Antagonistic pleiotropy and aging

Is antagonistic pleiotropy universal in the biology of aging?

Steven N Austad, Jessica M Hoffman: Is antagonistic pleiotropy ubiquitous in aging biology? Evolution, Medicine, and Public Health, 2018.

For references and references, see the original article.

Translated by Evgenia Ryabtseva

Resume

60 years ago, a hypothesis was proposed according to which the evolutionary mechanism of aging is a genetic compromise between fitness at a young age and mortality in old age. At that time, there was no genetic evidence in favor of this hypothesis, but by now they have accumulated quite a lot. Such compromises, known as antagonistic pleiotropy, are very common, and perhaps even universal. In 1957, an article by George Williams formulated the hypothesis of antagonistic pleiotropy in aging, the first hints of which were given by Peter Medawar. According to the hypothesis of antagonistic pleiotropy of aging, animals have genes that enhance fitness at an early age, but reduce it at later stages of life. At the same time, such genes may be preferred for natural selection, even if they cause the development of the aging phenotype, since the effect of selection is more pronounced in the early period of life. 60 years ago, none of the genes predicted by Williams were known, but the methods of modern molecular biology have made it possible to identify hundreds of genes whose strengthening, weakening or complete suppression of activity increases life expectancy and improves health in the laboratory. Is this a convincing proof of Williams' hypothesis? What applications does the Williams hypothesis have for the development of modern medical interventions aimed at improving human health and prolonging the period of healthy life? This article provides a brief overview of the current level of study of the issue of antagonistic pleiotropy in both natural and laboratory conditions. In general, in all cases when the effects of antagonistic pleiotropy have been seriously studied, they have been identified. However, not all compromises are made directly between reproductive ability and longevity, as is often believed. The identification of the prevalence, if not universality, of antagonistic pleiotropy suggests that many molecular mechanisms of aging may be common to different organisms, and these aging mechanisms can potentially be weakened by targeted interventions.

Introduction: the puzzle of aging

The logic of evolution by natural selection is straightforward. In any population, the occurrence of gene alleles of organisms that leave a larger number of reproducing descendants will increase in subsequent generations due to a decrease in the occurrence of alleles of organisms that are less successful in reproduction. In order to leave many descendants, organisms must be successful in survival, that is, they must live long enough to reach reproductive age and subsequently continue reproduction. According to this logic and process, natural selection ultimately produces organisms that survive and reproduce superbly in their environment.

From this point of view, aging is an evolutionary puzzle. If long-term survival and reproduction are always welcomed by natural selection, why is aging, which from an evolutionary point of view can be defined as an age-related decline in survival and reproduction, practically universal in the natural world? Or, as George Williams put it, "it's amazing that after a seemingly supernatural process of morphogenesis, a complex multicellular organism should not have the ability to perform a much simpler task, namely, maintaining and preserving what has already been formed." In other words, why doesn't evolution shape the biology of organisms in such a way that aging never happens?

One of the possible solutions to this puzzle is that evolution shapes the biology of organisms so that they never age in their natural conditions, that is, in the environment in which they appeared and evolved. In rare cases, aging can develop in nature and becomes apparent only when animals live much longer than they could live in natural conditions, that is, when we protect them from natural threats by turning them into pets or livestock, as well as when kept in zoos. In such cases, we provide them, as well as ourselves, with a life in a controlled climate and without threat from predators. Some gerontologists and biomedics consider this hypothesis to be correct. However, this is not the case, and to date, the results of many field studies indicate that the aging of wild animals is a very common phenomenon, if not close to universal.

Thus, in order to understand how aging develops in natural populations, we will have to solve a real puzzle. Fortunately, evolutionary biologists have solved this mystery.

