Genetics of aging and how to deal with it

Roundworms Caenorhabditis elegans age and die within a few weeks, whereas people in some cases even survive the centenary. This suggests that the mutations accumulated in the process of evolution, which resulted in the appearance of man, increased life expectancy by at least 2000 times. For many centuries, people have been trying to unravel the secret of longevity, but only recently scientists have begun to gradually approach the solution.

For many years, molecular biologists specializing in the mechanisms of regulation of physiological and biochemical processes have ignored the issues of aging, since, according to traditional ideas, the deterioration of tissues associated with aging is the result of a passive process of wear. However, now we already know that the aging process, like many other biological processes, is controlled by classical signaling mechanisms and transcription factors. As a rule, these mechanisms are identified when studying small organisms with a short lifespan, such as yeast, worms and fruit flies, but most of them have similar effects on mammals. The study of these mechanisms and the influence of physiological and external factors on their work opens up prospects for the creation of drugs that slow down the aging process of a person.

There is an opinion that attempts to slow down the aging process mean imminent death from age-related diseases, such as cancer or Alzheimer's disease. However, as the results of scientific research show, aging-slowing mutations, as a rule, postpone the onset of the development of such diseases.

Mechanisms regulating aging

Many life-prolonging mutations affect genes encoding nutrient receptors and proteins involved in the formation of stress reactions. In conditions of abundance of food and lack of stress, these genes contribute to the growth of the body and its reproduction. In unfavorable conditions for life, the activity of these genes changes: some of them begin to work actively, while the rest are blocked. As a result, there is a global physiological shift aimed at protecting cells and maintaining their vital functions. This shift not only allows the body to survive an unfavorable period, but also increases life expectancy.

The most well-known of the factors that increase life expectancy is a low-calorie diet, which is shown on a wide range of organisms, ranging from yeast to monkeys. This phenomenon was first discovered in experiments on rats conducted during the Great Depression amid fears that chronic malnutrition is fraught with a decrease in human life expectancy. Initially, experts explained the "magic" effect of starvation by reducing the rate of accumulation of cellular damage, which is a byproduct of normal metabolism. However, a well-planned experiment on fruit flies (Mair et al., Demography of dietary restriction and death in Drosophila. Science 301, 1731–1733 (2003)) He showed that a low-calorie diet leads to a sharp decrease in the mortality rate (the number of deaths per day). This indicates that the effects of starvation are the result of an acute process. Now we know that a number of mechanisms of nutrient recognition are involved in the development of the effects of a low-calorie diet, including those mediated by proteins such as the enzymes AMP kinase and, also belonging to the class of kinases, the target of rapamycin (target of rapamycin, TOR), as well as sirtuins and hormones insulin and insulin-like growth factor-1 (IGF-1). An unexpected finding was the fact that the main role of a particular mechanism in prolonging the life of the body depends on the nature of fasting. For example, experiments on C.elegans have shown that three variants of calorie restriction schemes (fasting throughout life, feeding every other day and switching to a low-calorie diet in middle age) they launch various mechanisms with the same end result – an increase in life expectancy.

Many other factors can also increase life expectancy, including chemo- and thermosensory signals (both an increase and a decrease in ambient temperature), heating, oxidative stress, signals from the reproductive system, as well as a decrease in the rate of cellular respiration or translation. In most, and perhaps in all of these cases, the process of increasing life expectancy is actively controlled by special regulatory proteins.

Aging causes global extinction of the functions of all body tissues, therefore, at first glance, slowing it down looks like an impossible task. However, experiments on laboratory animals have shown that for this it is not necessary to fight individually with each of the manifestations of aging, such as atrophy of muscle tissue, wrinkles and accumulation of defective mitochondria – it is enough only to change the work of a single gene, and the body will do the rest itself. In other words, living beings are potentially capable of living longer than is considered normal.

