Currently, there are many theories of aging, most of which consider the actual mechanisms of aging - this is, first of all, the theory of oxidative damage (Harman, 1987; Sohal, Weindruch, 1996) and the telomere theory (Slovnikov A.M., 1971, Hayflick, 1998). While revealing the underlying mechanisms of aging, these theories, however, do not set direct limits on life expectancy (LS), since they do not determine the rate at which these mechanisms unfold and thus how quickly the aging process proceeds. Another part of the theories is devoted to the development of aging over time, primarily the theory of the pace of life (TTL - Pearl, 1928, Sohal, 1986; Lints, 1989).

In recent years, the theory of oxidative damage has increasingly emerged as a concept that most adequately reflects the accumulated knowledge about the mechanisms of aging (Harman, 1987; Fleming et ai, 1992; Sohal, Weindruch, 1996; Orr, 1996; Zhizhina and Blyukhterova, 1999) . This theory states that aging is caused by the production of oxidants that damage body structures, and “the lifespan of organisms with the same metabolic rate should correlate with the level of their antioxidant defense” (Fleming et ai, 1992). There is now a close connection between TLC and the theory of oxidative damage: “The pace of life theory of aging can be expressed as the free radical theory, based on the fact that free radicals arise as a normal product of metabolism” (Parsons, 1996).

All modern theories of aging are, to one degree or another, related to the concept of body homeostasis. Genetic studies have revealed deep connections between lifespan and the body’s abilities (Tatar, 1999). In theoretical gerontology, the concept of homeostasis is considered in a broader context than in its classical understanding (Arking, 1991; Holliday, 1995). In physiology, homeostasis is considered as maintaining a constant chemical composition of body fluids (Cannon, 1932; Sarkisov, 1981; Novoseltsev, 1978). The physiological mechanisms of homeostasis provide for this the delivery of oxygen (blood circulation, respiration) and nutrients (digestive system), as well as the elimination of waste products (excretory systems). For gerontology, the constancy of cellular structures is of interest - somatic homeostasis, which is supported by molecular genetic and cellular mechanisms (Sohal, Weindruch, 1996; Tatar, 1999).

Physiological mechanisms of homeostasis operate on a faster time scale than somatic ones, which is fundamental for theoretical gerontology important fact. In humans, fast time scales cover the range from several seconds to several hours (for example, in this range, sequential mechanisms in the circulatory system are activated - Guyton, 1982). The slow time scale reflects age-related changes in the somatic mechanisms of homeostasis (Comfort, 1967; Frolkis and Muradyan, 1992).

An important aspect of the homeostatic approach to aging is the concept of natural death as “death of old age.” “The medical model of disease...believes that death is always the result of disease progression; if there were no disease, there would be no death” (Fries, 1980; Hyflik, 1998). In fact, after a certain age, the body's ability to maintain homeostasis decreases, and at some point even slight disturbances make its restoration impossible. “The inevitable result is natural death, which occurs even without disease” (Fries, 1980, p. 131). However, natural death from old age as a result of depletion of homeostatic resources becomes a significant cause of death only when individuals are completely protected from environmental influences. Today this is true only for experimental populations of animals, in particular insects.

Based on the modern version of the pace of life theory, a homeostatic model of aging has been developed, in which physiological aging is associated with the accumulation of oxidative damage in the body within the framework of general biological concepts of the homeostasis of the body (Novoseltsev et al., 1997, Novoseltsev et al, 2000)

An adult insect enters the life cycle with homeostatic mechanisms (their power So is determined by the genotype) and an antioxidant defense mechanism (the body’s susceptibility to the action of oxidants is also determined by its genotype, which sets the age pattern of its “oxidative vulnerability” B.

Life processes are associated with oxygen consumption (the rate of consumption of which is described by the time pattern Wz). In proportion to oxygen consumption in the body, oxidants are produced and oxidative damage accumulates, which leads to an age-related decrease in the value of S. As a result, oxygen delivery to the body gradually decreases, and the current quasi-stationary oxygen level, indicated by the symbol X, slowly decreases, at some age falling to the maximum permissible level XD When this level is reached, death occurs.

Thus, aging is conceptualized as an age-related decline in the body's homeostatic abilities, and the rate of aging is determined by two factors—the rate of oxygen consumption (with the byproduct of oxidant production) and the effectiveness of antioxidant defenses.

2 MAIN MODERN THEORIES OF AGING OF A LIVING ORGANISM

All theories of aging can be divided into two large groups: evolutionary theories and theories based on random cell damage. The first believe that aging is not a necessary property of living organisms, but a programmed process. According to them, aging developed as a result of evolution due to some advantages it provides to an entire population. In contrast, damage theories suggest that aging is the result of a natural process of damage accumulating over time that the body tries to combat, and differences in aging different organisms is the result of the varying effectiveness of this struggle. The latter approach is now considered established in the biology of aging. However, some researchers still defend the evolutionary approach, and some others completely ignore the division between evolutionary and damage theories. The latter statement is partly the result of a change in terminology: in some recent work, the term "evolutionary theories" refers not to theories of "programmed aging", which propose the evolutionary emergence of aging as a beneficial phenomenon, but to an approach that describes why organisms should age, as opposed to the question of biochemical and physiological basis of aging. The hormonal-genetic approach is that during a person’s life, starting from birth, there is an increase in the sensitivity threshold of the hypothalamus, which ultimately, after 40 years, leads to hormonal imbalance and progressive disruption of all types of metabolism, including hypercholesterolemia. Therefore, the treatment of diseases of old age it is necessary to start with improving the sensitivity of the hypothalamus.

The theory of apoptosis (cell suicide). Academician V.P. Skulachev calls his theory the theory of cell apoptosis. Apoptosis (Greek: leaf fall) is the process of programmed cell death. Just as trees get rid of parts in order to preserve the whole, so each individual cell, having gone through its life cycle, must die off and a new one must take its place. If a cell becomes infected with a virus, or a mutation occurs in it leading to malignancy, or its lifespan simply expires, then in order not to endanger the entire organism, it must die. Unlike necrosis - violent cell death due to injury, burn, poisoning, lack of oxygen as a result of blockage of blood vessels, etc., during apoptosis the cell carefully disassembles itself into parts, and neighboring cells use its fragments as building material.
Mitochondria also undergo self-destruction - having studied this process, Skulachev called it mitoptosis. Mitoptosis occurs when too many free radicals are produced in the mitochondria. When the number of dead mitochondria is too high, their breakdown products poison the cell and lead to its apoptosis. Aging, from Skulachev’s point of view, is the result of the fact that more cells die in the body than are born, and dying functional cells are replaced by connective tissue. The essence of his work is the search for methods to counteract the destruction of cellular structures by free radicals. According to the scientist, old age is a disease that can and should be treated; the body’s aging program can be disabled and thereby turn off the mechanism that shortens our lives.

According to Skulachev, the main active form of oxygen that leads to the death of mitochondria and cells is hydrogen peroxide. Currently, under his leadership, the drug SKQ, designed to prevent signs of aging, is being tested.

Free radical theory. Almost simultaneously put forward by D. Harman (1956) and N.M. Emanuel (1958), the free radical theory explains not only the mechanism of aging, but also a wide range of associated pathological processes (cardiovascular diseases, weakened immunity, brain dysfunction, cataracts , cancer and some others). According to this theory, the cause of cell dysfunction is free radicals, which are necessary for many biochemical processes - reactive oxygen species, synthesized mainly in mitochondria - the energy factories of cells.

If a very aggressive, chemically active free radical accidentally leaves the place where it is needed, it can damage DNA, RNA, proteins, and lipids. Nature has provided a mechanism for protecting against excess free radicals: in addition to superoxide dismutase and some other enzymes synthesized in mitochondria and cells, many substances that enter the body with food have an antioxidant effect - incl. vitamins A, C and E. Regular consumption of vegetables and fruits and even a few cups of tea or coffee a day will provide you with an adequate dose of polyphenols, which are also good antioxidants. Unfortunately, an excess of antioxidants - for example, with an overdose of dietary supplements - is not only not beneficial, but can even increase oxidative processes in cells.

Adaptation-regulatory theory. The aging model developed by the outstanding Ukrainian physiologist and gerontologist V.V. Frolkis in the 1960s and 70s, is based on the widespread idea that old age and death are genetically programmed. The “highlight” of Frolkis’ theory is that age development and life expectancy are determined by the balance of two processes: along with the destructive process of aging, the process of “antiaging” unfolds, for which Frolkis proposed the term “vitauct” (Latin vita - life, auctum - to increase). This process is aimed at maintaining the vitality of the body, its adaptation, and increasing life expectancy. The concept of anti-aging (vitauct) has become widespread. Thus, in 1995, the first international congress on this issue.