Evolutionary theories of aging

Sir Peter Medawar, one of the most influential pioneers of the study of evolutionary aging, noted the similarities between the puzzle of aging and the puzzle of Huntington's disease – an inevitably fatal autosomal dominant neurological disease. If this disease is inherited and always leads to death, why did natural selection not exclude the alleles responsible for this from human genes? This is due to the fact that Huntington's disease usually develops late – during or even after the end of the reproductive period. From an evolutionary point of view, an allele harmful to health that does not affect the reproductive success of its carriers is not subject to the cleansing effect of natural selection. On the contrary, it is obvious that mutant alleles that disrupt reproductive ability in the early stages of life will be in great disfavor with natural selection. Following this logic, the earlier the effects of an allele are felt from a reproductive point of view, the more selection affects its fate. The meaning of this simple idea is that the power of natural selection in relation to the preservation or elimination of new alleles is less, the later their effects manifest themselves throughout life.

Medawar's guess was that he applied the same logic to aging. He suggested that, since new mutations occur constantly and are much more often destructive than beneficial, any new destructive mutation that has an effect on reproduction or survival that manifests itself only in the later stages of life will not be sufficiently exposed to the pressure of natural selection. As a result, such alleles can accumulate in genomes over generations. This concept is known as the Medawar mutation accumulation hypothesis.

George Williams recognized Medawar's fundamental idea, but he noticed something implied by this idea, although Medawar himself mentioned it only in passing. He noted that alleles that have a positive effect on survival or reproduction in the early stages of life under strong pressure of natural selection, but cause disastrous effects at an older age, when its pressure weakens, can be actively preserved under the influence of natural selection, despite the harm they cause in the later stages of life. The positive effect of the allele at a young age in comparison with its later negative effects was called antagonistic pleiotropy. Pleiotropy in this case is used as a descriptive term for multiple effects of a single gene. An additional conclusion from Williams' hypothesis states that new mutations that increase life expectancy or slow down aging are more likely to have any negative impact on early survival or reproduction. In addition to developing the general concept of antagonistic pleiotropy, in 1957 Williams published an article in which he made 9 specific assumptions about the existence and relative rate of physiological aging under certain conditions. Surprisingly, 60 years later, 6 out of 9 assumptions have at least limited empirical evidence.

However, which of the theories of aging – accumulation of mutations or antagonistic pleiotropy – is more universal for representatives of different species? An almost unnoticed consequence of the Medavar mutation accumulation hypothesis is that due to the random nature of mutagenesis, a complex of destructive mutations accumulating in one genetic lineage will be characteristic only for it and, accordingly, will inevitably differ from mutation complexes in other lines. Therefore, the mechanisms underlying aging, given that the accumulation of mutations is its main cause, for genetic lines within one species will differ less than expected between different species. On the other hand, we assume that a limited number of biological processes have rather strange characteristics that make them useful in the early stages of life and disastrous in the later stages, and the hypothesis of antagonistic pleotropy of Williams states that many mechanisms of aging can be universal for different species. The modern use of model organisms for the study of aging in general allows the existence of antagonistic pleiotropy. Is this assumption justified?

Testing evolutionary theories

To date, the hypothesis about the genetic mechanisms of aging is the most frequently tested in the laboratory. One important advantage of laboratory experiments is that they allow you to carefully control the environment. However, from the point of view of testing evolutionary hypotheses, they have a serious drawback – the absence of even a distant similarity with the conditions in which the evolution of species and the studied traits actually took place. In the laboratory, the physical conditions are constant and safe, unlike the unpredictably varying conditions of the real world. Biological conditions, including the absence of predators, competitors and parasites, are also safe and unchangeable. The experimental results obtained in the laboratory should be interpreted with caution, while taking into account their evolutionary significance. As an example, we can cite certain hypomorphic mutations of the insulin receptor locus and the insulin-like growth factor daf-2 in C.elegans nematodes, which steadily increase life expectancy and viability. This raises an evolutionary question: why have wild-type alleles not been replaced by such hypomorphic alleles in natural conditions? The answer to this question was obtained as a result of creating conditions for simple competition between a long-lived mutant line, which was initially declared to have a normal growth rate and fertility, with a wild-type line. Long-lived mutants disappear after several generations due to a small, previously unnoticed, decrease in fertility in the early stages of life. Similarly, the content of worms in the soil, which is their natural habitat, and not in agar – their usual habitat in the laboratory – completely eliminates the advantage of a similar long-lived mutant daf-2 line. These results demonstrate several reasons why evolutionary hypotheses are much better tested in natural or at least close to natural conditions.

