Antagonistic Pleiotropy Aging Theory
Antagonistic pleiotropy is an evolutionary theory of non-programmed aging, suggesting the presence of genes, the functioning of which is beneficial for the organism in the early stages of life but has negative effects in older ages. The term “antagonistic pleiotropy” means that a gene has several different effects of opposite value, but since the proposal of “antagonistic pleiotropy aging theory,” the term is often used as the name of this theory of aging.
Pleiotropy, i.e., the ability of one hereditary factor (gene) to influence several traits of the organism
The antagonism of pleiotropic effects, which can affect the fitness of the organism in an opposing way
An example of the manifestation of antagonistic pleiotropy may be a certain hypothetical gene, whose effect increases the reproductive capacity of the organism in the early period of life but shortens its life span. In this case, we speak of the cost due to an increase in reproductive abilities. In a broader sense, we can say that there is a compromise between the “positive” and “negative” effects of the antagonistic features of a pleiotropic gene. The theory of antagonistic pleiotropy suggests such a strong connection between the negative and positive effects that the positive effect prevents the elimination of the pleiotropic gene by natural selection. An objection for the theory is that the evolutionary process might “attempt” to destroy this connection to obtain an organism structure that implements a favorable function without a presumably adverse effect (Goldsmith 2013).
Negative phenotypic effects can manifest themselves in the later periods of life, which are unattainable by the organism in natural conditions, thus, almost not falling under the influence of natural selection.
In addition to formulating the theory of antagonistic pleiotropy, Williams put forward nine verifiable theses. In part, they relate to the phylogeny of aging, and partially to the physiological effects. Williamsʼ last, ninth thesis concerns the expected results of artificial selection concerning the increase in longevity and maintains that “Successful selection for increased longevity should result in decreased vigor in youth.”
Key Research Findings
The phenomenon of pleiotropy was noticed by Gregor Mendel. In his famous work Experiments in Plant Hybridization (Mendel 1866), as one of the dominant features in the experiments with peas, he considered “the gray, gray-brown, or leather brown color of the seed-coat, in association with violet-red blossoms and reddish spots in the leaf axils.” Mendel noted the joint transfer of the color of the seed coat and the color of flowers: “Expt. 3: Color of the seed–coats. –– Among 929 plants, 705 bore violet–red flowers and gray-brown seed-coats; 224 had white flowers and white seed-coats, giving the proportion 3.15:1.” Mendel did not analyze such a joint transmission of traits in detail.
The term “pleiotropy” was first introduced in (Plate 1910). Plate (1910, p. 597) writes: “Pleiotrop nenne ich eine Einheit, wenn von ihr mehrere Merkmale abhängen, die dann natürlich stets zusammen auftreten und daher als korrelativ gebunden erscheinen.”
The study of pleiotropy with regard to the issues of evolution and aging proved to be a very productive direction (Stearns 2010). In 1952, Medawar published a paper (Medawar 1952), in which he put forward, nowadays generally accepted, the idea of the role of correlation of internal and external causes of mortality in evolutionary processes (Goldsmith 2013). The essence of Medawarʼs concept is that factors that reduce the life span of an individual below reproductive age will be counteracted by natural selection since such a species will not be viable. On the other hand, eliminating the internal causes of death and prolonging the reproduction age beyond the time when 100% of the population will die of external causes (predators, environmental conditions, lack of food, etc.) also do not bear evolutionary benefits. The pressure of evolutionary factors aimed at increasing the life span of the body is reduced starting from a specific moment of life (Goldsmith 2016).
Medawarʼs conclusions are widely used in the whole family of theories of aging, such as the mutation accumulation theory (formulated by Medawar), the theory of antagonistic pleiotropy (Williams 1957), and the disposable soma theory (Kirkwood and Holliday 1979). Common to these theories is the idea of aging as negative from an evolutionary point of view because it reduces individual fitness.
Medawar (1952) suggested that a delayed negative effect may persist in the process of evolution due to the pleiotropic effect or close linkage between genes: “... postponement may sometimes be the only way in which elimination can be achieved; but I cannot argue this without an appeal to the phenomena of pleiotropy and linkage ....” Formulating the theory of antagonistic pleiotropy, Williams, however, emphasized that even close linkage is not enough to preserve negative traits; for this, the probability of crossing-over should be infinitely small. Besides, the effect of a gene on fitness and, consequently, the probability of its preservation in evolution depends not only on the magnitude of the effect but also on the time of its manifestation.