Insulin and insulin-like growth factor-1

The first of the "regulators" of the aging rate discovered by scientists is a signaling mechanism mediated by insulin and insulin-like growth factor-1. A mutation that reduces the activity of the daf-2 gene in the genome of C.elegans, encoding a hormone receptor similar to insulin and IGF-1 receptors in mammals, more than twice prolongs the life of worms. Mutations affecting the activity of kinase enzymes involved in this signaling mechanism: phosphatidylinositol-3-kinase (PI(3)K), AKT kinase and pyruvate dehydrogenase (PDK) also increase the lifespan of these organisms. The most impressive feature of these (and many other) long-lived mutants is their ability to retain all the signs of a young organism for a long time. Suppression of the signaling mechanism mediated by insulin and IGF-1 affects life expectancy by changing the expression of genes encoding a number of transcription factors (including DAF-16, FOXO, HSF-1 and SKN-1). These factors, in turn, stimulate or inhibit the expression of other genes, including those involved in the development of stress reactions, providing autophagy mechanisms (processing defective cell fragments for the synthesis of new organelles), as well as encoding antimicrobial peptides, chaperone proteins, apolipoproteins, lipases and ion channels. The cumulative effect of the changes occurring in this case is an increase in life expectancy. An interesting fact is that a number of genes normally expressed in germ cells are abnormally expressed in somatic cells of daf-2 mutants. Apparently, these genes (at least partially) cause an increase in the lifespan of the organism, and a detailed study of their work can give scientists more than one surprise. For example, the activity of some of these genes in daf-2 mutant cells is doubled. So far, we can only guess what will happen if their activity is increased tenfold.

A change in the operation of the discussed signaling mechanism in one tissue affects the functioning of other body tissues and leads to the establishment of a new homeostasis. For example, an increase in the activity of the transcription factor DAF-16 in one wild-type C.elegans tissue, by triggering the mechanism of reverse regulation of the expression of the insulin gene, leads to an increase in the activity of this factor in all tissues, that is, there is a so-called non-autonomous cellular reaction. In addition, the expression of the daf-16 gene in one tissue (for example, fatty or nervous) prolongs the life of non-long–lived worms with a double mutation, daf-16(–) daf-2(-). Other transcription factors, including HSF-1 and SKN-1, have similar properties. Understanding the mechanisms of this complex system of interstitial relationships will allow us to coordinate the aging rates of various tissues.

The influence of the insulin- and IGF-1-mediated signaling mechanism on life expectancy has been preserved in the course of evolution. Systemic suppression of this mechanism, as well as selective stimulation of the activity of the transcription factor FOXO (analog of DAF-16) in adipose tissue prolongs the life of fruit flies. Inbred mouse lines also showed a pronounced inverse relationship between IGF-1 levels and life expectancy. Mutations that suppress the activity of insulin receptors and IGF-1, as well as other proteins participating in the signaling mechanism, also have a similar effect. A similar relationship is observed in dogs. There is evidence that dogs of short breeds with a mutation that reduces the activity of IGF-1 live longer than large dogs. However, for fruit flies and mice, the existence of a relationship between body size and life expectancy has not been confirmed.

The signaling mechanism mediated by insulin and IGF-1 plays an important role in the vital activity of all animals, therefore, the longevity of organisms carrying mutations that disrupt its work is somewhat unexpected. In fact, knocking out the insulin receptor gene leads to the development of diabetes in mice. Therefore, when interfering with this mechanism, it is very important to choose the right target to get positive results. It is also interesting that longevity can cause mutations that both increase and decrease insulin sensitivity. It is possible that the suppression of the signaling mechanism mediated by insulin and IGF-1 and the activity of DAF-16 (FOXO) analog proteins triggers an aging-slowing shift of physiological processes towards protecting and maintaining the vital activity of the cell.