In laboratory conditions, evolutionary hypotheses can be effectively tested using experimental evolutionary paradigms. This implies the application of a specific selection regime and monitoring of evolutionary changes over generations. For example, Stearns and colleagues have applied high accidental mortality to one group of fruit flies for 60 generations, and low accidental mortality to another group. As a result, it turned out that the high mortality regime led to a shortening of life expectancy, a decrease in the age of puberty and an acceleration of the reproductive trajectory compared to the low mortality regime. These data turned out to be completely comparable with the results of a natural experiment in which opossums naturally evolving on an island devoid of predators were compared with opossums of a normal population on a predator-populated mainland.

Below are two examples of the hypothesis of antagonistic pleiotropy in natural populations, followed by more specific examples for each of the four organisms traditionally studied in the laboratory: yeast, roundworms, fruit flies and mice. This will demonstrate how laboratory organisms allow researchers to identify individual genes of antagonistic pleotropy. It should be remembered that, despite the applicability of the effects of antagonistic pleiotropy (that is, compromises between reproduction and longevity) to humans, there is still no convincing evidence of the responsibility of any gene or allele for such compromises. This is due to the fact that studies of human genetics are more observational than experimental in nature and, accordingly, are based on correlations that are not necessarily causal. Therefore, despite the fact that the authors discuss human-related conclusions below, they do not indicate which of them are purely speculative.

Over the past decades, ecologists and evolutionary biologists have identified dozens of compromises in natural populations regarding traits that have emerged as a result of evolution. Most of them concern the "reproduction fee": individuals who reproduce (or reproduce more) demonstrate a corresponding decrease in the severity of any fitness parameter, whether it is immunity, vigor or longevity. It should be noted that such compromises confirm the hypothesis of antagonistic pleiotropy, however, due to the fact that the genetic basis of compromises in natural populations is usually unknown, they cannot be fully explained by this mechanism. In addition, such compromises confirm Kirkwood's theory of aging, known as the theory of disposable soma, which is also comparable to the theory of antagonistic pleiotropy. There is a huge amount of literature on trade-offs in natural populations and other reviews describe the integration of many aspects of the "breeding fee". This article provides only a few examples that may have an antagonistic pleiotropic basis: reproduction and longevity, as well as reproduction and immunity.

Reproduction and longevity

The compromise most often observed in natural populations implies a negative association between fertility and longevity. Negative correlations between life expectancy and reproduction have been described for a variety of vertebrates, including reptiles, birds and mammals. In addition, trade-offs characteristic of mammals are widely described, but usually their study is carried out in a laboratory context that allows for individual study of captured wild animals. For example, in a large population of Western gulls, early mating individuals are characterized by an increased risk of mortality compared to individuals starting to mate at an older age. Similarly, mating common squirrels have a shorter lifespan compared to individuals postponing the first mating. An interesting fact is that these compromises are often not observed in populations of mammals and birds living in captivity. This indicates that the selection pressure driving antagonistic pleiotropy is relieved under safe environmental conditions. Thus, while tradeoffs between life expectancy and reproduction seem commonplace in natural populations, the genes involved in this are unknown in most cases, so we cannot unequivocally attribute them either to the hypothesis of antagonistic pleiotropy or to the hypothesis of disposable soma.

