A matter of life and death
TWELVE MYSTERIES OF AGING"In the world of science" No. 7-2009
Today, science still cannot clearly answer the questions of what aging is, what causes it, what are its mechanisms and how to prevent it. But the experiments of recent years allow us to learn more about this phenomenon. The Science for Life Extension Foundation appealed to well-known scientists working in various fields of biology with a request to answer fundamental questions concerning aging. For the first time, scientists are trying to develop a unified point of view on this process.
Panelists:
David Gems, Specialist in the Biology of Aging, Institute of Healthy Aging, University College London, United Kingdom
Aubrey de Grey, Scientific Director of the Methuselah Foundation and the SENS Program, United Kingdom
Denis Noble, Professor of Systems Biology, Head of the Physiom Program, Oxford, UK
Evgeny Ilyich Mayevsky, Deputy Director of the Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences
Alexey Aleksandrovich Moskalev, Head of the Molecular Radiobiology Group at the Institute of Biology of the Komi Scientific Center of the Russian Academy of Sciences
Fyodor Fedorovich Severin, Head of the Laboratory for the Study of Programmed Death of Microorganisms at the Institute of Physico-Chemical Biology named after Belozersky MSU
Maxim Vladimirovich Skulachev, Director of the Mitoengineering Center of Moscow State University
– Why does the body undergo a progressive and irreversible reduction of physiological functions in the last part of its life?Aubrey de Grey:
– Many of our normal metabolic processes, thanks to which we live for so long, have accumulating side effects, such as, for example, the loss of cells or the formation of indigestible molecules. But in order for enough "damage" to accumulate in the body, and for them to cause any harm, it takes time. Eventually, the damage becomes so much that the physiological functions deteriorate."
Alexey Moskalev:
– Firstly, the processes of damage to structures and their restoration are opposed to each other already at the zygote stage, and even earlier - in the gametes of parents. But any protection has an efficiency other than 100%, so damage accumulates. Secondly, already at the early embryonic stages, somatic cells choose two ways – to become immortal stem cells (to have active telomerase, segregate damage, effectively maintain DNA integrity, be resistant to apoptosis), or to differentiate and perform specialized functions, but at the same time become mortal. As long as the former effectively create a replacement for the latter, the body remains relatively healthy. However, the more proliferative stresses (the need to divide quickly) stem cells experience during their lifetime, the faster, despite their enhanced protection, they accumulate errors and are depleted. Hypothetically, such a process may take place: under severe stress, "immortal" stem cells predominantly form differentiating cells, "forgetting" to replenish their own population. On the other hand, "regional" stem cells exist in a special microenvironment – a "niche", which, with the help of growth factors, signals to the stem cell at what rate and which differentiated cells to give. The niche is represented by differentiated cells that are susceptible to cellular aging. As we already know, aging cells secrete inflammatory cytokines. Thus, stem cells with age begin to experience the influence of "aging" niches, i.e. they stop replenishing, incorrectly differentiate, or begin to divide uncontrollably, which leads either to suppression of tissue regeneration, or to hyperproliferation and oncogenesis. Thirdly, cellular aging and impaired regeneration affect the functionality of neuroendocrine centers (hypothalamus, etc.), which provide adequate levels of hormones regulating metabolism, the functioning of stem niches and the activity of stem cells themselves. As a result, our aging is caused by an imbalance at four levels – metabolism, stress resistance, regeneration and neuroendocrine regulation.
Evgeny Mayevsky:
– The change of functions – the reduction of some and the appearance of others – is a constant process. For example, at the birth of a person, the synthesis of fetal hemoglobin comes to naught, and an adult hemoglobin synthesis program is launched instead. This is due to the fact that the conditions of oxygenation change during the transition from intrauterine life to life outside placental protection. Constellations – sets and activity of enzymes of the digestive tract – change when the nature of nutrition changes: some enzymes cease to be synthesized, others appear. And there are many such examples. This is not so much aging as ontogenetic and adaptive development, adaptation to changing conditions of the external and internal environment. Although the depreciation of the resource (it is far from clear in each case what it is) always occurs. Wear is especially great if the recovery processes are significantly inferior to the intensity of the loads on a particular device. There is no definitive answer. Although the role of metabolic and genetic factors, and a set of stem cells as generators of recovery, and much more is essential here.