The existing statistical data confirm the hypothesis that the effects of modulation of the insulin- and IGF-1-mediated signaling mechanism extend to humans. Mutations that disrupt the functions of the IGF-1 receptor are characteristic of the cohort of Ashkenazi Jews who have crossed the centennial milestone, and certain DNA variations in the insulin receptor gene are associated with longevity in the Japanese cohort. Variants of the AKT and FOXO3A genes are associated with longevity in three and seven cohorts of centenarians, respectively. Cohorts characterized by FOXO3A hyperexpression are scattered around the world, they include: Haitians of Japanese origin, Ashkenazi Jews, representatives of the population of Italy, Germany, China, California and New England. Moreover, the longevity-associated variant of the FOXO3A gene is more common in people over the age of 100 than in ninety-year-olds, which confirms its role in longevity.

Since the signaling mechanism mediated by insulin and IGF-1 ensures the recognition of nutrients and affects the development of C.elegans in conditions of limited access to food, it is highly likely to participate in the development of the body's reaction to starvation (Fig. 1, 2). According to existing scientific data, feeding every second day prolongs the life of C.elegans by suppressing the operation of this signaling mechanism. Long-lived lines of fruit flies with mutations of the genes that ensure its operation react to a low-calorie diet as if they are already somewhat limited in calories due to their genetic characteristics, which indicates a partial overlap of the two mechanisms under consideration. A low-calorie diet does not increase the life expectancy of mice with mutations of the growth hormone receptor gene, which is one of the links of the insulin- and IGF-1-mediated signaling mechanism, so it is logical to assume that its effect on ordinary animals is mediated by the suppression of the transmission of appropriate signals. And finally, a low-calorie diet can suppress the development of cancer by suppressing the activity of the insulin-mediated and IGF-1 signaling mechanism. This is supported by observations according to which calorie restriction does not affect the development of tumors caused by mutations that provide persistent activation of this mechanism.

Figure 1. Mechanisms involved in increasing life expectancy in conditions of chronic starvation. The results of the geno- and phenotypic analysis indicate that chronic starvation increases the life expectancy of worms, fruit flies and mice by suppressing the activity of TOR. The TOR-mediated mechanism (purple arrows) regulates the processes of autophagy and translation. The transcription factor PHA-4 is necessary for autophagy and affects the expression of stress response genes under fasting conditions. Its effect on the broadcast has not been studied. In drosophila, a decrease in TOR activity improves cellular respiration by preventing translational inhibition of the components of the electron transport chain. By activating the transcription factor SKN-1 in neurons (green arrows), chronic fasting also stimulates cellular respiration in worms and, accordingly, prolongs their life. Chronic fasting prolongs the life of fruit flies and mice (at least partially) and by suppressing the activity of the insulin- and IGF-1-mediated signaling mechanism (IIS, red arrows). Sirtuin proteins are also involved in the realization of the fasting effect, but their role in the signaling mechanisms mediated by TOR, insulin and IGF-1 has not been studied.

Figure 2. Various nutrient receptors (red) and transcription factors (blue) that ensure the prolongation of the life of C.elegans in various models of a low-calorie diet. Mutations of the eat-2 gene that suppress the supply of nutrients throughout life are likely to increase life expectancy by suppressing TOR activity, since additional suppression of the expression of this protein does not cause a further increase in the lifespan of eat-2 mutants. The transcription factor SKN-1 is involved in the life-prolonging effect of chronic fasting, but its interaction with TOR has not been studied. Interestingly, the presence of the SIR-2.1 functional gene is necessary for the manifestation of the ability of weak (but not strong) mutations of the eat-2 gene to change life expectancy. If fasting begins in middle age, functional variants of the AMP kinase and DAF-16 genes are needed to increase life expectancy. Feeding every other day most likely prolongs life by suppressing the signaling mechanism mediated by insulin and IGF-1, since it does not affect daf-2 mutants and depends on the activity of the daf-16 gene (illustrations from the article by Cynthia J. Kenyon “The genetics of aging” // Nature 464, 504-512).

Suppression of the acuity (or change) of the sense of smell and sense of taste also prolongs the life of C.elegans by suppressing the insulin-mediated and IGF-1 signaling mechanism. The decrease in sensory acuity also affects the lifespan of fruit flies, enhancing the effect of a low-calorie diet. It is not known whether the acuity of smell and taste affects a person's life expectancy, but the sense of smell of food consumed increases the level of insulin in the blood.