Reproduction and immunity

While the trade-off between reproduction and longevity or other parameters of aging is the most studied "reproduction fee", the negative effect of the immune system on reproduction at an early age has also been demonstrated. In a pathogen-rich environment, weakened immune function should reduce life expectancy. For example, females of common gags that raise large broods have a reduced immune function, which may reduce survival in the future, as well as suppress the future reproduction of surviving individuals. Similarly, the mating of striped ground crickets suppresses certain aspects of immunity, which increases the mortality of individuals who have entered into mating. In addition, male fruit flies of drosophila, mated with a large number of females, have a reduced ability to cure bacterial infections. Similarly, trade-offs between reproduction and the ability to resist parasitic infections in white-necked flycatchers have been described, which indirectly affects longevity. All these tradeoffs between reproduction and immunity can potentially cause other tradeoffs between reproduction and longevity, that is, they can be potentially mediated by genes of antagonistic pleiotropy.

Antagonistic pleiotropy in the laboratory

While tradeoffs between reproduction and other fitness parameters are very common, and perhaps even ubiquitous in natural populations, individual genes that provide these tradeoffs are rarely studied for many reasons, including due to the lack of genomic resources for many species and due to weak interest on the part of ecologists studying natural populations. Genes contributing to antagonistic pleiotropy were most often identified in model organisms under laboratory conditions. In this regard, the focus of this short review will be shifted towards the antagonistic pleiotropic effects of certain genes identified in the four most actively studied laboratory models: yeast, roundworms, fruit flies and mice. The discovery of antagonistic pleiotropy in laboratory conditions was due to (i) experiments on direct selection on the basis of longevity or (ii) partial or complete inactivation of a gene providing a significant increase in life expectancy, which, upon subsequent study, had a detrimental effect on any aspect of fitness at a young age. Table 1 presents several well-studied genes discovered using the experiments described above on traditional model organisms.

Table 1. Examples of genes whose mutations in laboratory conditions lead to an increase in life expectancy, accompanied by antagonistic pleiotropic effects

Yeasts

Unicellular budding (or baker's) yeast (Saccharomyces cerevisiae) is one of the most well-studied models of aging, and many genes having antagonistic effects have been identified in yeast experiments. For example, 65% of all yeast lines with an increased duration of replicative life due to inactivation of single genes have reduced adaptability compared to wild-type yeast in direct competition experiments. For the most part, the decrease in adaptability is due to a decrease in the growth rate compared to wild-type yeast. In addition, the results of earlier analyses conducted using methods of systems biology indicate that antagonistic pleiotropy can make a significant contribution to the functioning of mechanisms of protein interactions and the integrity of systems. In another type of yeast, dividing yeast (Schizosaccharomyces pombe), chromosomal rearrangements can simultaneously lead to a decrease in reproduction (meiosis) and an increase in growth (mitosis) by the type of antagonistic pleiotropy.

Roundworms

The roundworms Caenorhabditis elegans are the most studied invertebrate model in the study of aging. In studies on these worms, hundreds of genes have been identified, the suppression of the activity of which increases life expectancy. However, experiments on such long-lived mutants often do not allow us to determine whether mutations have any effect on reproduction (neither in terms of fertility, nor in terms of the length of periods between egg laying). However, a more thorough search usually leads to the identification of the effects of antagonistic pleiotropy.

As mentioned in the introduction, the daf-2 gene encoding the insulin receptor/insulin-like growth factor has the most stable and pronounced positive effect on the lifespan of C.elegans. Hypomorphic mutations of this gene provide a significant reduction in reproductive activity (by 18-23%) compared to wild-type individuals, while doubling life expectancy. However, reproductive effects manifest themselves in the early stages of life, when the selection pressure is greatest. With direct competition, daf-2 mutants were quickly displaced by wild-type worms. In conditions of constant presence of nutrients, daf-2 mutants disappeared in 4 generations, and with periodic feeding, they died out even faster - in 3 generations. Hypomorphic mutations of the age-1 gene, also involved in the signaling mechanism mediated by insulin/insulin-like growth factor, increase life expectancy by 65% compared to wild-type worms. Interestingly, in direct competition with wild-type individuals in conditions of an unlimited amount of food, neither side has advantages. However, with the occasional availability of food, which brings the living conditions closer to natural, age-1 mutants quickly die out, which explains the preservation of the wild-type allele in nature.