Maxim Skulachev:
– It's not like that. Many higher organisms in the last part of their lives only increase the power of their functions, and then die abruptly for one reason or another. Our experiments have shown this.
David Gems:
– This question can be answered in two ways. Firstly, from an evolutionary point of view: aging is the result of a decrease in the power of natural selection, when at the end of life the functions of many genes weaken. This happens because the probability of producing offspring in old age decreases, especially because of the increased risk of death. Consequently, at the end of life, harmful effects accumulate that cause aging. From this point of view, aging is a form of late genetic disease, to which all mankind is subject. But another aspect – the biological mechanisms underlying aging – remains unclear, although there are many versions. The most likely one is that aging is the result of the accumulation of damage, especially at the molecular level – proteins, fats and DNA.
Fedor Severin:
– This is part of the individual development program, which is aimed at increasing the dynamism of the population.
– Why do life expectancy or the rate of aging differ within one species and between species?Aubrey de Grey:
– Because different species – and, to a lesser extent, different individuals of the same species – have different characteristics of built-in "anti-aging mechanisms". Species that live longer automatically repair higher proportions of damage produced by their metabolism.
Alexey Moskalev:
– Interspecific differences can be explained by the rate of metabolism and the effectiveness of the body's stress response and regeneration systems. The causes of intraspecific variability are polymorphism of genes responsible for metabolism, stress resistance, regeneration and neuroendocrine regulation, as well as features of the individual's ecological environment and stochastic factors.
Denis Noble:
– All biological processes are stochastic, so we assume variations even within one species. Perhaps different species have different rates of reaching reproductive age. There may be a balance here – on the one hand, rapid reproduction and short life expectancy can contribute to adaptation to new conditions, on the other hand, complex organisms need more time to develop. The interaction of these factors from an evolutionary point of view determines the different life expectancy.
Maxim Skulachev:
– Almost any signs of organisms vary within one species or between species.
Evgeny Mayevsky:
– There are a lot of explanations for this fact. To quote Asimov: "A person is what is inherent in him, and circumstances." Firstly, very significant factors are the availability and quality of food. Secondly, and perhaps more importantly, the genotype. And, finally, living conditions, upbringing, the likelihood of encountering infection, injury, etc. To an even greater extent, the body and its components wear out from their "disuse". Everyone knows cases of muscle atrophy, loss of visual acuity when closing one eye for a long time. The lack of load on the fabric is even more disastrous than the work of wear and tear. A rational ratio (I would like to know what it is!) intensity, duration, variety of loads, as well as restoration of functions is a key problem of rehabilitation of healthy people and, possibly, increasing the duration of their active life.
David Gems:
– Aging is very strongly influenced by both the genotype and the impact of the environment. Deviations and variations of both factors lead to the fact that the aging processes proceed differently. Environmental factors play an important role in variability within species, including in humans, but at the same time, many differences in the course of the aging process in humans occur due to genetic variations. From an evolutionary point of view, differences between different species in the rate of aging processes largely reflect different levels of mortality from external causes. For example, bats live much longer than land mammals of the same size – most likely because their ability to fly reduces the risk of death from external causes, and primarily due to their ability to hide from predators. This leads to high reproduction in later years of life, and as a result, natural selection in later life works against genes with harmful effects, which may lead to delayed aging.
Fedor Severin:
– Optimal life expectancy (from the point of view of the population) depends on the duration and nuances of the course of classical ontogenesis, as well as on the degree of rigidity of the pressure of natural selection on the population and intraspecific selection. These parameters may differ both between species and between populations of organisms of the same species.
– Why do experimental influences, such as calorie restriction, slow down the onset of many age-related changes and increase the average and maximum life expectancy of animals?Aubrey de Grey:
– Because evolution has discovered such a pattern: it is more useful to change the ratio of resources between reproduction and simple maintenance of the vital activity of the body, depending on the availability of nutrients. Give priority to reproduction when there is a lot of food, and maintaining the body (and delaying aging) when there is a shortage. On average, organisms that tend to respond to a lack of nutrients in this way have offspring with a more pronounced ability to survive.