An essential component of Frolkis' theory is the gene regulatory hypothesis he developed, according to which the primary mechanisms of aging are disruptions in the functioning of regulatory genes that control the activity of structural genes and, as a result, the intensity of synthesis of the proteins encoded in them. Age-related disorders of gene regulation can lead not only to changes in the ratio of synthesized proteins, but also to the expression of previously inactive genes, the appearance of previously unsynthesized proteins and, as a result, to aging and cell death.

V.V. Frolkis believed that gene regulatory mechanisms of aging are the basis for the development of common types of age-related pathologies - atherosclerosis, cancer, diabetes, Parkinson's and Alzheimer's diseases. Depending on the activation or suppression of the functions of certain genes, one or another aging syndrome, one or another pathology will develop. Based on these ideas, the idea of ​​gene regulatory therapy was put forward, designed to prevent changes that underlie the development of age-related pathology.

Telomere theory. In 1961, the American gerontologist L. Hayflick established that human fibroblasts - skin cells capable of dividing - “in vitro” can divide no more than 50 times. In honor of its discoverer, this phenomenon was called the “Hayflick limit.” However, Hayflick offered no explanation for this phenomenon. In 1971, researcher at the Institute of Biochemical Physics of the Russian Academy of Sciences A.M. Olovnikov, using data on the principles of DNA synthesis in cells, proposed a hypothesis according to which the “Hayflick limit” is explained by the fact that with each cell division the chromosomes are slightly shortened. Chromosomes have special terminal sections - telomeres, which after each doubling of chromosomes become slightly shorter, and at some point shorten so much that the cell can no longer divide. Then it gradually loses its viability - this, according to the telomere theory, is what cell aging consists of. The discovery in 1985 of the telomerase enzyme, which completes shortened telomeres in germ cells and tumor cells, ensuring their immortality, was a brilliant confirmation of Olovnikov’s theory. True, the limit of 50-60 divisions is not true for all cells: cancer and stem cells can theoretically divide indefinitely; in a living organism, stem cells can divide not tens, but thousands of times, but the connection between cell aging and telomere shortening is generally accepted. It is curious that the author himself recently decided that the telomeric hypothesis does not explain the causes of aging, and first put forward another one, the redusomal one, and then a second, no less fantastic one - the lunar-gravitational one. Both of them received neither experimental confirmation nor peer approval.

Elevation (ontogenetic) theory of aging. In the early 1950s, the famous Russian gerontologist V.M. Dilman put forward and substantiated the idea of ​​the existence of a single regulatory mechanism that determines the patterns of age-related changes in various homeostatic (maintaining constancy) internal environment) body systems. According to Dilman's hypothesis, the main link in the mechanisms of both development (Latin elevatio - rise, in a figurative sense - development) and subsequent aging of the body is the hypothalamus - the “conductor” of the endocrine system. main reason aging is an age-related decrease in the sensitivity of the hypothalamus to regulatory signals coming from nervous system and endocrine glands. Throughout the 1960-80s. with the help of experimental studies and clinical observations, it was found that it is this process that leads to age-related changes in functions reproductive system and the hypothalamic-pituitary-adrenal system, which provides the necessary level of glucocorticoids produced by the adrenal cortex - “stress hormones”, daily fluctuations in their concentration and increased secretion under stress, and, ultimately, to the development of a state of so-called “hyperadaptosis”.

According to Dilman's concept, aging and related diseases are a by-product of the implementation of the genetic program of ontogenesis - the development of the body. The ontogenetic model of age-related pathology has opened up new approaches to the prevention of premature aging and age-related diseases that are the main causes of human death: heart disease, malignant neoplasms, strokes, metabolic immunosuppression, atherosclerosis, diabetes mellitus the elderly and obesity, mental depression, autoimmune and some other diseases. From the ontogenetic model it follows that the development of diseases and natural senile changes can be slowed down if the state of homeostasis is stabilized at the level achieved by the end of the development of the organism. If you slow down the rate of aging, then, as V.M. believed. Dilman, it is possible to increase the species limits of human life.

The theory of accumulation of mutations(eng. Mutations accumulation theory) - an evolutionary-genetic theory of the occurrence of aging, proposed by Peter Medawar in 1952. This theory views aging as a byproduct of natural selection (as well as, for example, the evolutionary explanation for the development of blindness in cave and subterranean animals).

The probability of an individual's reproduction depends on its age, increasing from zero at the time of birth, and reaching a peak in young adult organisms (immediately after reaching sexual maturity), after which it decreases due to the increasing probability of death from external factors (predators, diseases, accidents). and internal (aging) causes. Moreover, under natural conditions, organisms very rarely survive to an age when aging becomes noticeable, that is, mortality almost exclusively depends on external causes, on which aging has no influence. There are thus very strong evolutionary pressures against deleterious mutations in alleles that appear at a young age, since they have a strong impact on the likelihood of reproduction. On the other hand, deleterious mutations that appear late in life, at an age that most of the population does not live to see, will experience significantly less evolutionary pressure because their carriers have already passed on their genes to the next generation and the reduction in the number of heirs due to these mutations insignificant.

Mutations can affect the success of an organism both directly and indirectly. For example, a hypothetical mutation that increases the risk of fractures due to decreased calcium fixation is less harmful than a mutation that affects eggs in the uterus. From an evolutionary point of view, it does not matter why an organism's ability to reproduce decreases. Importantly, individuals who carry a deleterious mutation have less opportunity to reproduce if the deleterious effect of that mutation occurs earlier in life. For example, people with progeria (a genetic disease with symptoms of premature aging) live only 15-20 years, and are practically unable to pass on their mutant genes to the next generation (considering the mutation dominant). Under such conditions, progeria occurs only as a result of new mutations, and not from the genes of the parents. In contrast, people with another genetic disease, Alzheimer's disease, which manifests itself late, manage to leave offspring before its manifestation. Thus, the disease is transmitted to new generations and is random. In other words, the mutation accumulation theory predicts that the frequency of genetic mutations that remain in the gene pool increases with age.

Mutation accumulation theory allows researchers to make several testable predictions. In particular, this theory stipulates that the dependence of the maximum lifespan of the offspring population on the maximum lifespan of the maternal organism should not be linear, as is observed for almost any other quantitative trait that heredity demonstrates (for example, body height). This means that the relationship should have an unusual nonlinear shape, with an increasing slope for the relationship of offspring life span to maternal lifespan among longer-lived parents. This prediction follows directly from the theory's key statement that the equilibrium frequency of genes where a deleterious mutation is possible should increase with age due to weak evolutionary pressures against these mutations (Equilibrium gene frequency means the time-independent gene frequency that determines the balance between the occurrence of mutations and evolutionary pressure against them).

According to the mutation accumulation theory, genetic changes in maximum life expectancy are expected to increase with age. Thus, in a heterogeneous population, the same change in phenotype corresponds to a large number of changes in the genotype. The intended increase in additive genetic variation can be identified by studying the relationship of genetic changes given similar phenotypic changes. This relationship, the so-called heritability of life expectancy in the narrow sense, can be estimated as twice the slope of the regression line depending on the life expectancy of offspring from maternal life expectancy. Therefore, if age at death is indeed determined by the accumulation of deleterious late-acting mutations, this slope would be expected to steepen as maternal age at death increases. This prediction was tested by analysis of genealogical data on heredity in European royal and noble families, which are very well documented. It was found that the slope of the descendant regression line actually increases with the maximum age of the ancestors, as predicted by mutation accumulation theory. Similar results were obtained using studies of other model organisms, for example, the fruit fly Drosophila melanogaster

Today, however, the theory of accumulation of mutations has not been confirmed in the example of specific genes and remains a hypothesis that requires further confirmation.

Disposable soma theory, sometimes the disposable soma theory, is an evolutionary-physiological model that attempts to explain the evolutionary origins of the aging process. The theory was proposed in 1977 by Thomas Kirkwood, then an employee of the British National Institute of Biological Standards and Control, in his review article. This theory asks how the body should allocate its resources (in the first version of the theory it was only about energy) between the support and repair of the soma and other functions necessary for survival. The need for compromise in the use of these resources arises due to the limited resources and the need to choose the best way to use them.