Another example for C.elegans is the clk-1 gene encoding an enzyme necessary for ubiquinone biosynthesis. With genetic damage to the clk-1 gene, life expectancy increases by 20-40%, depending on the ambient temperature. There are also many antagonistic pleiotropic effects of the early stages of life, including a decrease in metabolic activity, an elongation of the development period and a decrease in the rate of reproduction. Similarly, life-extending mutations of 24 genes that affect the development process also reduce fertility. Many of these genes, such as clk-1, are involved not only in a well-studied signaling mechanism mediated by insulin/insulin-like growth factor.

Taken together, these results indicate that life-prolonging genetic interventions can have very different antagonistic pleotropic effects. While not all of them have a direct impact on reproductive function, certain aspects of fitness in the early stages of life are inevitably suppressed, which in natural habitat reduces the likelihood of selection of alleles that contribute to longevity.

In addition to knocking out individual genes, information about the ubiquitous role of antagonistic pleiotropy in evolutionary compromises was provided by selection experiments on roundworms. When selecting on the basis of early reproduction for more than 40 generations, there was a compromise with late reproduction, but not with a decrease in life expectancy. This experiment was carried out under laboratory conditions, so its results should be interpreted with caution. However, they indicate that, despite its universality, the limitations of antagonistic pleiotropy do not always concern longevity. They can also have an impact on reproductive longevity.

A basic model describing the mechanism by which laboratory mutations lead to an increase in life expectancy with a simultaneous decrease in reproductive success.

Fruit flies

Various species of fruit flies of the genus Drosophila are perhaps the most well-described group of species used to study the evolutionary issues of aging. Experiments on fruit flies range from empirical studies of the effect of selection based on delayed reproduction on longevity in the laboratory to the currently more popular identification of genes that increase life expectancy. To date, several dozen genes have already been discovered, the inactivation or increased expression of which increases the lifespan of the most widely used species of fruit flies, D.melanogaster. However, as can be seen from experiments on roundworms, the results of many studies on the effect of these mutations on longevity both do not demonstrate an effect on reproduction or other fitness components in the early stages of life, and have not been reproduced by other laboratories. For this reason, this article focuses on a number of the most reproducible mutations of individual genes, as well as several of the many breeding experiments conducted on D.melanogaster.

The experimental evolution of the selected lines and hybrids indicates that the main genetic mechanism underlying the late mortality of fruit flies is antagonistic pleiotropy rather than the accumulation of Medavar mutations. D.melanogaster lines selected on the basis of late reproduction live longer with reduced reproduction activity in the early stages of life, compared with the control line. In addition, a negative correlation was found between early reproduction and resistance to starvation – a traditionally estimated value, the value of which decreases in fruit flies as they age. Similarly, the lines of D.simulans selected on the basis of delayed growth differ in longevity, which also confirms the existence of antagonistic pleiotropy, but in this case delayed maturation does not lead to a general decrease in fertility, as could be assumed. At the same time, in natural conditions, delayed maturation can potentially lead to negative, from the point of view of fitness, consequences, which makes this trait unfavorable for selection. The second set of D.melanogaster lines, selected for signs of early or late reproduction, demonstrated a longer life expectancy in late-breeding lines in the absence of a decrease in early reproduction activity. However, the larvae of short-lived early breeding lines had a competitive advantage over the larvae of late breeding lines. This indicates antagonistically pleiotropic trade-offs between larval growth and longevity, rather than reproduction and longevity, which highlights the existence of several important fitness components in the early stages of life. An interesting fact is that experiments on various lines selected artificially independently of each other demonstrate that laboratory conditions can have a pronounced effect on the parameters of the life cycle, especially fertility. This indicates that the effects of antagonistic pleiotropy genes are so influenced by environmental factors that one laboratory can identify a compromise between longevity and reproduction, while others do not succeed even when working with the same lines.