In mammals, in response to the intake of glucose into the body, insulin levels rise, which can be regarded as a prognostic factor for reducing life expectancy. The addition of 2% glucose to the nutrient bacterial mass shortens the life of C.elegans by suppressing the activity of DAF-16/FOXO and HSF-1. Curiously, such a diet shortened the life of long-lived C.elegans lines with mutations of insulin and IGF-1 receptors to almost normal values. The reasons for this are unclear, however, if this pattern also applies to mammals, mice with mutations in the insulin and IGF-1 receptor genes, whose life expectancy is 15-40% longer than normal, will be able to live even longer on a low-carb diet. In general, these data indicate that such a diet can be useful for humans. In addition, they lead to the paradoxical conclusion that, if a low-carb diet is followed, diseases characterized by impaired functioning of insulin receptors can contribute to longevity.

The pressure of natural selection cannot be the reason for the preservation of mutations that ensure longevity, since it is primarily aimed at the survival of the fittest individuals of childbearing age and loses its significance as the body ages and loses its ability to reproduce. Mechanisms that ensure a shift in metabolism towards protecting and maintaining cell viability could appear as a result of the selection of individuals capable of experiencing unfavorable periods for life with the least losses. An increase in life expectancy (including on the scale of the evolution of the living) may be a kind of "side effect" provided by these mechanisms to slow down the wear and tear of the metabolic systems of the body.

Target of rapamycin (target of rapamycin, TOR)

TOR kinase is the most important sensor of amino acids and other nutrients, stimulating the growth of the body and blocking autophagy and other mechanisms of waste disposal in conditions of abundance of food. Suppression of the activity of the TOR-mediated mechanism increases resistance to environmental factors and increases the life expectancy of many organisms (Fig. 1, 2). However, at least in C.elegans, suppression of TOR activity prolongs life independently of DAF-16/FOXO3 transcription factors, which indicates the absence of a relationship between it and insulin-mediated and IGF-1 signaling mechanism.

As in the case of the previously described signaling mechanism regulated by insulin and IGF-1, changes in the work of transcription factors are necessary for the manifestation of reduced TOR activity on life expectancy. This statement applies at least to roundworms (PHA-4/FOXA transcription factor) and yeast. When nutrients enter the body, TOR stimulates translation, and vice versa, in conditions of a low-calorie diet, the activity of TOR and, accordingly, translation decreases, which prolongs the life of yeast, roundworms, fruit flies and mice. Suppression of translation by other mechanisms also increases the lifespan of yeast, roundworms and fruit flies.

Suppression of TOR activity also stimulates autophagy, which is a necessary condition for increasing life expectancy, at least in roundworms and fruit flies. In this case, intermediate mechanisms can stimulate autophagy – for example, in roundworms, the transcription factor PHA-4/FOXA is involved in this.

Of all the mechanisms for registering nutrients entering the body, the TOR-mediated signaling mechanism has the most pronounced relationship with the processes triggered by fasting. The physiological effects of suppressing TOR activity are similar to the effects of a low-calorie diet, which does not cause a further increase in the lifespan of yeast, roundworms and fruit flies, in which TOR activity is suppressed in the body.

Reducing the amount of the amino acid methionine in the diet of mammals and protein in the diet of fruit flies increases the lifespan of these organisms. It is possible that different types of diets trigger different mechanisms aimed at protecting cells and, as a result, increasing life expectancy. Apparently, a low-carb diet suppresses the signaling mechanism mediated by insulin and IGF-1, and a decrease in the amount of amino acids in the diet suppresses the activity of TOR. Perhaps in the future, scientists will find a recipe for an optimal diet of longevity and health.