This theory was proposed in an attempt to provide an evolutionary framework for understanding the existence and variation in the process of aging that is universal to all living organisms. It suggests that individuals should invest in maintaining and repairing their soma (peripheral body parts) in accordance with their expectations for future lifespan and reproductive capabilities. However, an individual's expectations of future livelihood prospects and the likelihood of reproduction are not constant. For different types, and sometimes even for different individuals within a species, it is thus necessary to maintain one's soma for different periods of time. The disposable soma theory stipulates that species and populations that, on average, have few external threats and low reproductive rates should invest much more in protecting their soma than species and populations that expect short lifespans and rapid reproduction. When organisms are exposed to protected conditions and freed from natural selection, differences in soma repair and maintenance manifest themselves as interspecies and interpopulation differences in the rate of aging and maximum lifespan.

The theory is supported by observations of wild animal populations in nature, which show that the number and activity of predators influence the population's survival strategy. For example, studies of guppy populations have shown an evolution in lifespan that occurs very quickly in response to changes in mortality. Representatives of the guppy population, which grows in conditions of increased mortality, are smaller in size, grow faster, and reproduce at a higher rate. early age and devote more resources to reproduction than guppies, which live in conditions of low external mortality. It has also been suggested that one of the reasons that birds and bats live longer than similarly sized land animals is that, by being able to fly, they were freed from much of the evolutionary predation pressure that land animals experience . Another study that confirmed some of the basics of the theory was conducted on two populations of Virginia opossums. One population of possums, found on Sapelo Island (Georgia), has no natural land predators, while another, found on the mainland of the state, is hunted by cougars, foxes and bobcats. As a result, it was found that the island population gave birth to fewer young than the continental group, and generally survived until the second breeding season, receiving a second opportunity to reproduce. Members of this group are smaller in size, have a 25% longer average lifespan, and a 50% longer maximum lifespan than the continental group.

It is important to note that because the disposable soma theory considers only the evolutionary aspects of aging, the relationship between consumption, reproduction, and aging is viewed in terms of the end result rather than specific mechanisms. If an individual animal has the ability to reproduce, it cannot expect biological immortality, since it needs to maintain its soma only to such a level that the average individual within the population can survive beyond the time necessary to produce the required number of offspring. However, the lack of opportunity to reproduce may have a positive effect on aging and lifespan. This does not imply that there is a connection between sustenance, reproduction, soma support and longevity; disposable soma theory only envisions a trade-off between soma support and reproduction, mediated by the process of resource allocation. The theory suggests two reasons for the change of organisms. First, an increase in mortality expectancy in adulthood should lead to a decrease in soma support. If an organism does not expect to live long, it has less need to protect itself. Second, an increase in expected reproductive rate should result in a decrease in soma support as individuals anticipate a lack of resources necessary for reproduction.

The disposable soma theory does not postulate any specific mechanisms soma support, and is therefore compatible with most mechanistic models of aging, such as the accumulation of somatic mutations, altered proteins, mitochondrial theory, free radical theory, etc. In addition, species that have the lowest mortality rates from external causes and low reproduction rates also have the best protection against oxidative stress and the resulting mutations and protein damage. For example, DNA repair is much worse in rodents than in primates, and mouse somatic cells are much more sensitive to chemically induced oxidative stress than the cells of long-lived mammals. Kidney epithelial cells from relatively long-lived birds are also more resistant to chemical and radiation damage than corresponding cells from mice.

Overall, the disposable soma theory provides a useful evolutionary framework for understanding the aging process. A large amount of indirect evidence supports this theory, but detailed experimental studies are still lacking.

Mitochondrial theory. The importance of the link between molecular stress and aging has been suggested based on observations of the effect of accumulation of mutations in mitochondrial DNA (mtDNA). These findings were reinforced by the observation that the number of cells lacking cytochrome c oxidase (COX) increases with age, which is associated with mtDNA mutations. Such cells often have disturbances in ATP production and cellular energy balance.

Theory of somatic mutations. Many studies have shown an increase in somatic mutations and other forms of DNA damage with age, suggesting DNA repair as an important factor in supporting cell longevity. DNA damage is typical for cells, and is caused by factors such as hard radiation and reactive oxygen species, and therefore DNA integrity can only be maintained through repair mechanisms. Indeed, there is a relationship between longevity and DNA repair, as has been demonstrated by the enzyme poly-ADP-ribose polymerase-1 (PARP-1), an important player in the cellular response to stress-induced DNA damage. Higher PARP-1 levels are associated with longer lifespan.

Gompertz-Makeham law of mortality(sometimes simply Gompertz's Law, Gompertz Distribution) is a statistical distribution that describes the mortality rate of humans and most multiparous animals. According to the Gompertz-Makeham law, mortality is the sum of an age-independent component (Makeham term) and an age-dependent component (Gompertz function), which increases exponentially with age and describes the aging of the organism. In protected environments where external reasons deaths are absent (in laboratory conditions, in zoos or for people in developed countries), the age-independent component often becomes small and the formula simplifies to a Gompertz function. The distribution was derived and published by actuary and mathematician Benjamin Gompertz in 1832.

According to the Gompertz-Makeham law, the probability of death within a fixed short period of time after reaching age x is:

p = a + bx,

where x is age,

p - relative probability of death over a certain period of time,

a and b are coefficients.

Thus, population size decreases with age at a double exponential rate:

s(x) = exp[ − m(bx + c)].

The Gompertz-Makeham law of mortality best describes the dynamics of human mortality in the age range of 30-80 years. In the area of ​​higher age, mortality does not increase as quickly as provided for by this law of mortality.

Historically, human mortality before the 1950s was largely caused by the time-independent component of the mortality law (the Makeham term or parameter), while the age-dependent component (the Gompertz function) remained almost unchanged. After the 1950s, the picture changed, leading to a decrease in mortality in late age and the so-called “derectangularization” (smoothing) of the survival curve.

In terms of reliability theory, the Gompertz-Makeham mortality law is the law of failure, where the rate of risk is a combination of age-independent failures and failures associated with aging, with an exponential increase in the rate of these failures.

Gompertz's law is a special case of the Fisher-Tippett distribution for negative age.

Epigenetic theory of aging. Cells slowly lose markers of repressed chromatin over time, which may be associated with cell differentiation in the body. The loss of repression markers should sooner or later lead to derepression of dormant transposons and, accordingly, to an increase in the amount of DNA damage caused by them with subsequent activation cellular systems DNA repair. The latter, in addition to participating in DNA repair, also cause unauthorized recombinations in telomeres. It is also possible that transposon recombinases can directly initiate such recombinations. As a result, extended sections of telomeric DNA are converted into rings and lost, and telomeres are shortened by the length of the lost circular DNA. This process accelerates the loss of telomeric DNA tens of times, and the subsequent apoptosis of most cells determines aging as a biological phenomenon. The proposed theory is an alternative to the hypothesis of genetically programmed aging and the hypothesis of aging as a consequence of the accumulation of errors and damage, explains the mechanism of accelerated telomere loss in the case of oxidative stress and DNA damage, as well as the relationship between aging and the occurrence of tumors.

Evolutionary genetic approach. The hypothesis that formed the basis of the genetic approach was proposed by Peter Medawar in 1952 and is now known as the “mutations accumulation theory.” Medawar noted that animals in nature very rarely live to an age when aging becomes noticeable. According to his idea, alleles that emerge late in life and that arise from mutations in germ cells are subject to fairly weak evolutionary pressure, even if traits such as survival and reproduction suffer as a result. Thus, these mutations can accumulate in the genome over many generations. However, any individual that has managed to avoid death for a long time experiences their effects, which manifests itself as aging. The same is true for animals in protected environments.

Subsequently, in 1957, D. Williams proposed the existence of pleiotropic genes, which have different effects on the survival of organisms during different periods of life, that is, they are useful at a young age, when the effect of natural selection is strong, but harmful later, when the effect of natural selection is weak . This idea is now known as “antagonistic pleiotropy.”

Together, these two theories form the basis of modern understanding of the genetics of aging. However, identification of the genes responsible has had only limited success. Evidence for the accumulation of mutations remains controversial, while evidence for the presence of pleiotropic genes is stronger, but also poorly substantiated. Examples of pleiotropic genes include the telomerase gene in eukaryotes and sigma factor 70 in bacteria. Although many genes are known to influence lifespan in various organisms, no other clear examples of pleiotropic genes have yet been discovered.

Evolutionary-physiological approach. The theory of antagonistic pleiotropy predicts that there should be genes with a pleiotropic effect, the natural selection of which leads to the occurrence of aging. Several genes with a pleiotropic effect at different stages of life were indeed found - sigma-70 in E. coli, telomerase in eukaryotes, but a direct connection with aging was not shown, much less it was not shown that this is a typical phenomenon for all organisms, responsible for everything effects of aging. That is, these genes can only be considered as candidates for the role of genes predicted by theory. On the other hand, a number physiological effects shown without identifying the genes responsible for them. We can often talk about trade-offs similar to those predicted by antagonistic pleiotropy theory without clearly identifying the genes on which they depend. The physiological basis for such compromises is laid down in the so-called “disposable soma theory”. This theory asks how the body should allocate its resources (in the first version of the theory it was only about energy) between the support and repair of the soma and other functions necessary for survival. The need for compromise arises from limited resources or the need to choose the best way to use them.