Alexey Moskalev:
– Reducing the amount of food received to a certain threshold (up to 30% of the desired), especially for the protein component, is a moderate stress that stimulates stress resistance systems and increases the efficiency of metabolism. The system moves to a higher level of protection against spontaneous exogenous and endogenous stresses, which slows down the aging process.
Maxim Skulachev:
– I'm afraid that the plural is not very appropriate here. And what besides a low-calorie diet "slows down the onset of many age-related physiological and pathological changes and increases the average and maximum life expectancy of animals"? Unfortunately, I do not know the mechanism of action of caloric restriction. As far as I understand, no one knows this.
Evgeny Mayevsky:
– The answer has long been known: everything is good in moderation. We come to the problem again: the most difficult thing is to determine the relationship between energy costs, synthesis costs and rational nutrition, as well as recovery through nutrition. This is the crux of the problem. Hence the global formulation of the question emerges: what is a rational diet for different contingents of people, with different genotypes and phenotypes, different ages, different professions, with different lifestyles, place of residence, etc.?
David Gems:
– This is not yet completely clear, and it seems that multiple mechanisms play a role here, which vary greatly in different species and depend on different types of low-calorie diets. For example, it is not always the decisive factor affecting life expectancy that is the direct restriction of calories. Such a mechanism is possible when the body responds to a limited diet by switching to another biological state – reproductive "hibernation". In this state, opposite mechanisms are activated that protect against the manifestations of aging, for example, recovery processes are activated, mechanisms for suppressing tumor development, etc. Another possible factor is a decrease in the consumption of toxic components during a diet. However, this may affect the life expectancy itself, and not the aging processes (many factors shorten life expectancy without affecting aging – smoking, accidents, etc.).
– Do these factors affect aging and diseases associated with aging independently of each other?Aubrey de Grey:
— no. All aspects of aging interact closely with each other. However, this does not necessarily mean that they should be launched by a single "magic bullet".
Alexey Moskalev:
– Aging predisposes to pathologies and makes them inevitable, so it is difficult to separate one from the other.
Maxim Skulachev:
– Unknown.
David Gems:
– No, it seems that the aging process causes age-dependent diseases (cardiovascular, neurodegenerative, cancer, type II diabetes, etc.). As has been shown in experiments on rodents, interventions that slow down aging simultaneously protect against all age-related pathologies. This shows that, at least in animals, by influencing the aging process itself, it is possible to provide protection against a wide range of age-dependent diseases.
Evgeny Mayevsky:
– A rough answer: there are no independent functions in the human body. These are the inventions of young healthy people. Read Sechenov – the body as an integral system.
Fedor Severin:
– Diseases associated with aging are a manifestation of aging.
– Do age-related changes in the body increase the susceptibility to diseases, or do diseases develop independently, and only then aggravate the manifestations of aging?Aubrey de Grey:
– Age-dependent changes in the body increase the susceptibility to external diseases, such as infections. They also directly cause internal diseases, such as cardiovascular diseases or type II diabetes: it is believed that these diseases are components of the later stages of aging. There are also situations when external diseases, especially certain "permanent" infections, such as cytomegalovirus, damage the body and accelerate some aspects of aging.
Denis Noble:
– I suspect that both phenomena are involved in the aging process and are interrelated.
Evgeny Mayevsky:
– We read the previous answers: any loads that are inadequate for the body's regenerative forces, whether it is a disease or something else, accelerate aging. And vice versa: against the background of wear, the previously insignificant load becomes inadequately prohibitive. Again, the problem is: where is the measure and what is the measure?
David Gems:
– In many ways, these are parts of one whole. For example, damage at the molecular level increases with age, including DNA damage. As a result, an increase in the number of mutations affects oncology with age.
Fedor Severin:
– Rather, age-related changes in the body increase the susceptibility to diseases. One of the earliest manifestations of aging is a decrease in the flexibility of the immune system.