Adenosine Monophosphate kinase

The enzyme AMP kinase is a sensor of nutrients and energy that activates catabolism (reactions associated with the breakdown of substances, their oxidation and excretion of decay products from the body) and suppresses anabolism (the opposite process of synthesis and assimilation of substances) with an increase in the intracellular ratio of AMP/ATP energy carrier molecules. An increase in the expression of AMP kinase prolongs the life of C.elegans, and the antidiabetic drug metformin activating this enzyme prolongs the life of mice. AMP kinase is also involved in the realization of the effects of life-extending mutations that reduce the activity of the insulin- and IGF-1-mediated signaling mechanism, but its role in this process is unclear.

AMP-kinase is also involved in the mechanisms that ensure the prolongation of life in conditions of starvation. In C.elegans, an increase in life expectancy due to the transition to a low-calorie diet in middle age is impossible without the participation of AMP kinase, which directly phosphorylates and activates the transcription factor DAF-16/FOXO. This mechanism is not involved in the processes that cause the prolongation of life in conditions of starvation throughout life, and vice versa, the genes involved in these processes (pha-4/FOXA and skn-1/NRF) remain out of work when switching to a low-calorie diet in middle age. Thus, the choice of mechanisms that affect life expectancy is largely due to the diet, rather than the amount of food entering the body.

Sirtuins

Sirtuins are NAD+-dependent protein deacetylases, the overexpression of which increases the lifespan of yeast, roundworms and fruit flies. The mechanisms of this phenomenon are currently unclear. It has been suggested that sirtuin Sir2 prolongs the life of yeast by suppressing the formation of toxic extra-chromosomal ribosomal ring DNA, but it can also act through other mechanisms. An interesting fact is that Sir2 contributes to the segregation of damaged proteins in the mother cell during cell division, but the overexpression of this protein, although it prolongs life, does not affect the segregation process. Recent data indicate that Sir2 increases life expectancy by keeping telomere genes inactive. This mechanism of protection against aging is most likely important for multicellular organisms that do not have ring DNA.

Under conditions of oxidative stress, mammalian SIRT1 directly deacetylates FOXO proteins, as a result, a gene involved in the formation of resistance to stress becomes their target. Apparently, oxidative stress has a similar effect on C.elegans, since it stimulates the binding of SIR-2.1 and DAF-16 and can increase the lifespan of worms through the SIR-2.1- and DAF-16-dependent mechanism. Sirtuins are able to deacetylate transcription factors of the FOXO family. At the same time, the longevity of organisms with mutations that disrupt the work of the insulin- and IGF-1-mediated signaling mechanism does not require the participation of Sir2.1, therefore, it is logical to assume that in roundworms, sirtuins affect the functioning of DAF-16/FOXO and life expectancy regardless of the indicated signaling mechanism. A similar pattern extends to another stress reaction regulator, Jun-1 kinase (JNK–1), which prolongs the life of roundworms and fruit flies by phosphorylation of DAF-16/FOXO. However, (at least in drosophila) JNK-1 modulates the activity of the lipocaine protein, which, in turn, affects the signaling mechanism mediated by insulin and IGF-1.

Long-lived drosophila fly lines, which are characterized by SIR2 overexpression, also differ in the overexpression of the chaperone protein, which prevents the launch of SIR2-mediated cell death. Therefore, confirmation of the ability of SIR2 to increase the lifespan of fruit flies requires further research. It is also unknown whether the transcription factor FOXO plays any role in the longevity of these insects, however, apparently, histone deacetylase RPD3 and the tumor suppressor protein p53 are involved in this mechanism.

To date, there is no evidence of the ability of sirtuins to prolong the life of mammals. Within the framework of one carefully planned work (Pearson, K.J. et al., “Resveratrol delays age-related determination and mimics transcriptional aspects of dietary restriction without extending life span” // Cell Metab. 8, 157-168 (2008)) scientists have demonstrated that resveratrol (resveratrol), a plant polyphenol that enhances the effect of sirtuins on many processes, prolongs the life of mice kept on a fat–rich diet, but does not affect the life expectancy of animals consuming conventional feed. The relationship between sirtuins and resveratrol is complex and poorly understood, so these data do not mean that sirtuins do not affect the life expectancy of mammals, but indicate the need for further study of this issue.