Maintenance of the body should be carried out only as far as is necessary during the normal period of survival in nature. For example, since 90% of wild mice die within the first year of life, mostly from exposure, the investment of resources in long-term survival will only affect 10% of the population. Thus, the three-year lifespan of mice is completely sufficient for all the needs of nature, and from an evolutionary point of view, resources should be spent, for example, on improving heat conservation or reproduction, instead of fighting old age. Thus, the lifespan of a mouse best corresponds to the environmental conditions of its life.

The “disposable body” theory makes several assumptions that relate to the physiology of the aging process. According to this theory, aging results from nonideal repair and maintenance functions of somatic cells that are adapted to meet environmental demands. Damage, in turn, is the result of stochastic processes associated with the life of cells. Longevity is controlled through the control of genes that are responsible for these functions, and the immortality of generative cells, unlike somatic cells, is the result of large expenditures of resources and, possibly, the absence of some sources of damage. OPARIN-HAILDEN THEORY OF THE ORIGIN OF LIFE SYSTEM-STRUCTURAL ORGANIZATION AND SELF-ORGANIZATION IN LIVING NATURE Carbohydrates

Introduction

1. Theories of aging

2.2 Werner syndrome

2.3 Rothmund-Thomson syndrome

2.4 Cockayne syndrome

2.5 Down syndrome

5. Genes for human longevity

Conclusion

Introduction

Life expectancy is a complex quantitative trait. Identifying the genetic mechanisms of its formation is a fundamental problem in developmental biology, evolutionary genetics and molecular gerontology.

Aging in biology is the process of gradual inhibition of the basic functions of the body, including regenerative and reproductive, as a result of which the body becomes less adapted to the conditions environment(loses the ability to withstand stress, illness and injury), which makes the death of the body inevitable. Even under favorable laboratory conditions, aging occurs in the vast majority of animal species.

Aging occurs at different rates in different species, which seems to indicate that aging is caused not only by mechanical wear and tear, but also by genetic factors. Aging is a complex process of interaction between genes and environment, regulated by stress, metabolic factors and reproduction, as well as protective systems at the cellular, tissue and organism levels. Genomic regulation does not yet prove that aging is “programmed.” Changes in the activity (expression) of certain genes observed during aging may be a response to random damage (molecular errors, oxidative stress) or reflect side pleiotropic (multiple) effects of genes that control growth, development and metabolism.

1. Theories of aging

· Molecular genetic theory (The theory according to which the main cause of aging is the aging of the cell’s genetic apparatus. One of the main theories today)

· Telomere theory (In America in 1961, the gerontologist L. Hayflick established that human fibroblasts - skin cells capable of dividing - “in vitro” can divide no more than 50 times. The theory was not developed or approved by colleagues.)

· Elevation (ontogenetic) theory of aging (The main cause of aging is an age-related decrease in the sensitivity of the hypothalamus to regulatory signals coming from the nervous system and endocrine glands)

· Adaptation-regulatory theory(The theory of aging, developed by the famous Ukrainian physiologist and gerontologist V.V. Frolkis in the 1960-70s, is based on the widespread idea that death and old age are genetically programmed)

· Free radical theory(According to this theory, the cause of cell dysfunction is free radicals - reactive oxygen species, necessary for many biochemical processes, synthesized mainly in mitochondria - the energy factories of cells.)

· Aging is a mistake(The basis of the theory was that radiation causes cell mutation, which leads to aging of the body as a whole)

· Theory of apoptosis (cell suicide) (Academician V.P. Skulachev calls his theory the theory of cell apoptosis. Apoptosis is the process of programmed cell death.)

aging longevity gene theory

2. Hereditary premature aging

2.1 Hutchinson-Gilford syndrome

An extremely rare disease. Its incidence is 1 in 1,000,000 people. The patients’ phenotype is extremely characteristic: small stature, “bird-like face” with a beak-like profile, predominance of the size of the brain part of the skull over the facial part, a protruding venous network on the skin of the brain part, usually bare due to alopecia, often total, with loss of eyebrows and eyelashes. There is a sharp hypoplasia of the collarbones, defects in the shape and number of teeth, dry, thin skin, an almost complete absence of subcutaneous fatty tissue, and developmental delays, especially physical development. The patients are infertile, although the literature describes a case of the birth of a child in a patient with Hutchinson-Gilford syndrome. The average life expectancy of the described carriers of the syndrome is 13 years (a single 45-year-old patient was described as a rare observation). The cause of death, as a rule, is myocardial infarction, with autopsy revealing generalized atherosclerosis and myocardial fibrosis, as well as deposition of a fat-like substance in the tissues of the brain and parenchymal organs.

DNA repair in Hutchinson-Gilford syndrome is impaired: it has been established that the cells of its carriers are not able to get rid of DNA-protein cross-links caused by chemical agents. But the main diagnostic feature of cells from patients with this syndrome is the sharply reduced, compared to the norm, number of divisions that cells in culture are able to undergo (the so-called limit, or Hayflick number). In 1971 A.M. Olovnikov suggested that chromosomal telomeres shorten during cell development. And in 1992, it was shown that cells from patients with Hutchinson-Gilford syndrome are characterized by congenital shortening of telomeres. Analysis of the relationship between the Hayflick limit, telomere length and the activity of telomerase (an enzyme capable of extending the end of telomeric DNA) makes it possible to correlate natural aging and the process of formation of the clinical picture in Hutchinson-Gilford syndrome.

Extremely low frequency The occurrence of this form of progeria allows us only to make hypotheses about the type of inheritance. The autosomal recessive type suggests certain features of premature aging.

2.2 Werner syndrome

The cause of this disease is the defective development of the pituitary gland (the main endocrine gland, located at the base of the brain; regulates the action of the hormonal system) even in the prenatal period as a result of infection, intoxication, or injury suffered by a pregnant woman. A hereditary predisposition to defective development of the pituitary gland is also possible.

Symptoms and signs:

§ manifested by skin pathology - areas of wasting, atrophy, ulceration or areas of skin thickening

§ premature baldness and graying of hair

§ cysts are sometimes found in the pituitary gland

§ patients are short (dwarf stature) with atrophied genitals

§ Occasionally, gynecomastia occurs (development of the mammary glands in a man according to the female type with some endocrine diseases)

§ often there are bulging eyes and cataracts (clouding of the eye lens)

§ complaints of fatigue

§ X-ray examination often reveals calcification of the arteries, osteoporosis (a disease characterized by a decrease in bone density; the chemical composition of the bone does not change, but its density decreases, strength decreases and the likelihood of fractures increases)

§ at laboratory diagnostics an increased level of sugar in the blood and a decrease in the level of 17-ketosteroids in the urine are detected (read the article “17-ketosteroids” on the website)

Werner syndrome (WS) (adult progeria) is a rare hereditary autosomal recessive connective tissue disease (M1M 272,700). Manifested by premature aging of the skin, damage to the nervous, endocrine, skeletal and other body systems, as well as an increased risk of developing malignant neoplasms internal organs and skin: sarcomas, melanomas, non-melanotic skin cancers, skin lymphomas, etc. Men aged 20-30 years are more often affected. The molecular basis of VS is associated with mutations in the WRN gene, which encodes DNA helicase. In patients with VS, a decrease in the activity of natural killer cells was noted, which may be the reason for the increased incidence of tumors. However, the relationship of VS with other premature aging syndromes, such as metageria, acrogeria, and progeria, has not been determined.

Both syndromes are characterized by accelerated development of the usual signs of natural aging, but in the first case they begin to develop from birth and patients rarely live beyond 20 years. In the second case, accelerated aging begins from puberty and life expectancy can reach 30-40 years. It is noted that death occurs due to the decline of functions characteristic of extreme old age or from typical age-related pathologies, including cancer, heart failure, brain disorders and other diseases. Recently, the Werner syndrome gene (WRN) was cloned.

2.3 Rothmund-Thomson syndrome

a rare hereditary symptom complex characterized by specific skin lesions (poikiloderma, hyperkeratosis), cataracts, photosensitivity, dystrophy of hair, nails, teeth, short stature, hypogonadism, impaired ossification, and an increased risk of developing malignant neoplasia. In rare cases, mental retardation may occur. Range and severity clinical signs may vary widely among patients.