A number of studies on fruit flies have simultaneously revealed confirmations of theories of antagonistic pleiotropy and accumulation of mutations. This leads to the conclusion that the two potential evolutionary mechanisms of aging are not mutually exclusive. The results of recently conducted interesting work on drosophila lines obtained as a result of related crossing indicate that many single nucleotide polymorphisms are associated with both antagonistic pleiotropy and the accumulation of mutations in response to a number of stressors. While both antagonistic pleiotropy and the accumulation of mutations can contribute to the appearance of certain parameters of the life cycle in drosophila, it should be borne in mind that in all studies devoted to the study of the evolution of this group of species, at least one compromise on the principle of antagonistic pleiotropy is revealed.

Just as it was described in yeast and nematodes, individual genes can increase life expectancy, while having a negative effect on the reproduction of fruit flies. Just like in nematodes, many genes exhibiting such antagonistically pleiotropic effects, in the case of drosophila, are involved in the signaling mechanism mediated by insulin/insulin-like growth factor. For example, inactivation of the chico gene encoding the insulin receptor substrate (InR) in drosophila increases life expectancy, while simultaneously causing a decrease in fertility in heterozygous individuals. Females homozygous for this mutation are infertile and have a long lifespan. By itself, knockout of the InR gene in drosophila increases life expectancy, however, such females do not produce viable eggs, presumably due to the influence of the knockout gene on the expression of juvenile hormone. Direct knockout of the juvenile hormone gene also increases life expectancy while significantly suppressing egg production. However, reduced activity of insulin-mediated signaling pathway genes does not have a direct effect on fertility. For example, increased expression of the forkhead transcription factor (dFOXO) in drosophila increases life expectancy without an obvious effect on fertility. Similarly, long-lived mutants of the indy and jnk genes do not show a decrease in fertility associated with increased life expectancy. However, as mentioned above, in addition to general fertility, there are a number of fertility parameters in the early stages of life. Therefore, in such cases, compromises cannot be excluded. For example, very few researchers interested in aging analyze the competitive ability of larvae, even though the results of a number of studies have demonstrated compromises between this indicator and the longevity of adults. In fact, in several long-lived fruit fly lines, independent of each other, obtained by artificial selection, the most stably associated with a long lifespan feature was the reduced viability of larvae. Therefore, it is surprising that a number of genes have been identified in fruit flies that increase life expectancy without an obvious effect on fertility. However, on the other hand, fertility may not be the main antagonistic compromise with a long lifespan in fruit flies. In this regard, it is not surprising if it turns out that most of the genes that increase life expectancy have a negative impact on other aspects of overall fitness.

Mice

Neither field studies nor long–term laboratory selection studies, two preferred methods of verifying the validity of evolutionary hypotheses, were purposefully conducted on house mice (Mus musculus). However, the selection of laboratory mice for many generations has been carried out according to the high rate of reproduction and other characteristics associated with their commercial use in laboratory research, and it can be considered partly a "natural experiment". In laboratory conditions, domesticated mice have accelerated puberty and larger broods compared to wild-type mice (recent descendants of wild mice living in the laboratory). Taking into account selection on the basis of accelerated reproduction, according to the theory of antagonistic pleotropy, it can be assumed that as a result, laboratory mice should age faster than wild-type animals. And indeed, at least in laboratory conditions, these take place.