– What possible points of scientific breakthrough in research aimed at increasing life expectancy do you see?Aubrey de Grey:
– We are quite close to discoveries that together will have a small effect in slowing down aging. Most of these breakthroughs lie in various aspects of regenerative medicine – the restoration of the molecular and cellular structure of tissues to a state approaching that in which they were before the onset of damage. In our case, it's a matter of aging damage. And due to the fact that this damage is very complex, we will need many types of regenerative medicine to complete the whole task – but we are getting closer to it.
Alexey Moskalev:
– Learn how to stimulate stress resistance and restore the functions of aging stem niches.
Maxim Skulachev:
– If I knew, I would be a billionaire. Scientists in general very rarely "see the points of scientific breakthrough." As a rule, they consider what they are currently doing to be a breakthrough point. Therefore, I have to answer that these are mitochondrial antioxidants and other mitochondrial drugs.
Evgeny Mayevsky:
– There are two answers – social and biological. How should the life of the population be organized? It is diverse, emotionally intense, with a reasonable alternation of physical and mental loads, fostering interest in creative activity, minimizing irrational, irritating stresses, increasing the threshold for the perception of minor stresses – education. In-depth research is required to determine the adequacy of loads and their type for each individual in accordance with the available recovery potential and the prospect of its development or decline at a given time.
David Gems:
– There are many key tasks in biogerontology that need to be solved. One of them is to use drugs that would act point–by-point or in chains, affecting aging in a specific way. To show that they work successfully on animal models, and then prove their effectiveness for humans. Professor V.N. Anisimov from Russia is a pioneer in this kind of research. Another task is to understand, using animal models, how these chains control the aging process. And this brings us to the fundamental question: what is aging from a biological point of view? This is generally one of the main issues of modern science, which, I believe, will be resolved in ten years or so.
Fedor Severin:
– I think the basis of aging is the programmed death of individual cells. It is possible to fight this phenomenon both at the cellular level and at the level of the organism. At the cellular level, antioxidants and other anti-apoptotic effects are the most promising. At the level of the body – interference in hormonal regulation.
– At what evolutionary stage did aging occur, or did it accompany the phenomenon of life from the moment of its appearance?Aubrey de Grey:
– A kind of aging is observed in unicellular organisms, but it is so different from aging in large organisms that I would not call it aging at all. Multicellular organisms that do not have permanently non–dividing cells – plants, for example, or animals such as hydra - show extremely few signs of aging. Therefore, I would say that aging, as we know it and experience it for ourselves, arose at a time when animals evolved to organisms with long-lived, non-dividing cells. The most important of them are, of course, brain cells.
Alexey Moskalev:
– Molecular aging took place already at the stage of "pre-life" and in unicellular living beings. In eukaryotes, clonal (replicative) cellular aging is added, and in multicellular cells, stem niche aging and post–replicative aging, i.e., regeneration failure.
Denis Noble:
– A very interesting question. Many unicellular organisms are actually immortal, or their lineage is immortal. And, in the end, this is also true for germ cells in organisms with separate gametes. Aging, as we know it, is basically a characteristic of multicellular organisms. This is where the issue of stochasticity may turn out to be very important. If the levels of gene expression vary greatly between cells (as recent studies show), then there must be selection processes taking place in each tissue. This makes it necessary to have apoptosis, which kills "bad" cells.
Maxim Skulachev:
– It seems that there has always been aging (at least since unicellular eukaryotes). But why it disappeared at some evolutionary stages is a question!
Evgeny Mayevsky:
– In my opinion, there has always been aging. Without aging and death, without generational change, evolution is impossible.
David Gems:
– Aging can be traced wherever there are evolutionary conditions for this: it is noted even in bacteria and unicellular fungi. However, some species at first glance are not susceptible to aging, including animals (for example, Hydra vulgaris). Thus, aging is not a mandatory feature of living systems.
– Are the aging processes of the body a consequence of aging at the cellular level?Aubrey de Grey:
– Yes, cell aging is caused by some part of the aging process, but not the whole process. For example, the accumulation of harmful amyloid protein occurs between cells, not inside them. There are also various types of cellular aging: the type that was discovered by Leonard Hayflick and explained by A.M. Olovnikov and James Watson is just one type, and most likely not the most important.