This syndrome was first described by the German ophthalmologist August von Rothmund Jr. in 1868, who noted the combination of bilateral cataracts with a peculiar skin lesion (dyschromia, telangiectasia) in a child from an isolated degenerate Alpine village.

Much later, in 1923, the British dermatologist M. S. Thomson described a “hitherto undescribed hereditary disease" and called it "poikiloderma congenita", the characteristics of the clinical picture of which were identical skin manifestations, noted earlier by Rothmund (apparently, the author did not know about the publication of the German ophthalmologist). At the same time, Thomson did not note eye damage in the patient, which was the reason for identifying an independent nosology named in his honor.

At the same time, a number of authors deny the existence of Thomson syndrome, pointing to the possibility of the formation of the so-called “incomplete” Rothmund syndrome, in which clinical picture There is no disease, cataracts. An attempt to reconcile differing points of view was made by P. Wodniansky, proposing to use a single designation for these symptoms - “congenital poikiloderma”.

In the last three decades, the opinion that the syndromes are identical has prevailed, which led to the mention of the names of both authors in the nosological designation of the disease - Rothmund-Thomson syndrome. And finally, O. Braun-Falco chose the term “Rothmund-Thomson syndrome”, emphasizing that cataracts develop in approximately 50% of patients.

2.4 Cockayne syndrome

It is inherited in an autosomal recessive manner, with men and women affected with equal frequency. In the case of the development of this pathology, you can notice atrophic changes in the skin and subcutaneous fatty tissue, the thickness of which noticeably decreases, increased sensitivity to sunlight occurs, the size of the head is excessively small, as you grow, disproportionate dwarfism becomes more and more distinct, signs appear mental retardation. A more thorough examination in a specialized hospital reveals pathological changes in the organ of vision ( degenerative changes retina, optic nerve atrophy). Such people often suffer from hearing loss, even to the point of deafness. In addition, disorders of the nervous system (ataxia, peripheral neuropathy) are often observed.

Children with this hereditary pathology are born absolutely normal, completely indistinguishable from healthy ones. Signs of the disease can develop very early, at the age of 6 months, but in most cases begin to appear in the 2-3rd year of life. The first manifestation of Cockayne syndrome is increased sensitivity to sunlight in exposed areas of the body, which is expressed in the appearance of swelling and redness after sun exposure, which are located on the face in the form of a butterfly. Sometimes bullous rashes may appear. In addition, the child begins to noticeably lag behind his peers in growth, and also lags behind in weight, mental development, characterized by emotional instability, disturbances in gait and speech. Patients have a characteristic appearance: emaciated, short stature, small head, senile appearance, birdlike nose, sunken eyes, large ears, upper jaw protrudes excessively forward, the front teeth are strongly inclined forward, the limbs are disproportionately long, the hands and feet are large, the skin of the tip of the nose, ears, fingers and lips is bluish, the joints are deformed, there is a curvature of the spine, the chest is narrow. When conducting x-ray examination thickening of the skull bones, deposits of calcium salts in the cranial cavity and some other characteristic signs of the syndrome in question are detected. As a result of congenital underdevelopment of the glands, the intensity of sweat and tear production is reduced, the hair is thin, sparse, and turns gray early. In addition to changes in the retina, the appearance of photophobia, clouding of the cornea, and cataracts can be noted. Nervous system disorders usually include stuttering and abnormal movements. eyeballs. Sexual development is impaired in most cases. The prognosis for this syndrome is unfavorable, the disease is constantly progressing, in most cases ending in death between 20 and 30 years from the consequences of vascular atherosclerosis.

2.5 Down syndrome

Occurs as a result of a genetic abnormality. The signs of people with Down syndrome were first described in 1866 by the English physician John Langdon Down, whose name served as the name for this syndrome.

Down syndrome occurs as a result of a genetic abnormality. The signs of people with Down syndrome were first described in 1866 by the English physician John Langdon Down, whose name served as the name for this syndrome. The cause of the syndrome was discovered only in 1959 by the French scientist Jerome Lejeune.

The syndrome occurs due to the process of chromosome divergence during the formation of gametes (eggs and sperm), as a result of which the child receives an extra 21st chromosome from the mother (in 90% of cases) or from the father (in 10% of cases). Most patients with Down syndrome have three 21st chromosomes instead of the required two; in 5–8% of cases, the anomaly is associated with the presence not of a whole extra chromosome, but of its fragments.

Of the characteristic external signs The syndrome is characterized by a flat face with slanted eyes (like the Mongoloid race, which is why this disease was previously called mongolism), wide lips, a wide flat tongue with a deep longitudinal groove on it. Round head, sloping narrow forehead, ears reduced in the vertical direction, with an attached lobe, eyes with a spotted iris (Brushfield's spots). The hair on the head is soft, sparse, straight with a low growth line on the neck. People with Down syndrome are characterized by changes in the limbs - shortening and expansion of the hands and feet (acromicria). The little finger is shortened and curved, there are only two flexion grooves on it. On the palms there is only one transverse groove (four-fingered). There are abnormal growth of the teeth, a high palate, changes in the internal organs, especially the alimentary canal and the heart.

3. Genes of death and longevity in Drosophila melanogaster

Fruit fly Drosophila melanogaster - good model to study the genetic components of longevity. As with C. elegans, Drosophila mutants with different lifespans have been induced by chemical mutagenesis. Among the resulting lines, some had mutations in the superoxide dismutase (SOD) gene. Mutants homozygous for this gene developed normally, but their duration adult life decreased from 60 to 10 days. It has been shown that such mutants have increased sensitivity to substances that produce free radicals, and their sperm is not active enough. This may indicate the importance of SOD in protecting DNA from damage during gametogenesis. On the other hand, individuals with an increased number of copies of the SOD and catalase genes had a longer average and maximum life expectancy. Accelerated aging in D. melanogaster results not only from mutations in specific genes, but also from changes in the expression of epigenetic factors. Thus, in old flies it was found a sharp decline protein expression of the elongation factor EF-la, which precedes a general decrease in protein synthesis. Adding additional copies of the EF-la gene to the fly genome through genetic manipulation led to a significant increase in the lifespan of these flies.

Among fruit fly lines with a P element insertion, long-lived Indy (I am not dead yet) mutants with a twofold increased average lifespan and a 50% increased maximum lifespan were discovered (Rogina et al., 2000). This gene encodes a protein homologous to the mammalian Na-dicarboxylase transporter, which is responsible for the uptake and reuptake of Krebs cycle substrates such as succinic acid, citrate, and alpha-ketoglutarate.

Also, a mutation in the receptor for the steroid hormone ecdysone leads to an increase in the life expectancy of fruit flies. (Simon et al., 2003). Heterozygous flies with such mutations live 40-50% longer than wild-type flies and are characterized by increased resistance to stress. They lack defects in oogenesis and spermatogenesis, which suggests that the increase in life expectancy in these mutants is due to changes in the reproductive system.

4. Telomere theory of aging

American biochemist and gerontologist L. Hayflick L. in 1961. Studies have been published on the lifespan of human fibroblasts in vitro. It was found that cells can divide (and therefore self-renew) no more than 50 times. This phenomenon is called the Hayflick limit. The scientist himself was unable to offer a sufficiently substantiated explanation for the discovered phenomenon. Later, in 1971 Researcher at the Institute of Biochemical Physics of the Russian Academy of Sciences A.M. Olovnikov, using data on the principles of DNA synthesis in cells, proposed a hypothesis according to which the “Hayflick limit” is explained by the fact that with each cell division the chromosomes are slightly shortened. Chromosomes have special end sections - telomeres, which after each doubling of chromosomes become slightly shorter, and at some point shorten so much that the cell can no longer divide. Then it gradually loses its viability - this, according to the telomeric theory, is what cell aging consists of.

Some cells are able to divide constantly. For example, sex cells. There are known cultures of cancer cells that continue dividing for more than a hundred years. This phenomenon found an explanation in 1985, when an enzyme was discovered that allows the restoration of a reduced section of DNA - telomerase. This discovery, in turn, supported the telomerase theory of aging.

It was also found that the limit is 50-80 divisions human cells should be exhausted in an approximate time of 120 years, but in most cases we do not see this, and by the end of the life of the organism, telomeres are shortened, as if the cell divided exactly 60 times. This is explained by the fact that telomeres do not shorten evenly. Using regression analysis of data on the rate of telomere shortening in human cells from 15 different tissues and organs, ( Takubo et al. 2002) found that they shorten on average by 20-60 base pairs per year. The authors emphasize that telomere length does not have a clear correlation with the time of cell renewal in vivo and is rather an individual characteristic. Telomerase may be the key to the gates of immortality. But there are cells in which telomerase activity is sharply increased and the cells continue to divide - cancer cells. Further study of the mechanisms of telomerase activity continues.