All variants of a low-calorie diet, except for moderate chronic (throughout life) fasting, cause a pronounced increase in the lifespan of C.elegans, which do not have a functional sir2.1 gene. In experiments on fruit flies, only one fasting model was tested, in the implementation of the effect of which on the lifespan of insects involved sirtuins. Chronic fasting also has no effect on the lifespan of mice in the absence of the SIRT1 protein. Given that sirtuins are sensors of nutrients, it can be argued that – at least in mice – in conditions of starvation, these proteins perform important functions (in some cases completely unexpected) in the regulation of a wide range of metabolic mechanisms, as well as mechanisms for the development of stress reactions.

Decreased respiratory activity

A moderate decrease in cellular respiration activity prolongs the life of many organisms, including yeast, roundworms, fruit flies and mice. This statement contradicts the data according to which active breathing promotes longevity in conditions of starvation. However, it is possible that the activation of breathing increases life expectancy for one reason and decreases it for another. This idea is supported by the fact that a low-calorie diet increases the body's resistance to adverse environmental factors, and respiratory suppression does not have such an effect. In any case, these data explain a classic natural phenomenon – a pronounced correlation between the metabolic rate of mammals (decreasing as the size of the organism increases) and life expectancy (as a rule, the larger the organism, the longer it lives). Perhaps the longer lifespan of large mammals is partly due to slower metabolism. There are exceptions, which, however, do not refute this rule, since they can be explained by the participation of other mechanisms. For example, dogs of small breeds live longer than large dogs due to low IGF-1 levels.

In yeast, roundworms and mammalian cells, the suppression of cellular respiration triggers the so-called "retrograde reaction" preserved in the course of evolution, which consists in stimulating the work of genes that activate alternative energy production mechanisms, as well as cell protection mechanisms. At the same time, mutations that completely prevent the development of a "retrograde reaction" or block the work of individual genes involved in it, prevent an increase in the lifespan of yeast and roundworms. Interestingly, an increase in the life expectancy of roundworms (but not drosophila) occurs with a decrease in respiratory activity during the development of the organism, which indicates the participation of the phenomenon of molecular memory. A similar situation is observed in mice. In addition, the suppression of neuronal respiration prolongs the life of at least fruit flies. This suggests that in this case there is a non-autonomous cellular reaction.

Signals of the reproductive system

It is known that mating shortens the life of animals of some species. This confirms the idea that an animal is forced to "choose" what it is better to spend the available resources on: reproduction or a long life. However, many of the recently identified mechanisms of life extension are practically (or at all) they do not affect the reproductive function. Moreover, many of the long-lived mutants leave behind more offspring than normal animals. And the observation of guppy fish has shown that the removal of predators, under natural conditions exerting strong pressure on them, increases not only life expectancy, but also the number of offspring. Thus, longevity is not always bought at the price of not reproducing.

Removal of the entire reproductive system does not affect the lifespan of C.elegans, whereas removal of only germ cells increases it by 60%.

Perhaps this is due to the fact that the signals of the reproductive system about the "unpreparedness" of the organism for reproduction postpone its aging. Apparently, this mechanism also appeared in the early stages of evolution, since the suppression of mitosis and stimulation of germ cell meiosis increases the lifespan of both worms and flies. Moreover, in both cases, there is an increase in the activity of the FOXO transcription factor involved in the mechanisms of prolongation of life.

The loss of germ cells activates DAF-16/FOXO through a special mechanism unrelated to the signaling pathway mediated by insulin and IGF-1. To start it, the auxiliary protein KRI-1 and the transcription factor elongation/splicing homolog TCER-1 are needed. The loss of germ cells significantly prolongs the life of already long-lived daf-2 mutants, which indicates the synergy of these two mechanisms. The effects of germ cell loss on the body are mediated by the action of sex hormones and currently unidentified signals activating the expression of the TCER-1 gene. It is possible to activate the described mechanism without removing the germ cells. For example, overexpression of TCER-1 prolongs the life of worms without disrupting their reproductive function.

