Aging - program
“The strongest survives,” - sometimes pathetically declare all sorts of “masters of life”, distorting the original meaning of Darwin's thought.
“The fittest survives,” - meant Darwin, explain to us evolutionary biologists.
Adapted to what? To maximum reproduction in current conditions. Who is this “fit”? Individual or rabbit? Of course not. An individual will not survive anyway. Survives that team of genes that created the most “fit” rabbit. One that will chase the brethren in providing their genes with maximum survival by creating as many copies as possible.
And what is “maximum survival”? What parameter will we maximize? “This is to your liking,” Game Theory tells us. Want a local maximum of your copies at a single point in time? Get it, sign it. Just do not complain that oh, how happiness is fleeting, after you become extinct from the exhaustion of resources.
Want to live happily ever after? That is, to maximize the area under the curve of your copies in time? Then be kind to learn how to control the resource consumption of your replicators, or at least give them skills to wait out long periods of adverse conditions. And the best is both.
But the most chic is to grow their intellect, so that they start controlling their population for you, plan the consumption of their resources, and even come up with more and more efficient ways to extract these resources. Such replicators can produce as many as 7.5 billion of your gene cooperatives of 30–40 trillion copies each. For bacteria, of course, these are ridiculous numbers , but for eukaryotes, this is quite an indicator.
True, the intelligence to grow for a long time, and there is a chance not to grow, the Neanderthals tell us. That's right: if you, as a young, daring start-up cooperative, use the “trillion monkey on typewriters” method to code your thinking skills in your replicators, then until your code is ready for a production release, you have tothe population of these very beta replicators itself is also controlled. And then another sabrutin called be fruitful and multiply () and seemingly tries to keep all your efforts in / dev / null. Therefore, the cooperative "Genes and Sons" and had to first hone the ability not to let their creatures die out or multiply strongly. For what he first nakodil mechanisms for controlling the inflow and outflow of the population . Having learned to control the influx of individuals through the shutdown of reproduction, and the outflow through phenoptosis is either sharp like that of a salmon, or smooth like that of a mouse.
Is Pacific Salmon Death Programmed ? I think almost anyone who is in the subject, admits that yes. But about whether it is programmed with us, there is a heated debate.
What distinguishes a program from a non-program? It's all very simple. A program is when changes occur on purpose. Nonprogram - when stochastically, randomly.
After all, no one argues that embryogenesis is random. Or that puberty is a stochastic process. No, everything is clearly programmed: stages, dates. And that is why we do not observe single sexually mature babies or 80-year-old women in labor, as they should have been if these were random processes. And if the nature of aging is random, then why do some species of animals live for several days, and others for hundreds of years? Indeed, similar statistical processes are characterized by similar statistical distributions of their results. But for some reason, the parameters of these distributions are very different. even for such close relatives as a mouse (2–3 years of life), a squirrel (10–12 years old) and a naked mole rat (30 years old):
Moreover, in social animals, the lifespan can differ by an order of magnitude even for twins with identical DNA. The uterus lives 20–40 times longer than the working individual.
Along with this, we know that very different species have common molecular mechanisms of aging. What worms, mammals - for example, the notorious cascade of insulin-like growth factor (IGF-1), which first helps the body to mature, and then die. At the same time, the rates of aging are very different: the nematode lives 2–3 weeks, and the mouse is 2–3 years old. And this, too, does not fit well with the hypothesis of the random nature of age-related changes.
At the same time, all gerontologists agree that in our body the ability to repair damage and debris is reduced with age. And that it is this decline that leads to the accumulation of both, and ultimately to death - that is, everyone agrees that this process of degradation is the main cause of our aging.
The only stumbling block - is it an accidental decrease in age or is it purposeful? It seems to me that all the data indicate that the role of chance in this process is minimal. We see how the body purposefully destroys our thymus from the age of 15, from 25 to our brain, from 45 to our muscles, and from 60 to our bones. And the same processes, only accelerated by 20–30 times, we observe even in mice. And to believe that they are all random is very difficult.
I already wrote about the main mechanism of control and synchronization of important processes in the body - epigenetics. With age, it all changes in the same way - the “epigenetic clock” perfectly predicts our biological age, and the fact that the Yamanaki factors prolonged the life of these epigenetic hours by prolonging the life of mice confirms this hypothesis for me.
