nothing to expect from good spirits! And Gahar is not the last! The whole clan fled in indescribable panic. And Atara!? Why didn't you save Atara!? Uh. Through the mouth of Atara, Raukaa told me that he did not want to flee the fire of the "Great Mountain"! As they rushed into the deserted camp. Despite the noise of the volcano, Rahan and Ogoo could hear cries. The coward! Gahar abandoned Atara to so he could flee faster! Go Ogoo, go. Join yours! Perhaps Rahan can save the little man! As the incandescent stones fell everywhere, Rahan rushed towards the sacred hut. The child was there. Frightened by the incessant rumbling and explosions of volcanic bombs. He only stopped crying when the strong hands of the son of Crao grabbed him. Page Eight. He had not gone a hundred steps when the hut collapsed, dislocated by a huge rock! Atara narrowly missed it! The anger of the Great Mountain redoubled. Here and there were worrying cracks that Rahan had to jump. He saw the clan taking refuge on a rock platform at the edge of a salient. Profanation! “Hair-of-Fire” has defiled Atara with his hands! Unaware of what the hunters' reactions would be, the son of Crao froze. Rahan told you that no sacrifice would appease the “Grand-mountain”! Gahar lied to you! Gahar deceived you by claiming that Raukaa-the-chief spoke to him through the mouth of Atara! Atara, like all little men, does not yet speak! Page Nine. And since Gahar and him alone! Had the privilege of seeing and touching Atara. Why did he not do anything to protect him!? Gahar is just a coward! To save his miserable life he did not hesitate to abandon the child he said he venerated! The hunters observed Rahan, then the sorcerer, then Rahan. But they did not flinch. Kill him! Kill him! Then, mad with Rage, Gahar descended the Rocks, rushing towards the son of fierce ages! The bone points of his formidable head smasher reflected the fire of his eyes. The “Grand Mountain” thundered even more loudly. The ground shook more fiercely. Rahan placed the child on the ground, to face the sorcerer who was coming towards him. Page Ten. He was unarmed but he knew how to parry the first blow. His hand flew towards his ivory knife, and slid into Gahar's belt. Rahan will not let you steal his life! Knife versus “Head breaker”. Rahan was ready for an unequal fight. When a shock, stronger than the others threw him off balance. Screaming with joy Gahar, rushed towards his opponent who was on the ground. Rahan reared up instinctively, avoiding the fatal blow. But the weapon clipped his wrist with incredible violence. And his cutlass fluttered far away! He was at the mercy of the sorcerer! But he suddenly faltered and the son of Crao felt the earth open beneath him! His hands grabbed at a root. Page Eleven. Argh! Clinging to this root he is alive to everything at once. Gahar, who disappeared into the crevasse and the child who fell there in turn! An extraordinary reflex made him grab one of the infant chief’s legs in mid-air! But now, his good hand was no longer of any help to him. And he would not find the strength in his injured hand to hold on for very long! By abandoning Atara, he could still save himself. But this thought did not even cross his mind. We will live Atara! Yours are coming! Despite the rumblings of the "Grand-Mountain" he heard the clamors of the hunters who were quickly approaching the crevasse. Ogoo was the first to look into it. “Hair of Fire” is alive! He has saved Atara once again! Bring us vines! Quickly! Quickly! Page Twelve. An instant later. Ra-ha-ha! Rahan shouted with joy, because what he had feared had not happened. His knife had not disappeared into the bowels of the earth! What is happening "Fire hair"? Gahar unmasked himself in front of my brothers! No one will cry for this coward! But our clan, now no longer has a sorcerer or leader! Rahan maliciously observed the hunters. One day, perhaps Atara will become head of the clan. But many seasons will pass before he becomes strong and brave like his father! Until that day, why would the clan not appoint as leader the one who first had the wisdom and courage to oppose Gahar the perfidious! The "Grand-Mountain" still thundered while Ogoo was being hailed. But the earth no longer shook and the clan was safe. Who would adopt Atara? The son of Crao, happy, took pleasure in watching the women happily arguing over he who had been "The Infant Chief". Index: https://rumble.com/v3486cm-rahan-index-of-episodes-by-roger-lecureux..html