One study on mice conducted in simulated field conditions should be mentioned. Initially, it was shown that the removal of one of the splice variants of the p66shc protein, which provides signaling in the cytoplasm, reacting to stress and growth factors, increases life expectancy and increases the cellular resistance of mice to oxidative stress. Despite the fact that subsequent studies failed to reproduce the effect of increasing life expectancy, other health-improving signs were revealed in mice with knocked-out p66shc, including increased tissue sensitivity to insulin, as well as resistance to the development of obesity, atherosclerosis and ischemic damage. And again, within the framework of the hypothesis of antagonistic pleotropy, these health-improving signs are associated with a lack of the protein product of a normal gene, which presumably should have negative consequences from the point of view of fitness. Indeed, when wild-type laboratory mice and mice with a fully knocked-out p66shc gene or heterozygotes were settled in an extensive open-air enclosure in western Russia, the number of mice with the wild-type genotype increased almost 3 times in 13 months, while the number of mice with knocked-out p66shc decreased 4 times, and the number of heterozygotes remained approximately at the initial level. Further laboratory studies revealed possible reasons for the low viability of mice with one or two knockout alleles of p66shc. These include: reduced resistance to cold and starvation, as well as lower fertility and less pronounced maternal instinct. Thus, both fully and haplo-knocked-out genotypes had reduced Darwinian fitness compared to the wild-type genotype, at least under these conditions. This also does not contradict the antagonistic pleotropy associated with the p66shc gene.

To date, there are more than two dozen modified mouse genotypes that increase life expectancy in the laboratory. However, abnormalities in development or reproduction are rarely detected in mice modified to slow aging or increase life expectancy. Perhaps the most well-described from the point of view of reproduction are the Ames and Snell dwarf mice, because the parameters of their development and reproduction were studied in a number of early studies before their exceptional longevity was revealed. Ames dwarf mice show the largest increase in life expectancy of the effects obtained with the help of all known mutations, and have only one damaged transcription factor (prop-1) necessary for the development of the pituitary gland. Accordingly, they are characterized by a deficiency of several pituitary hormones (growth hormone, prolactin and thyroid-stimulating hormone), which makes them small, sensitive to cold and infertile. Snell dwarf mice do not have a transcription factor (pit-1) activated by prop-1. Their phenotype is almost identical to the Ames phenotype, and both lines show many manifestations resembling delayed aging. In addition, both genotypes are distinguished by longevity: Ames mice live by 48-67%, and Snell mice – by 42% longer than control individuals. Both dwarf genotypes also have reduced fertility or sterility associated with longevity. Obviously, this can be interpreted as antagonistic pleotropy in laboratory conditions, and such mutations would never have been preserved during selection in wild populations.

Conclusion

When George Williams first proposed his theory of antagonistic pleiotropy in 1957, he proposed a hypothetical example of a gene that accelerates the formation of arteries during development, but leads to calcification of arterial walls in the later stages of life. He was pushed to this by the absence at that time of known genes that have such a strange feature – to benefit at the beginning of life and have a disastrous effect later. Over the past 20 years or so, molecular biology has become a cornucopia of such genes, and over the past 60 years, 6 out of 9 predictions made by Williams have been confirmed. Paradoxically, another type of antagonistic pleiotropy is at the forefront of aging research today – benefits in the later stages of life at the expense of harm in its early stages.

Here we have only touched the surface of a very large topic in passing. However, this topic should attract more and more interest, since the biology of aging is on the verge of a number of serious discoveries. Based on the available data, in the animal world (and, perhaps, this applies to all living things) antagonistic pleiotropy is very common, if not universal. When identifying any allele or a new mutation that increases life expectancy, almost always some negative manifestation is detected in the early stages of life. This explains the inability of longevity alleles to withstand selection in natural populations. However, while antagonistic pleiotropy seems to be practically universal, most of the alleles acting on the principle of antagonistic pleiotropy in natural populations have not yet been identified, and laboratory studies describing life-extending alleles have not revealed an effect on fitness in the early stages of life. These gaps in knowledge still need to be filled and it can be assumed that the results of work in both directions will provide more convincing evidence in favor of the theory of antagonistic pleiotropy in aging. One of the latest discoveries, especially comforting for people who dream of prolonging the period of healthy life of medical interventions, is that such interventions should not be used until a relatively late age – until the end of the reproductive period. In such cases, it is unclear whether the effects of antagonistic pleiotropy will manifest in the early stages of life. Thus, evolutionary biology does not exclude the possibility of using medical interventions to slow down the aging process.