Who sets the clock for these watches and drives them forward? Most likely, our brain. Or rather, the hypothalamus with the pituitary gland, based on the circadian rhythms of the pineal gland. Here is an interesting study., showing how stress through corticosteroid hormones causes epigenetic changes in 5-year-old children, similar to those that we see with normal aging. Who produces cortisol? The axis of the hypothalamus-pituitary-adrenal glands. And the above study well confirms the role of epigenetics in the implementation of the aging program - stress accelerates it, factors of Yamanaki roll back.
And we see how similar these processes are in all organisms. The primitive neuroendocrine system is still in nematodes - in fact, the beginnings of the hypothalamus-pituitary-gonad axis. And it is this axis that controls their growth and development.. If there is a shortage of food, it also includes a mode of non-aging — a power stage in which a nematode can stay for months, and then again includes a growth process, and the worm matures, multiplies, and dies in its standard few weeks.
By the way, remember the above-mentioned cascade of insulin-like growth factor (IGF-1)? This is also one of the genes for aging. In nematodes, it is called daf-2 . His knockout (deletion) extended the life of nematodes 10 times, and the mice - by 2. And this cascade is very evolutionary old, just superstar (sorry) - it is in yeast, and in nematodes, and in us .
In this case, of course, we still do not fully understand all the mechanisms of these processes. If (or rather, when) we understand, then all debates about the nature of aging will be resolved. The question “where is the program” will have an unequivocal answer: here it is, the genes are such and such, the mechanisms of their control are such, the input parameters are the algorithm.
I have a very simple and applied approach here: if the hypothesis of the aging program allows us to stop this aging or at least prolong our life 10 times, this will be more than enough for me. So far, no other hypotheses have found a better life extension than fasting, and it is ineffective for primates .
Another hypothesis: if aging is a program, it must have some key mechanisms that vary the main parameter of the program - life expectancy. By influencing these mechanisms, we must see the effect on the outcome of the program. The results of life extension are shown to us at times with the help of knockout of developmental / aging genes on nematodes and mice.
I do not know, I did not hold a candle. I will express only the cautious assumption that billions of years ago, aging, most likely, was not. As it is not observed, for example, in viruses. But at some point it arose from single-celled and gave them an advantage in survival by preventing their extinction due to overpopulation (or some other way). We know two such mechanisms of aging in unicellular organisms - apoptosis and telomeres. Moreover, these mechanisms perfectly show the action of group selection - for each individual cell to limit its division or to self-destruct does not clearly help to carry out the task of reproduction. But their genes are very helpful.
When multicellular organisms arose, the war between the selection at the level of an individual and the selection of a group received a new round. Group selection encouraged new and new aging mechanisms, and individual selection tried to crack them.
And for hundreds of millions of years, those species that did not have sufficiently strong mechanisms for protection against hacking, bypassed their aging program, fixed the genes of this hacking in their population due to selection pressure at the individual level, which, of course, is stronger than group selection pressure ( since the reproductive advantage of an individual from life extension is realized much faster than the onset of the negative consequences of this advantage for the entire population). But in the end, these species, when this advantage was already fixed in the genes of a sufficiently large number of individuals, died out because of the famine caused by overpopulation, from which such a species suffered at least once during millions of years of evolution. And only those species in which group selection secured a sufficient number of duplicating mechanisms of aging, and those
By the way, multidirectional action (antagonistic pleiotropy) IGF1 is just the mechanism that allows the aging program to remain in the population. Moreover, the mechanism is very tricky, because this gene gives an evolutionary advantage to individuals in the early stages of development - rapid growth - which fixes it in the population, in exchange for the fact that these rapidly breeding individuals remain mortal.
At the same time, such multidirectionality of IGF-1 is not inevitable and is not caused by any physical law. Evolution could have done without it if it had not been given the task of preventing overpopulation. After all, the coupling of rapid growth with aging imposes obvious restrictions on the fecundity of each individual individual. And those individuals who could break this hitch would receive a clear evolutionary advantage in reproduction.
Couldn't evolution be able to untie the genes of puberty from their negative manifestations in the form of the involution of the thymus and other manifestations of aging over billions of years? After all, she was able to invent amazing things — first, make single cells from multicellular ones, then expel the fish to dry land, teach them to breathe air, and then teach them to fly some more. She was able to create huge dinosaurs and whales, as well as many other completely fantastic forms of life and ecosystems. But at the same time, the overwhelming majority of her creatures have the same linkage between the genes of puberty and aging: even the nematode, even the human. It is much more plausible that evolution "actively did not want" to break this hitch, and not "could not."