5. Genes for human longevity

It is currently accepted that only one gene, apolipoprotein E (ApoE), is essential for human longevity. In centenarians, a clear predominance of the ApoE E2 allele over the E4 allele was revealed (Schachter et al., 1994). In contrast, a predominance of the E4 allele predisposes to hypercholesterolemia, coronary heart disease, and Alzheimer's disease (but not cancer or diabetes). In individuals over 90 years of age, the risk of Alzheimer's disease associated with ApoE E4 reaches a plateau. Moreover, some centenarians with the E4/E4 polymorphism are completely intact mentally, and it is unknown whether this is determined by the protective effect of some gene or simply by chance (Finch and Ruvkun, 2001). It is believed that ApoE should be considered a frailty gene rather than a longevity gene (Gerdes et al., 2000). The genes that determine the MHC haplotype, methylene tetrafolate reductase and angiotensin-converting enzyme can also claim the role of genes that determine longevity (or “frailty”).

The p53 protein gene is also extremely important both for controlling the evolution of cancer cells, limiting their uncontrolled growth and even causing regression of tumors, and for cellular aging, performing the function of removing old, non-functioning cells. The p53 protein behaves as an antioncogene: its introduction into transformed cells suppresses their uncontrolled proliferation. It was found that while normal p53 is involved in the control of tissue growth by activating genes involved in growth suppression, its mutant forms can interfere with this process and initiate tumor formation. Mutations of the p53 gene are the most common mutations in human tumor cells and have been found in tumors various localizations(Rodin, Rodin, 1998). Recently, there has been evidence that the klotho locus is associated with human survival, defined as postnatal life expectancy, and is also associated with longevity, defined as life expectancy after age 75 years (Arking et al., 2002).

The apolipoprotein E (ApoE) and angiotensin-converting enzyme (ACE) genes play an important role in lipid metabolism, and since cardiovascular diseases are the leading cause of death in humans, they directly affect life expectancy.

It has been established that caloric restriction of almost all biological objects is accompanied by an increase in life expectancy. The key biological parameter in this case is low levels of insulin and IGF-1. It is logical to assume that genetically determined changes in the genome, leading to the effects of calorie restriction, can be realized by an increase in individual life expectancy.

In general, the results of studies of candidate genes for human longevity are quite contradictory. To a large extent, these contradictions may be due to the heterogeneity of the population and problems of adequate selection of individuals both for the study group and for control

Conclusion

Data obtained in experiments with lower organisms (yeast, nematode, Drosophila) indicate that aging and longevity to a certain extent depend on the response to various stress factors (De Benedictis et al., 2001). In vertebrates, the immuno-neuroendocrine self-regulatory system is capable of functioning effectively for a long time, despite the damage that accumulates with age. In this regard, the developed by S. Franceschi et al deserves attention. (2000c) view that mammalian aging is a consequence of chronic stress. The ability to recover from stress decreases with age. In genetically heterogeneous human populations, the dynamics of the ability to maintain an adequate response to stress, that is, within limits comparable to the reaction of healthy individuals, is very similar to the dependence of survival on age (De Benedictis et al., 2001). Healthy centenarians (Franceschi et al., 2000a) appear to represent the very tail of this curve, which is formed by the most effectively adapting individuals, that is, those who have the ability to constantly “reconfigure” themselves in the face of challenges that arise over time.

List of sources used

1. Frolkis V.V. / Aging and increasing life expectancy. / L.: Nauka, 1988.

Vilenchik M.M. / Biological basis of aging and longevity. / M.: Medicine, 1986.

Konev V.S. / Encyclopedia of longevity. / 2003.

Anisimov V.N. Priority areas of fundamental research in gerontology: the contribution of Russia. Successes gerontol. 2003; T.12. P.9-27.

Moskalev AA Genetics and epigenetics of aging and longevity / Ecological Genetics, 2013. T.11, N1. P.3-11

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July 11, 2008

The mechanisms of aging are quite complex and diverse. Today there are several alternative theories, which partly contradict each other and partly complement each other. Modern biology pays great attention to the problem of aging, and every year new facts appear that allow us to better understand the mechanisms of this process.

MOLECULAR GENETIC THEORIES

The hypothesis according to which the cause of aging is changes in the genetic apparatus of the cell is one of the most recognized in modern gerontology.

Molecular genetic theories are divided into two large groups. Some scientists consider age-related changes in the genome as hereditarily programmed. Others believe that aging is the result of the accumulation of random mutations. It follows that the aging process can be either a natural result of the growth and development of the body, or a consequence of the accumulation of random errors in the system of storage and transmission of genetic information.

Telomere theory

In 1961, the American gerontologist L. Hayflick established that human fibroblasts - skin cells capable of dividing - “in vitro” can divide no more than 50 times. In honor of its discoverer, this phenomenon was called the “Hayflick limit.” However, Hayflick offered no explanation for this phenomenon. In 1971, researcher at the Institute of Biochemical Physics of the Russian Academy of Sciences A.M. Olovnikov, using data on the principles of DNA synthesis in cells, proposed a hypothesis according to which the “Hayflick limit” is explained by the fact that with each cell division the chromosomes are slightly shortened. Chromosomes have special terminal sections - telomeres, which after each doubling of chromosomes become slightly shorter, and at some point shorten so much that the cell can no longer divide. Then it gradually loses its viability - this, according to the telomere theory, is what cell aging consists of. The discovery in 1985 of the telomerase enzyme, which completes shortened telomeres in germ cells and tumor cells, ensuring their immortality, was a brilliant confirmation of Olovnikov’s theory. True, the limit of 50-60 divisions is not true for all cells: cancer and stem cells can theoretically divide indefinitely; in a living organism, stem cells can divide not tens, but thousands of times, but the connection between cell aging and telomere shortening is generally accepted. It is curious that the author himself recently decided that the telomeric hypothesis does not explain the causes of aging, and first put forward another one, the redusomal one, and then a second, no less fantastic one - the lunar-gravitational one. Both of them received neither experimental confirmation nor peer approval.

Elevation (ontogenetic) theory of aging

In the early 1950s, the famous Russian gerontologist V.M. Dilman put forward and substantiated the idea of ​​the existence of a single regulatory mechanism that determines the patterns of age-related changes in various homeostatic (maintaining the constancy of the internal environment) systems of the body. According to Dilman's hypothesis, the main link in the mechanisms of both development (Latin elevatio - rise, in a figurative sense - development) and subsequent aging of the body is the hypothalamus - the “conductor” of the endocrine system. The main cause of aging is an age-related decrease in the sensitivity of the hypothalamus to regulatory signals coming from the nervous system and endocrine glands. Throughout the 1960-80s. With the help of experimental studies and clinical observations, it was established that it is this process that leads to age-related changes in the functions of the reproductive system and the hypothalamic-pituitary-adrenal system, which ensures the necessary level of glucocorticoids produced by the adrenal cortex - “stress hormones”, daily fluctuations in their concentration and increased secretion during stress, and, ultimately, to the development of a state of so-called “hyperadaptosis”.
According to Dilman's concept, aging and related diseases are a by-product of the implementation of the genetic program of ontogenesis - the development of the body. The ontogenetic model of age-related pathology has opened up new approaches to the prevention of premature aging and diseases associated with age and which are the main causes of human death: heart disease, malignant neoplasms, strokes, metabolic immunosuppression, atherosclerosis, diabetes mellitus in the elderly and obesity, mental depression, autoimmune diseases and some others. diseases. From the ontogenetic model it follows that the development of diseases and natural senile changes can be slowed down if the state of homeostasis is stabilized at the level achieved by the end of the development of the organism. If you slow down the rate of aging, then, as V.M. believed. Dilman, it is possible to increase the species limits of human life.

Adaptation-regulatory theory

The aging model developed by the outstanding Ukrainian physiologist and gerontologist V.V. Frolkis in the 1960s and 70s, is based on the widespread idea that old age and death are genetically programmed. The “highlight” of Frolkis’ theory is that age-related development and life expectancy are determined by the balance of two processes: along with the destructive process of aging, the process of “antiaging” unfolds, for which Frolkis proposed the term “vitauct” (Latin vita - life, auctum - increase) . This process is aimed at maintaining the vitality of the body, its adaptation, and increasing life expectancy. The concept of anti-aging (vitauct) has become widespread. Thus, in 1995, the first international congress on this problem was held in the USA.