The mammalian reproductive system can also have an impact on life expectancy. Transplantation of the ovaries of young mice to old mice prolongs their life. Women gradually lose their germ cells as they age, while the removal of somatic ovarian tissues significantly increases their mortality from various causes. To date, it is still too early to talk about the relationship or simple coincidence between the described phenomenon and the situation observed in C.elegans, but this is definitely suggestive.

Telomeres

Telomeres shorten with age and have an effect on the aging of the body, but their action differs from the action of the mechanisms described earlier. Genetically modified mice with abnormally long telomeres live longer than normal animals, but only if manipulations performed on their genome ensure their resistance to malignant diseases. A low-calorie diet, changes in the functioning of nutrient sensors and a decrease in cellular respiration activity also inhibit tumor growth. (Mutations that increased life expectancy during evolution may also have prevented the development of cancer, the frequency of which is closely related to the physiological aging of many species.) All these facts indicate that telomere lengthening increases life expectancy not due to a shift in metabolism towards a protective physiological state, but due to some other mechanism, for example, a delayed reduction in the stem cell population. It would be very interesting to know whether the combination of telomere lengthening and a low-calorie diet or mutations of nutrient receptor genes will lead to a noticeable increase in life expectancy without cancer?

Causes of aging

Despite all the efforts of scientists, a number of aspects of aging continue to remain under the veil of secrecy. One of these mysteries is the actual cause of aging.

With age, the protein homeostasis of the body is disrupted, which leads to the accumulation of macromolecular damage, traditionally considered the cause of aging. However, there is no unambiguous evidence of this theory, and it is not known what kind of damage triggers the aging process. The main contenders are considered to be damage caused by reactive oxygen species (ROS), which are by-products of cellular respiration. Many long-lived mutants are resistant to oxidative stress. Testing of mammalian cells with a long lifespan in laboratory conditions also demonstrated their high stress resistance. However, given that the respiratory chain has undergone centuries of evolution, it is logical to assume that mechanisms for neutralizing its toxic by-products have evolved in parallel with it.

In recent years, the theory of the role of reactive oxygen species in the aging process has undergone fundamental changes. Firstly, it has been established that a small amount of reactive oxygen species can be useful for the body and, under certain conditions, even prolongs the life of roundworms. Physical activity activates AMP kinase in human cells, which stimulates the absorption of glucose contained in the blood. Antioxidants prevent the stimulation of glucose uptake, which indicates the possible participation of reactive oxygen species in this process. Overexpression of the antioxidant superoxide dismutase (SOD) prolongs the life of fruit flies, but it stimulates the expression of many FOXO target genes, which indicates the role of this enzyme in triggering the FOXO-mediated signaling mechanism. Inactivation of superoxide dismutase genes increases the level of oxidative damage, but does not reduce, but even increases life expectancy, while taking antioxidants reduces the amount of oxidative damage without increasing life expectancy. Despite the existence of a relationship between stress resistance and longevity in many long-lived mutants, in some cases the independence of these phenomena from each other has been demonstrated. None of these facts supports the idea that molecular damage causes aging. They even partially refute it, since in each case the actual cause may be a completely different type of damage.

Key moments of time

At a certain age, most people develop hyperopia and there is a redistribution of fat in the body, menopause occurs in women. Why do these changes all occur at about the same age? One possible explanation is that over time, the level of agents regulating the rate of aging decreases in the body, and reaching a certain threshold triggers various aging mechanisms. C.elegans has identified genes whose expression changes with age. Many of these genes contain the binding center of the transcription factor GATA, binding and factor DAF-16/FOXO. DAF-16, in turn, is regulated in adulthood by the lin-4 microRNA, which controls the onset of the next stage of development at an earlier age. Perhaps this microRNA (or some other factor) changes the activity of DAF-16 or GATA, while controlling the aging process. In yeast and mice, the activity of sirtuins and the level of sirtuin-dependent chromatin modifications decreases with time, which reduces the lifespan of at least yeast. In mammals, as they age, the content of signaling proteins of the Wnt family increases in the blood, which triggers the aging of muscle stem cells.