And yes, in the vast majority of species, but not in all. There are species that do not have a direct relationship.between fertility (and this is the main criterion of the effectiveness of developmental genes) and aging. Someone fertility with age only increases:
And what could such paleontological evidence look like? How to distinguish the fossilized remains of an immortal organism from a mortal? Especially since aging has arisen, most likely, even in single-celled cells, as we see in yeast. And, by the way, unicellular aging is indirect palaeontological evidence.
Well, as a hypothesis: 252 million years ago, about 90% of all species died out on earth . One of the possible causes of this catastrophe is the explosive growth of unicellular bacteria that destroyed one of the basic links in the ecological pyramid. After all, with the extinction of a whole link in the ecological pyramid, everything above this link in the pyramid is also at risk of becoming extinct. And there were several such disasters on Earth:
First of all, genes are still the driver of evolution, and, roughly speaking, do not care if we or our descendants multiply them. At the same time, the paths of evolution are inscrutable - it could go this way, it could have done so. Could we be able to fly and breathe nitrogen? Maybe they could. But it turned out so well.
By the way, evolution, perhaps, has already been able to invent such an “immortal” species - this is the favorite hydra by gerontologists, which does not age. But for this she had to learn cryptobiosis(wait hungry times), as well as reproduce and sexually, and budding. When food is plentiful, the hydra clones itself by budding. And when it is not enough, it grows itself either male or female genitals, and makes love, leaving fertilized eggs to wait for better times at the bottom of the ocean. That is how she learned to wait out the adverse conditions - parents can die of hunger, but children will wait out hunger, as their development is frozen until better times. Just like the nematode power larva.
And one more view on the threshold of immortality is us, Homo Sapiens. Just to learn not to die from overpopulation, we had to first grow our brains, and then use them to come up with culture and society, and even scientific and technical progress that will provide us with technical capabilities not to die from depletion of resources in any population. There is no doubt that we will break this stupid program of aging. It's a question of time.
And I would very much like this to happen not in 50 years, but in 20. But for some reason Reasonable Man still does not understand that in this matter the delay of death is like.
“The fittest survives,” - meant Darwin, explain to us evolutionary biologists.
Adapted to what? To maximum reproduction in current conditions. Who is this “fit”? Individual or rabbit? Of course not. An individual will not survive anyway. Survives that team of genes that created the most “fit” rabbit. One that will chase the brethren in providing their genes with maximum survival by creating as many copies as possible.
And what is “maximum survival”? What parameter will we maximize? “This is to your liking,” Game Theory tells us. Want a local maximum of your copies at a single point in time? Get it, sign it. Just do not complain that oh, how happiness is fleeting, after you become extinct from the exhaustion of resources.
Want to live happily ever after? That is, to maximize the area under the curve of your copies in time? Then be kind to learn how to control the resource consumption of your replicators, or at least give them skills to wait out long periods of adverse conditions. And the best is both.
But the most chic is to grow their intellect, so that they start controlling their population for you, plan the consumption of their resources, and even come up with more and more efficient ways to extract these resources. Such replicators can produce as many as 7.5 billion of your gene cooperatives of 30–40 trillion copies each. For bacteria, of course, these are ridiculous numbers , but for eukaryotes, this is quite an indicator.
True, the intelligence to grow for a long time, and there is a chance not to grow, the Neanderthals tell us. That's right: if you, as a young, daring start-up cooperative, use the “trillion monkey on typewriters” method to code your thinking skills in your replicators, then until your code is ready for a production release, you have tothe population of these very beta replicators itself is also controlled. And then another sabrutin called be fruitful and multiply () and seemingly tries to keep all your efforts in / dev / null. Therefore, the cooperative "Genes and Sons" and had to first hone the ability not to let their creatures die out or multiply strongly. For what he first nakodil mechanisms for controlling the inflow and outflow of the population . Having learned to control the influx of individuals through the shutdown of reproduction, and the outflow through phenoptosis is either sharp like that of a salmon, or smooth like that of a mouse.
Is Pacific Salmon Death Programmed ? I think almost anyone who is in the subject, admits that yes. But about whether it is programmed with us, there is a heated debate.
This is a scary word - “program”
What distinguishes a program from a non-program? It's all very simple. A program is when changes occur on purpose. Nonprogram - when stochastically, randomly.