An essential component of Frolkis' theory is the gene regulatory hypothesis he developed, according to which the primary mechanisms of aging are disruptions in the functioning of regulatory genes that control the activity of structural genes and, as a result, the intensity of synthesis of the proteins encoded in them. Age-related disorders of gene regulation can lead not only to changes in the ratio of synthesized proteins, but also to the expression of previously inactive genes, the appearance of previously unsynthesized proteins and, as a result, to aging and cell death.

V.V. Frolkis believed that gene regulatory mechanisms of aging are the basis for the development of common types of age-related pathologies - atherosclerosis, cancer, diabetes, Parkinson's and Alzheimer's diseases. Depending on the activation or suppression of the functions of certain genes, one or another aging syndrome, one or another pathology will develop. Based on these ideas, the idea of ​​gene regulatory therapy was put forward, designed to prevent changes that underlie the development of age-related pathology.

STOCHASTIC (PROBABILITY) THEORIES

According to this group of theories, aging is the result of random processes at the molecular level. We talked about this above: many researchers believe that aging is a consequence of the accumulation of random mutations in chromosomes as a result of wear and tear of DNA repair mechanisms - correcting errors when copying it during cell division.

Free radical theory

Almost simultaneously put forward by D. Harman (1956) and N.M. Emanuel (1958), the free radical theory explains not only the mechanism of aging, but also a wide range of associated pathological processes (cardiovascular diseases, weakened immunity, brain dysfunction, cataracts , cancer and some others). According to this theory, the cause of cell dysfunction is free radicals, which are necessary for many biochemical processes - reactive oxygen species, synthesized mainly in mitochondria - the energy factories of cells.

If a very aggressive, chemically active free radical accidentally leaves the place where it is needed, it can damage DNA, RNA, proteins, and lipids. Nature has provided a mechanism for protecting against excess free radicals: in addition to superoxide dismutase and some other enzymes synthesized in mitochondria and cells, many substances that enter the body with food have an antioxidant effect - incl. vitamins A, C and E. Regular consumption of vegetables and fruits and even a few cups of tea or coffee a day will provide you with an adequate dose of polyphenols, which are also good antioxidants. Unfortunately, an excess of antioxidants - for example, with an overdose of dietary supplements - is not only not beneficial, but can even increase oxidative processes in cells.

Aging is a mistake

The “aging by mistake” hypothesis was put forward in 1954 by the American physicist M. Szilard. Studying the effects of radiation on living organisms, he showed that the effect of ionizing radiation significantly shortens the lifespan of people and animals. Under the influence of radiation, numerous mutations occur in the DNA molecule and initiate some symptoms of aging, such as gray hair or cancerous tumors. From his observations, Szilard concluded that mutations are the direct cause of aging in living organisms. However, he did not explain the fact of aging of people and animals that were not exposed to radiation.

His follower L. Orgel believed that mutations in the genetic apparatus of a cell can be either spontaneous or occur in response to exposure to aggressive factors - ionizing radiation, ultraviolet radiation, exposure to viruses and toxic (mutagenic) substances, etc. Over time, the DNA repair system wears out, causing the body to age.

Theory of apoptosis (cell suicide)

Academician V.P. Skulachev calls his theory the theory of cell apoptosis. Apoptosis (Greek: leaf fall) is the process of programmed cell death. Just as trees get rid of parts in order to preserve the whole, so each individual cell, having gone through its life cycle, must die off and a new one must take its place. If a cell becomes infected with a virus, or a mutation occurs in it leading to malignancy, or its lifespan simply expires, then in order not to endanger the entire organism, it must die. Unlike necrosis - violent cell death due to injury, burn, poisoning, lack of oxygen as a result of blockage of blood vessels, etc., during apoptosis the cell carefully disassembles itself into parts, and neighboring cells use its fragments as building material.
Mitochondria also undergo self-destruction - having studied this process, Skulachev called it mitoptosis. Mitoptosis occurs when too many free radicals are produced in the mitochondria. When the number of dead mitochondria is too high, their breakdown products poison the cell and lead to its apoptosis. Aging, from Skulachev’s point of view, is the result of the fact that more cells die in the body than are born, and dying functional cells are replaced by connective tissue. The essence of his work is the search for methods to counteract the destruction of cellular structures by free radicals. According to the scientist, old age is a disease that can and should be treated; the body’s aging program can be disabled and thereby turn off the mechanism that shortens our lives.

According to Skulachev, the main active form of oxygen that leads to the death of mitochondria and cells is hydrogen peroxide. Currently, under his leadership, the drug SKQ, designed to prevent signs of aging, is being tested.

All theories of aging can be divided into two large groups: evolutionary theories and theories based on random cell damage. The first believe that aging is not a necessary property of living organisms, but a programmed process. According to them, aging developed as a result of evolution due to some advantages it provides to an entire population. In contrast, damage theories suggest that aging is the result of a natural process of accumulation of damage that the body tries to combat, and that differences in aging between organisms result from differences in the effectiveness of this fight. The latter approach is now considered established in the biology of aging. However, some researchers still defend the evolutionary approach, and some others completely ignore the division between evolutionary and damage theories. The latter statement is partly the result of a change in terminology: in some recent work, the term "evolutionary theories" refers not to theories of "programmed aging", which propose the evolutionary emergence of aging as a beneficial phenomenon, but to an approach that describes why organisms should age, as opposed to the question of the biochemical and physiological basis of aging. The hormonal-genetic approach is that during a person’s life, starting from birth, there is an increase in the sensitivity threshold of the hypothalamus, which ultimately, after 40 years, leads to hormonal imbalance and progressive disruption of all types of metabolism, including hypercholesterolemia. Therefore, treatment of diseases of old age must begin with improving the sensitivity of the hypothalamus. There are also many other theories, such as the mutation accumulation theory, mitochondrial theory, free radical theory, etc.

Why does aging occur? Let's consider the main approaches to this issue.

Evolutionary genetic approach. The hypothesis that formed the basis of the genetic approach was proposed by Peter Medawar in 1952 and is now known as the “mutation accumulation theory.” Medawar noted that animals in nature very rarely live to an age when aging becomes noticeable. According to his idea, alleles that emerge late in life and that arise from mutations in germ cells are subject to fairly weak evolutionary pressure, even if traits such as survival and reproduction suffer as a result. Thus, these mutations can accumulate in the genome over many generations. However, any individual that has managed to avoid death for a long time experiences their effects, which manifests itself as aging. The same is true for animals in protected environments.

Antagonistic pleiotropy. Subsequently, in 1957, D. Williams proposed the existence of pleiotropic genes, which have different effects on the survival of organisms during different periods of life, that is, they are useful at a young age, when the effect of natural selection is strong, but harmful later, when the effect of natural selection is weak . Together, these two theories form the basis of modern understanding of the genetics of aging. However, identification of the genes responsible has had only limited success. Evidence for the accumulation of mutations remains controversial, while evidence for the presence of pleiotropic genes is stronger, but also poorly substantiated. Examples of pleiotropic genes include the telomerase gene in eukaryotes and the sigma factor γ70 in bacteria. Although many genes are known to influence lifespan in various organisms, no other clear examples of pleiotropic genes have yet been discovered.

Evolutionary-physiological approach.

The theory of antagonistic pleiotropy predicts that there should be genes with a pleiotropic effect, the natural selection of which leads to the occurrence of aging. Several genes with a pleiotropic effect at different stages of life were indeed found - sigma-70 in bacteria, telomerase in eukaryotes, but a direct connection with aging was not shown, much less it was not shown that this is a typical phenomenon for all organisms, responsible for all the effects aging. That is, these genes can only be considered as candidates for the role of genes predicted by theory. On the other hand, a number of physiological effects are shown without identifying the genes responsible for them. We can often talk about trade-offs similar to those predicted by antagonistic pleiotropy theory without clearly identifying the genes on which they depend. The physiological basis for such trade-offs lies in the so-called “disposable soma theory.”

This theory asks how the body should allocate its resources (in the first version of the theory it was only about energy) between the support and repair of the soma and other functions necessary for survival. The need for compromise arises from limited resources or the need to choose the best way to use them. Maintenance of the body should be carried out only as far as is necessary during the normal period of survival in nature. For example, since 90% of wild mice die within the first year of life, mostly from exposure, the investment of resources to survive over the long term will concern only 10% of the population. Thus, the three-year lifespan of mice is completely sufficient for all the needs of nature, and from an evolutionary point of view, resources should be spent, for example, on improving heat conservation or reproduction, instead of fighting old age. Thus, the lifespan of a mouse best corresponds to the environmental conditions of its life. The “disposable body” theory makes several assumptions that relate to the physiology of the aging process. According to this theory, aging results from nonideal repair and maintenance functions of somatic cells that are adapted to meet environmental demands. Damage, in turn, is the result of stochastic processes associated with the life of cells. Longevity is controlled through the control of genes that are responsible for these functions, and the immortality of generative cells, unlike somatic cells, is the result of large expenditures of resources and, possibly, the absence of some sources of damage.

