Is it possible to program aging (1)

Can aging be programmed? A critical literature review Axel Kowald and Thomas B. L. Kirkwood, Aging Cell, 2016

Translated by Evgenia Ryabtseva

Introduction

The evolution of the aging process has long remained a biological mystery, since the evolution of a trait that does not bring obvious advantages to an individual is difficult to explain. More than 60 years ago, Medawar realized that the power of natural selection fades with increasing chronological age due to the inevitable risks associated with environmental exposure. This formed the basis of the generally accepted theory that aging is a consequence of the extinction of selection pressure aimed at the endless maintenance of the physiological functions of living beings. However, in recent years, a number of articles have appeared indicating the existence of specific aging genes, that is, that the aging process is genetically programmed. If this assumption is correct, it is of great importance for experiments devoted to the study and postponement of aging. Therefore, the authors of this article analyzed in detail various specific assumptions according to which aging should be programmed. It turned out that none of them can withstand a thorough check of their assumptions or simulation results. Theories of unprogrammed aging based on Medawar's vision (later revised by Hamilton and Charlesworth) still remain the best explanation for the evolution of the aging process. The authors hope that this analysis will help clarify the problems associated with the idea of programmed aging.

Many people who are thinking for the first time about the question "why and how does aging occur?" are naturally attracted to the idea of a genetic program. According to this idea, aging is necessary either to prevent overpopulation of the habitat of a species, or to stimulate evolutionary changes by accelerating generational change. The idea that aging is a programmed property that positively affects the survival of a species was first formulated by Weismann (1891), but is now generally recognized as incorrect, since it is based on group selection, usually much weaker than selection acting at the individual level. In addition, it is cyclical, since it admits that elderly individuals who are not subject to aging as a whole "wear out".

Instead of the theory of programmed aging, the explanation of the causes of aging has recently been decided to choose between three ideas based on the principle that for iteropar species (reproducing repeatedly as opposed to species reproducing once in a lifetime and dying soon after), the pressure of natural selection fades during adulthood. This extinction occurs because as the age increases, there is a progressive decrease in the remaining share of the total potential reproductive yield, which selection can influence in order to separate more viable genotypes from less viable ones.

According to the theory of accumulation of mutations proposed by Medavar in 1952, with the passage of evolutionary time, there is a continuous accumulation of destructive mutations that are expressed only after a certain age. Natural selection as a whole contributes to the elimination of harmful genes, but its pressure weakens with age, while against the background of the constant appearance of new mutations, a balance is formed between mutations and selection, which (for dominant mutations) is described as µ/s, where µ is the rate of mutation appearance, and s is an unfavorable sign from the point of view of selection.

According to the theory of antagonistic pleiotropy, a gene that has a positive effect at an early age, but has a detrimental effect at later stages of life, can have a beneficial resultant effect and therefore undergo active positive selection. Possible examples of antagonistic effects are high testosterone levels, which is good for enhanced reproduction, but may increase the risk of prostate cancer in later life, or telomerase deactivation, which prevents the development of cancer, while simultaneously leading to the entry of cells into the phase of physiological aging.

The theory of disposable soma describes the optimization of resource allocation between maintaining viability on the one hand and other processes like growth and reproduction on the other hand. An organism that invests most of its energy budget in preventing the accumulation of damage to its proteins, cells and organs will have a slower rate of aging, but it will have fewer resources at its disposal that can be spent on growth and reproduction, and vice versa. Mathematical models of this concept demonstrate that the optimal investment in maintaining viability (maximizing viability) is always lower than the fraction necessary to prevent aging.

One of the arguments against programmed aging was the opinion generally accepted for a long time, according to which in the wild only a small part of the population survives long enough to die from age-related causes. The absence of a significant role of physiological aging in the wild would indicate against the evolution of programmed aging, both by eliminating any potential advantage of active destruction of aged individuals (which would not be noticeable under normal conditions), and by reducing the evidence of how a program could arise that drives a process that is generally not given importance.

However, recent field studies have provided convincing evidence that aging is a phenomenon that can also be observed in wild populations of a wide range of species. It is obvious that the rarity of observing aging in wildlife could never be unconditional, since even for unprogrammed theories, a complex arsenal of mechanisms for ensuring longevity could be formed only in the case of insufficient age mortality in wildlife to create the necessary selection pressure. This would be a special case of the evolution of increased longevity, which, as is commonly believed, is often the result of adaptations aimed at reducing mortality from external causes (for example, due to the appearance of the ability to fly in birds and bats), which would leave populations exposed to increased depletion under the influence of internal causes (physiological aging) before the appearance of secondary adaptations that increase the likelihood of longevity. However, the new view that aging is widespread in living nature has weakened the strength of one of the traditional arguments against programmed aging, preserving its theoretical possibility. Therefore, it is most important to analyze specific versions of theories of programmed aging and explain the reasons for their failure.

This discussion is not only interesting from a theoretical point of view, but also has practical application for conducting a certain type of experiments, the purpose of which is to study the mechanistic foundations of aging. If the genetic program of aging existed, there would also be genes with specific functions that disrupt the functioning of the body and thus aging it. Under such conditions, experiments could be planned to identify and inhibit these genes and, accordingly, modify and even prevent the aging process. However, if aging is not programmed, the situation changes completely. The search for genes that actively cause aging would be a waste of effort, in addition, it would be too easy to misinterpret the changes in gene expression occurring with aging as the primary driving mechanisms of the phenotype of physiological aging, and not secondary reactions (for example, reactions to molecular and cellular defects). Undoubtedly, genes have an impact on longevity, but the nature of the corresponding genes should differ significantly depending on whether aging is programmed or not.

Despite convincing arguments in favor of the fact that aging is not programmed, attempts are still being made to formulate a theory of programmed aging that has convincing confirmation in the form of quantitative models. It is important to take such statements seriously, since protesting against conventional wisdom is a path that often leads to scientific progress. However, it is also important to remember that such statements should be considered very carefully, since similar efforts should be made to verify the accuracy and reliability of both the model and the experiment. This article provides a critical analysis of the models proposed to support the theories of programmed aging. In each case, the authors identified serious shortcomings that cast doubt on the conclusions drawn by the developers of these models. The analysis showed that the models under consideration were based mainly on simulation methods, and not on methods of mathematical analysis. While the advantage of analytical (mathematical) models in general is transparency, they are of little use in cases where the analyzed phenomenon depends on parameters such as spatial effects, which are the cornerstone of a number of statements in favor of the theory of programmed aging. Therefore, most of this study is based on computer simulations of theoretical models, since the models had to be evaluated within their own framework. The authors believe that access to the necessary program code is important for reproducing simulations and searching for prerequisites that may not be clearly mentioned in publications. Therefore, the source code, as well as working versions of the programs, are available as additional material (Data S1–S6 in the original article).

Continuation: Life span adjustability

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31.10.2016