After all, no one argues that embryogenesis is random. Or that puberty is a stochastic process. No, everything is clearly programmed: stages, dates. And that is why we do not observe single sexually mature babies or 80-year-old women in labor, as they should have been if these were random processes. And if the nature of aging is random, then why do some species of animals live for several days, and others for hundreds of years? Indeed, similar statistical processes are characterized by similar statistical distributions of their results. But for some reason, the parameters of these distributions are very different. even for such close relatives as a mouse (2–3 years of life), a squirrel (10–12 years old) and a naked mole rat (30 years old):
Moreover, in social animals, the lifespan can differ by an order of magnitude even for twins with identical DNA. The uterus lives 20–40 times longer than the working individual.
Along with this, we know that very different species have common molecular mechanisms of aging. What worms, mammals - for example, the notorious cascade of insulin-like growth factor (IGF-1), which first helps the body to mature, and then die. At the same time, the rates of aging are very different: the nematode lives 2–3 weeks, and the mouse is 2–3 years old. And this, too, does not fit well with the hypothesis of the random nature of age-related changes.
At the same time, all gerontologists agree that in our body the ability to repair damage and debris is reduced with age. And that it is this decline that leads to the accumulation of both, and ultimately to death - that is, everyone agrees that this process of degradation is the main cause of our aging.
The only stumbling block - is it an accidental decrease in age or is it purposeful? It seems to me that all the data indicate that the role of chance in this process is minimal. We see how the body purposefully destroys our thymus from the age of 15, from 25 to our brain, from 45 to our muscles, and from 60 to our bones. And the same processes, only accelerated by 20–30 times, we observe even in mice. And to believe that they are all random is very difficult.
Where are the aging genes? Who manages this process?
I already wrote about the main mechanism of control and synchronization of important processes in the body - epigenetics. With age, it all changes in the same way - the “epigenetic clock” perfectly predicts our biological age, and the fact that the Yamanaki factors prolonged the life of these epigenetic hours by prolonging the life of mice confirms this hypothesis for me.
Who sets the clock for these watches and drives them forward? Most likely, our brain. Or rather, the hypothalamus with the pituitary gland, based on the circadian rhythms of the pineal gland. Here is an interesting study., showing how stress through corticosteroid hormones causes epigenetic changes in 5-year-old children, similar to those that we see with normal aging. Who produces cortisol? The axis of the hypothalamus-pituitary-adrenal glands. And the above study well confirms the role of epigenetics in the implementation of the aging program - stress accelerates it, factors of Yamanaki roll back.
And we see how similar these processes are in all organisms. The primitive neuroendocrine system is still in nematodes - in fact, the beginnings of the hypothalamus-pituitary-gonad axis. And it is this axis that controls their growth and development.. If there is a shortage of food, it also includes a mode of non-aging — a power stage in which a nematode can stay for months, and then again includes a growth process, and the worm matures, multiplies, and dies in its standard few weeks.
By the way, remember the above-mentioned cascade of insulin-like growth factor (IGF-1)? This is also one of the genes for aging. In nematodes, it is called daf-2 . His knockout (deletion) extended the life of nematodes 10 times, and the mice - by 2. And this cascade is very evolutionary old, just superstar (sorry) - it is in yeast, and in nematodes, and in us .
In this case, of course, we still do not fully understand all the mechanisms of these processes. If (or rather, when) we understand, then all debates about the nature of aging will be resolved. The question “where is the program” will have an unequivocal answer: here it is, the genes are such and such, the mechanisms of their control are such, the input parameters are the algorithm.
How to test the hypothesis of aging programming?
I have a very simple and applied approach here: if the hypothesis of the aging program allows us to stop this aging or at least prolong our life 10 times, this will be more than enough for me. So far, no other hypotheses have found a better life extension than fasting, and it is ineffective for primates .
Another hypothesis: if aging is a program, it must have some key mechanisms that vary the main parameter of the program - life expectancy. By influencing these mechanisms, we must see the effect on the outcome of the program. The results of life extension are shown to us at times with the help of knockout of developmental / aging genes on nematodes and mice.
How has evolution honed aging mechanisms?
I do not know, I did not hold a candle. I will express only the cautious assumption that billions of years ago, aging, most likely, was not. As it is not observed, for example, in viruses. But at some point it arose from single-celled and gave them an advantage in survival by preventing their extinction due to overpopulation (or some other way). We know two such mechanisms of aging in unicellular organisms - apoptosis and telomeres. Moreover, these mechanisms perfectly show the action of group selection - for each individual cell to limit its division or to self-destruct does not clearly help to carry out the task of reproduction. But their genes are very helpful.