Among other possible mechanisms for controlling the aging process, experts note the regulatory cascade triggered by the protein product of the period (per) gene, one of the proteins that ensure the functioning of the body's biological clock. This hypothesis is confirmed by the premature aging of mice with mutations of genes encoding transcription factors involved in the formation of circadian rhythms.

How do I stop the clock?

The literature describes the case of a girl who is 17 years old today, but she still remains an infant. The reason for stopping its growth and development is unknown. It is also unknown whether she will ever become an adult. Perhaps it will reveal some completely new information to humanity.

Random factors

In addition to genes and the environment, various random factors affect the rate of aging of the body. Life expectancy is not a constant parameter even for genetically identical organisms. Perhaps some kind of metabolic disorder or expression of the regulatory gene triggers a cascade of events that accelerates aging. To study the effect of stochastic factors on life expectancy, it is necessary to identify a marker that predicts the rate of aging already at the early stages of development, sort animals depending on the expression of this marker and analyze the characteristics of individuals of each of the resulting groups. Based on the results obtained, it will be possible to build various hypotheses and test them.

Significant increase in life expectancy

A decrease in cellular respiration activity increases the already significant lifespan of C.elegans lines with daf-2 gene mutations by two times, and manipulations of the reproductive system by six times. Complete blocking of one of the stages of the signaling mechanism mediated by insulin and IGF-1 introduces C.elegans into a kind of "hibernation" (dauer stage), which usually ensures the survival of larvae in adverse conditions. After leaving this state, the worms develop into adults who live ten times longer than normal. The life expectancy of long-lived mouse lines is less impressive, but the combination of mutations and a low-calorie diet makes it possible to achieve an almost twofold increase. The mechanisms underlying these phenomena are completely unclear, and only their detailed study will provide answers to many questions.

Evolution has created a huge range of life expectancy, which is perhaps an "easily changeable" trait. Is it possible to quickly change life expectancy with the help of mutations of regulatory genes? It is known that mutations of the IGF-1 gene ensure the long life of dogs of small breeds. There is a hypothesis according to which mutations affecting the activity of cellular respiration contributed to an increase in the life expectancy of large mammals. Further research may reveal previously unknown relationships between laboratory mutations and evolutionary causes of longevity.

Prospects for clinical application

Until recently, the possibility of a significant increase in life expectancy seemed completely unrealistic. However, today we have convincing evidence to the contrary: lines of healthy, long-lived roundworms, fruit flies and mice.

There is an officially approved drug for clinical use-the TOR inhibitor rapamycin (rapamycin), which prolongs the life of mice even at the beginning of therapy at an advanced age. However, at least to date, the U.S. Food and Drug Administration (FDA) does not consider old age as such an indication to start treatment. Therefore, such drugs can receive official approval only if they are effective in the treatment of a particular disease. Rapamycin is an immunosuppressant, which may neutralize its effect on life expectancy. Another officially approved drug from the group of farnesyltransferase inhibitors (FTI) neutralizes the abnormal nuclear protein lamin A, which causes Getchinson-Guilford disease characterized by premature aging. During normal aging, abnormal lamin accumulates in the nuclei, which indicates the potential use of this drug to prolong youth.

Drugs that affect the cholesterol carrier protein, the low activity of which is genetically interrelated with exceptional longevity, are currently undergoing clinical trials as a means of preventing vascular diseases. Also, drugs under development for the treatment of age-related diseases, including antitumor agents that block the activity of IGF-1, theoretically can not only improve overall health, but also increase life expectancy.

In general, the potential, as well as possible serious side effects of such drugs are unknown today. However, the search for substances and methods that affect already known and as yet undiscovered genes and signaling pathways associated with aging continues. Whether we will wait for the results with you is another question…

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Nature: Cynthia J. Kenyon, The genetics of aging.

13.04.2010