"Free radical theory of aging." There is evidence of several important mechanisms of damage to macromolecules, which usually act in parallel with one another or depend on one another. It is likely that any of these mechanisms may play a dominant role under certain circumstances. Reactive oxygen species (in particular, free radicals) play an important role in many of these processes, and evidence of their influence has been available for quite some time. Today, however, the mechanisms of aging are much more detailed.

Theory of somatic mutations. Many studies have shown an increase in somatic mutations and other forms of DNA damage with age, suggesting DNA repair as an important factor in supporting cell longevity. DNA damage is typical for cells, and is caused by factors such as hard radiation and reactive oxygen species, and therefore DNA integrity can only be maintained through repair mechanisms. Indeed, there is a relationship between longevity and DNA repair. Higher PARP-1 levels are associated with longer lifespan.

Accumulation of altered proteins. Protein turnover is also important for cell survival, for which the appearance of damaged and excess proteins is critical. Oxidized proteins are a typical result of the influence of reactive oxygen species, which are formed as a result of many metabolic processes of the cell and often interfere with the correct functioning of the protein. However, repair mechanisms cannot always recognize damaged proteins and become less efficient with age. In some cases, proteins are part of static structures, such as the cell wall, that cannot be easily destroyed. Protein turnover also depends on chaperone proteins, which help proteins obtain the required conformation. With age, there is a decrease in repair activity, although this decrease may be the result of an overload of damaged proteins. There is evidence that the accumulation of damaged proteins does occur with age and may be responsible for age-associated diseases such as Alzheimer's disease, Parkinson's disease and cataracts.

Mitochondrial theory. The mitochondrial theory of aging was first proposed in 1978. Its essence lies in the fact that the slowdown in the proliferation of mitochondria in highly differentiated cells due to a deficiency of mitochondrial proteins encoded in the nucleus creates conditions for the emergence and selective selection of defective deletion mtDNA, an increase in the proportion of which gradually reduces the energy supply of cells. In 1980, the radical mitochondrial theory of aging was proposed. The importance of the link between molecular stress and aging has been suggested based on observations of the effect of accumulation of mutations in mitochondrial DNA (mtDNA). These findings were reinforced by the observation that the number of cells lacking cytochrome c oxidase (COX) increases with age, which is associated with mtDNA mutations. Such cells often have disturbances in ATP production and cellular energy balance.

Telomere loss. In many human cells, the loss of the ability of cells to divide is associated with the loss of telomeres at the ends of chromosomes, which are lost after a certain number of divisions. This occurs due to the absence of the enzyme telomerase, which is usually expressed only in germ cells and stem cells. It has recently been discovered that oxidative stress (excessive production of reactive oxygen species) may also have an effect on telomere loss, significantly accelerating the process in certain tissues.

aging protein life telomere

Aging represents changes that affect all levels of organization of living matter, and these natural age-related changes in the body are called homeorez .

Today there are many theories trying to explain aging and adaptation-regulatory theory of aging and no less interesting apoptosis theory, but none of them is able to fully explain the complex process that occurs at all levels of the body, starting from the molecule, then the cell, tissue and organ. Indeed, every year the amount of new knowledge about this process increases, which leads to the birth of new theories of aging.

Telomere theory of aging

In the 1960s US gerontologist L. Hayflick found that human skin cells can divide only a limited number of times (from 40 to 60), but he could not explain this phenomenon. After 10 years, A.M. Olovnikov, at that time one of the employees of the Institute of Biochemical Physics of the Russian Academy of Sciences, based on Hayflick’s data, suggested that cell division limit due to the fact that with each cell division chromosome shortens a little.

Science knows that chromosomes have terminal sections ( telomeres ), which, due to doubling, gradually shorten, and over time the cell can no longer divide, and then it loses viability. This is what causes aging, according to the telomere theory. Olovnikov's hypothesis was challenged in the mid-1980s, when it was discovered telomerase enzyme , which was able to complete the shortened ends of chromosomes in tumor cells, which allowed them to be immortal. By the way, the limit of 50 divisions is not valid for every cell, for example, stem or cancer cells can be shared countless times.

By the way, A.M. himself Olovnikov subsequently decided that this theory did not explain the causes of aging, and he put forward redusomal theory of aging. In accordance with its postulates, linear DNA molecule redusomes (a redusome is a small nuclear particle located in the subtelomeric parts of the chromosome), gradually shortens due to a decrease in its linear DNA molecule covered proteins , which leads to a decrease in the various genes it contains. It is this shortening of redusomal DNA molecules that serves as a means of measuring biological time and is the cause of aging.

Elevation theory of aging (neuroendocrinological theory)

In the 1950s Soviet scientist V.M. Dilman put forward the idea that there is a single regulatory mechanism that determines the patterns of changes in various body systems associated with age. The main link of this mechanism is. More precisely, the main causes of aging are the decrease over time in the ability of the hypothalamus to sense blood levels, and its sensitivity to signals from the nervous system.

As a result, the amount of circulating hormones increases, which leads to various diseases characteristic of old age (, , diabetes , and others). All this leads to aging and death.

Subsequently, based on research and observation data, it was found that this is what leads to age-related changes in the functioning of the reproductive system. Dilman argued that aging is a byproduct ontogeny – development of the body. It was the elevation theory of aging that contributed to the discovery of new approaches to the prevention of premature aging and associated diseases.

Adaptation-regulatory theory of aging

was developed by Ukrainian gerontologist V.V. Frolkis in the 1960s. It is based on the idea that old age is a genetically programmed process, however V.V. Frolkis suggested that age-related development is determined by the balance of the aging process and the “anti-aging” process ( vituact ), aimed at increasing life expectancy. The scientist developed a gene regulatory hypothesis, according to which the primary mechanism of aging is disruption of the functioning of regulatory genes. And disruption of gene regulation leads to diabetes , atherosclerosis , And . The concept of gene regulatory therapy was immediately put forward to prevent the development of age-related pathologies.

Free radical theory

Apoptosis theory (cell suicide theory)

Belongs to academician V.P. Skulachev. According to the postulates of the theory, apoptosis is a programmed process of cell aging. Each cell, after passing through its life cycle or a mutation will occur in it, must die and give way to new, young cells. This hypothesis carries the same meaning as the telomere theory of aging. During apoptosis, the cell “disassembles itself”, and its parts can be used by neighboring cells as building material. The same thing happens with mitochondria if excess free radicals are formed in them. When there are too many dead mitochondria, their breakdown products lead to apoptosis, i.e. suicide. And aging occurs when fewer cells are born in the body than new ones are born.

The theory of "aging by mistake" (or the theory of somatic mutations)

This hypothesis was put forward by physicist M. Szilard in 1954 in the USA. According to his research, ionizing radiation shortens the lifespan of living organisms, and occurs in DNA molecules, which leads to aging. Thus, the cause of aging of the body, according to Szilard, is mutations . However, the theory of somatic mutations does not explain why people who have not been exposed to radiation age. Szilard's follower, M. Orgel, argued that with age, genetic damage accumulates in the body, caused by random mutations and caused by various factors ( stirrups , viruses , ultra-violet rays ), DNA damage accumulates, which leads to aging and wear and tear of the body.

There are also other theories of aging, for example, cross-linking theory, it has a similar meaning as the theory of free radicals, theory of disposable (consumable) dispute and some others.

Thus, the mechanisms of aging are complex. Today there are several theories that in some ways contradict each other, and in some ways complement one another. IN modern biology The problems of aging are receiving a lot of attention, and perhaps in the future, with increasing knowledge about this problem, a means will be found to slow down aging and prolong human life.

Education: Graduated from Vitebsk State medical University specialty "Surgery". At the university he headed the Council of the Student Scientific Society. Advanced training in 2010 - in the specialty "Oncology" and in 2011 - in the specialty "Mammology, visual forms of oncology".

Experience: Work in a general medical network for 3 years as a surgeon (Vitebsk Emergency Hospital medical care, Liozny Central District Hospital) and part-time as a district oncologist and traumatologist. Worked as a pharmaceutical representative for a year at the Rubicon company.

Presented 3 rationalization proposals on the topic “Optimization of antibiotic therapy depending on the species composition of microflora”, 2 works took prizes in the republican competition-review of student scientific works(categories 1 and 3).