When multicellular organisms arose, the war between the selection at the level of an individual and the selection of a group received a new round. Group selection encouraged new and new aging mechanisms, and individual selection tried to crack them.
And for hundreds of millions of years, those species that did not have sufficiently strong mechanisms for protection against hacking, bypassed their aging program, fixed the genes of this hacking in their population due to selection pressure at the individual level, which, of course, is stronger than group selection pressure ( since the reproductive advantage of an individual from life extension is realized much faster than the onset of the negative consequences of this advantage for the entire population). But in the end, these species, when this advantage was already fixed in the genes of a sufficiently large number of individuals, died out because of the famine caused by overpopulation, from which such a species suffered at least once during millions of years of evolution. And only those species in which group selection secured a sufficient number of duplicating mechanisms of aging, and those
By the way, multidirectional action (antagonistic pleiotropy) IGF1 is just the mechanism that allows the aging program to remain in the population. Moreover, the mechanism is very tricky, because this gene gives an evolutionary advantage to individuals in the early stages of development - rapid growth - which fixes it in the population, in exchange for the fact that these rapidly breeding individuals remain mortal.
At the same time, such multidirectionality of IGF-1 is not inevitable and is not caused by any physical law. Evolution could have done without it if it had not been given the task of preventing overpopulation. After all, the coupling of rapid growth with aging imposes obvious restrictions on the fecundity of each individual individual. And those individuals who could break this hitch would receive a clear evolutionary advantage in reproduction.
Couldn't evolution be able to untie the genes of puberty from their negative manifestations in the form of the involution of the thymus and other manifestations of aging over billions of years? After all, she was able to invent amazing things — first, make single cells from multicellular ones, then expel the fish to dry land, teach them to breathe air, and then teach them to fly some more. She was able to create huge dinosaurs and whales, as well as many other completely fantastic forms of life and ecosystems. But at the same time, the overwhelming majority of her creatures have the same linkage between the genes of puberty and aging: even the nematode, even the human. It is much more plausible that evolution "actively did not want" to break this hitch, and not "could not."
And yes, in the vast majority of species, but not in all. There are species that do not have a direct relationship.between fertility (and this is the main criterion of the effectiveness of developmental genes) and aging. Someone fertility with age only increases:
Where is the paleontological evidence of extinct immortal species?
And what could such paleontological evidence look like? How to distinguish the fossilized remains of an immortal organism from a mortal? Especially since aging has arisen, most likely, even in single-celled cells, as we see in yeast. And, by the way, unicellular aging is indirect palaeontological evidence.
Well, as a hypothesis: 252 million years ago, about 90% of all species died out on earth . One of the possible causes of this catastrophe is the explosive growth of unicellular bacteria that destroyed one of the basic links in the ecological pyramid. After all, with the extinction of a whole link in the ecological pyramid, everything above this link in the pyramid is also at risk of becoming extinct. And there were several such disasters on Earth:
Could evolution simply not invent an immortal species that does not cause overpopulation?
First of all, genes are still the driver of evolution, and, roughly speaking, do not care if we or our descendants multiply them. At the same time, the paths of evolution are inscrutable - it could go this way, it could have done so. Could we be able to fly and breathe nitrogen? Maybe they could. But it turned out so well.
By the way, evolution, perhaps, has already been able to invent such an “immortal” species - this is the favorite hydra by gerontologists, which does not age. But for this she had to learn cryptobiosis(wait hungry times), as well as reproduce and sexually, and budding. When food is plentiful, the hydra clones itself by budding. And when it is not enough, it grows itself either male or female genitals, and makes love, leaving fertilized eggs to wait for better times at the bottom of the ocean. That is how she learned to wait out the adverse conditions - parents can die of hunger, but children will wait out hunger, as their development is frozen until better times. Just like the nematode power larva.
And one more view on the threshold of immortality is us, Homo Sapiens. Just to learn not to die from overpopulation, we had to first grow our brains, and then use them to come up with culture and society, and even scientific and technical progress that will provide us with technical capabilities not to die from depletion of resources in any population. There is no doubt that we will break this stupid program of aging. It's a question of time.
And I would very much like this to happen not in 50 years, but in 20. But for some reason Reasonable Man still does not understand that in this matter the delay of death is like.