Alexey Moskalev:
– Yes and no. Each level of aging depends on all the others and is at the same time relatively independent. Aging has a fractal self-similar nature at all its levels (molecular, cellular, tissue, systemic, organismal).
Maxim Skulachev:
– And what is aging at the cellular level? Apparently, the term cell senescence is meant, which describes a very strange state of the cell, which has nothing to do with the aging of the organism (even unicellular).
Evgeny Mayevsky:
– Of course, but that's not the only thing. At the level of a multicellular organism, the aging of individual cells is strongly damped by reserve and regulatory systems.
David Gems:
– To a large extent. Aging is also observed in extracellular structures, but its degree should be controlled genetically, since the overall level of aging varies very seriously in different species. Therefore, it seems to be strongly influenced by the processes occurring inside the cell.
– To what extent are the aging processes genetically determined?
Aubrey de Grey:
– In one sense, aging does not depend on genetics at all. It is caused by the fact that genes that repair damage that the body does not repair itself are absent in humans. Therefore, the damage accumulates and eventually causes pathologies. In another sense, aging is completely genetically determined, since some species live much longer than others. And this is due to the fact that they have a more advanced anti-aging apparatus, which is encoded by genes. In the third sense, about 25% of aging is genetically determined: this is the percentage of variations in the life expectancy of individuals dying from age-dependent causes, which, again, can be explained with the help of genetics.
Alexey Moskalev:
– It is difficult to adequately estimate in numbers, because aging depends on the allelic state of hundreds of genes. The greatest influence is exerted by genes-"regulators" and "mediators" (synthesis of hormones and their receptors, kinases, deacetylases, methylases, transcription factors, p53, p21, p16, pRB). The individual contribution of "effector" genes (free radical interceptors, heat shock proteins, DNA repair enzymes, autophagy, xenobiotic detoxification) is less significant, but cumulatively they make a tangible contribution.
Maxim Skulachev:
– In a huge one.
Evgeny Mayevsky:
– Genetics determines a lot, but not everything. I do not exclude from consideration extreme deletions, mutations, etc., genetically programmed defects or rapid breakdowns of various processes.
Fedor Severin:
– Absolutely: I consider aging a part of ontogenesis.
– What is the reason for the existence of "ageless" species in nature?Aubrey de Grey:
– Some species with negligible aging, those that do not have long-lived cells, probably do not age at all. Others are probably still aging, but so slowly that we can't fix it yet. (If a species ages so slowly that individuals live longer than humans, it's hard to say that they age at all, especially if only a small number of them can be studied in the wild). I don't think there are species with negligible aging that don't age at all, even though they have very long-lived cells. But it is necessary to study species that age very slowly to understand why this happens.
Alexey Moskalev:
– Perhaps they are endowed with higher reliability of stress resistance systems (at the level of genes- "regulators", "mediators" and "effectors"), which provides "ageless" stem niches and effective tissue regeneration.
Maxim Skulachev:
– I can only offer an evolutionary explanation – why. How (through the cancellation of which mechanisms or through the acquisition of which tools) these species have achieved the neglect of their aging – a big mystery. By the way, it would be worth doing it properly, but, apparently, it is not yet possible to find approaches. Although we have some specific ideas and suggestions about this (for example, to study such a unique animal as a naked digger).
Evgeny Mayevsky:
– Too general a question. Everything is concrete. Someone has too low intensity of life activity relative to the possibilities. Others have genetically (!) programmed late death, i.e. long life of cells and tissues. Others have a large reserve – regenerative potential, powerful protective systems together with systems of repair, regeneration, renewal of tissues and cells.
David Gems:
– This question was perfectly answered by J. Williams in his classic 1958 work Negligible aging can occur when conditions for the evolution of aging do not exist. For example, when organisms increase fertility over time (i.e. they continue to grow in old age – like trees or some species of fish). Or in organisms with very low mortality from external causes (some turtles), as well as in organisms that do not have a clear separation between non-somatic (germinative) and somatic cells (the same hydra).
Fedor Severin:
– The loss of the aging program is beneficial for the species in the absence of intra- and interspecific selection pressure.
– Are reproduction and life expectancy interrelated or independent of each other?Aubrey de Grey:
– They are closely interrelated in evolution, but not so closely in a separate organism. The fact that you have offspring does not fundamentally affect life expectancy. However, it is very likely that the "ability" to have offspring, your fertility is related to various aspects of your ability to age slowly.
Alexey Moskalev:
– Both somatic and germinative tissues undergo unidirectional aging. At the same time, they are in a state of competition for the energy and plastic resources of the body. As a result, the strengthening of reproductive function entails the suppression of stress resistance, which reduces life expectancy.
Maxim Skulachev:
– When and how. Sometimes they are very closely related (for example, in species that reproduce only once in a lifetime and then die), sometimes in no way (for example, in turtles).
Evgeny Mayevsky:
– As a rule, different species have different ways, but they are always connected. There are a lot of examples of this, it doesn't even make sense to list them.
David Gems:
– The degree of productivity definitely affects the life expectancy of many species (but it is not clear whether this is caused by aging), and at the same time, in some species, aging does not depend on reproduction (as, for example, in C.elegans worms)"
Fedor Severin:
– Directly related: sex hormones are one of the main regulators of programmed cell death.
– And finally, what other issues do you consider fundamental for understanding the mechanisms of aging?Aubrey de Grey:
– I think it is necessary to separate: a) the questions that need to be answered in order to understand aging; and b) the questions that need to be answered in order to defeat it. We can defeat aging without a thorough understanding of all processes. I think that for this we need to understand a little better only in some things. One of them is the ALT mechanism, which some cancer cells use to maintain their telomeres without telomerase. We don't even know which genes are responsible for this, and it's likely that some of the unknown genes may be good targets to attack against them. Another is the rate at which "epigenetic noise" (random changes in the DNA structure that determine the level of gene expression) accumulates in the brain. I believe that this type of damage accumulates so slowly that we don't have to worry about it, but they are difficult to repair, so we really need to know this speed. Currently, the Methuselah Foundation sponsors work in both directions. In addition, it is necessary to develop methods and technologies that use the currently existing understanding of the mechanisms of aging to intervene in this process. All the other projects that the Methuselah Foundation oversees, and some more that we plan to finance, are of the same type. For example, the transfer of mitochondrial DNA into the nucleus so that it can work at the same time, the search for enzymes that decompose metabolic byproducts that the body cannot digest normally, the destruction of immune cells that do not die when they should, thymus regeneration, etc.
Denis Noble:
– I suspect that some answers will appear from the analysis of the complexity of the organism. The more complex an organism is, the more likely it is that over time it will stop working correctly. Large genomes need mechanisms for detecting breakdowns and repairing them. Stochasticity studies also play an important role here.
Evgeny Mayevsky:
– The question is how to make it so that: 1) everyone's life has become creative, filled with interest and harmonious under stress, not beyond the individual's strength; 2) determine the optimal conditions of existence at least at the level of the ratio of load and recovery potential, develop proper rational nutrition, etc. These cannot be only genetic, metabolic or oxidant markers. Absolutely insufficient attention is paid to the role of the higher mental component. There are more questions here today than there are ways to answers.
David Gems:
– A person's life, in principle, seriously depends on social factors, possibly due to the long-term impact on the state of health of the psychological status. This is very important to understand, and it is perfectly summarized by Michael Marmot in his book "Status Syndrome".
Fedor Severin:
– Hierarchy of tissues and organs in the aging of the body. Perhaps the aging of the body is initiated by the aging of its "command center".
Maxim Skulachev:
– For me, the question of principle is whether the "regulation" of aging is possible. And not rough (occurring, obviously, with progeria or in other catastrophic cases), namely fine-tuning (fine tuning). At the same time, it should be understood that aging is a complex process and, it seems, in different situations, its different components play a fundamental role. Some of these components may well be adjustable. I'm not sure it's possible to figure this out in principle. But the question, in my opinion, is extremely interesting. The answer to it will at the same time resolve the long-standing and, in my opinion, stupid dispute about the "programmed" or "spontaneity" of aging. Perhaps we can formulate a few more fundamental questions. But the above mentioned biologists should be enough for the next 10-50 years.
Portal "Eternal youth" http://vechnayamolodost.ru14.07.2009