One of the critical points of Williams’ theory, besides the existence of antagonistic pleiotropy as a phenomenon, is the assumption of “decreasing probability of reproduction with increasing adult age.”
According to Williams, the reproductive probability distribution increases to the age of reproductive maturity and reaches its peak value. Further, it falls due to the cumulative probability of death with or without senescence. Changes in fecundity, mortality, and other conditions can affect the reproductive probability distribution and, thus, the evolutionary effects in relation to aging: “Any factor that decreases the rate of decline in reproductive probability intensifies selection against senescence. Any factor that increases the rate of this decline causes a relaxed selection against senescence and a greater advantage in increasing youthful vigor at the price of vigor later on” (Williams 1957).
Examples of Application
Williams, in his work (Williams 1957), presented the theory of antagonistic pleiotropy as a complete logical construction based on several assumptions. Over the years since its publication, no fundamental changes have been made to it (Gavrilov and Gavrilova 2002), although the concept of pleiotropy as such has been carefully studied. Possible mechanisms for its implementation and classification (Hodgkin 1998), as well as quantitative aspects (Wagner and Zhang 2011), were investigated.
The presence of soma, which plays a vital role in reproduction, but is not transmitted in its process
Natural selection of alternative alleles in a population
The existence of pleiotropic genes acting antagonistically in different somatic environments
Decreasing probability of reproduction with increasing adult age
At the time of the formulation of the theory (1957), no reliable examples were confirming experimentally antagonistic pleiotropy aging theory. Williams referred to the difficulty of assessing the role of one or the other gene for survival in different periods of the life cycle. As possible examples, he gave mutations in Drosophila (D. melanogaster), which increase longevity: black (black body) and speck (black spot at the base of the wing). They rarely occur in nature, and Williams suggested that their wild type has the advantages of Drosophila development in early growth, compensating for a shorter life span. Williams mentioned several other mutations affecting the rate of development of individuals in Drosophila and the Ephestia moth. He did not focus on the search for cases of antagonistic pleiotropy to confirm his theory: “Pleiotropy in some form is universally recognized, and no one has ever suggested that all the effects of a gene need be equally beneficial or harmful, or that they must all be manifest at the same time” (Williams 1957).
To date, a significant amount of experimental data has been accumulated, which can be interpreted as manifestations of pleiotropic effects acting antagonistically in different periods of the life cycle of organisms. Considering aging as an age-related progressive deterioration of the physical condition/increase in the probability of death (Libertini 2014), one can study the dynamics of the signs of aging of individual cells and individual tissues and their gene regulation. In particular, it is possible to analyze such genes for their manifestation of pleiotropic properties of an antagonistic nature. In the work of Williams, it is a question of certain genes, whose products enhance the fitness of the organism but have negative consequences in old age.
For example, involutional loss of bone tissue is typical for humans, both for men and women. In women, this loss is accelerated in the first postmenopausal decade. A series of mononucleotide substitutions (SNPs) in the 12/15-lipoxygenase gene (ALOX15) was analyzed in (Cheung et al. 2008). It was shown that 1 intronic SNP and 1 SNP in the 3′ untranslated region lead to a statistically significant reduction in the risk of low mineral density in the femoral neck in premenopause, but increase in postmenopause. It should be noted that both substitutions are localized in untranslated regions.
The negative consequences of some alleles are often understood as a genetic predisposition to certain diseases, or the presence of such a disease. Genetic disorders, according to evolutionary concepts, should be eliminated. That is why their preservation in the population requires an explanation. One of these explanations may be the presence of pleiotropic effects increasing the adaptability. Under the improvement of fitness, a wide range of hereditary functional advantages can be implied. These are resistance to diseases, increased fertility, increased resistance to harmful environmental factors, etc.
A classic example in humans is sickle cell anemia, a hereditary disease associated with a mutation of the HBB gene, resulting in the synthesis of abnormal hemoglobin. In the homozygous form, the disease leads to severe consequences, but persists in the population, especially in regions that are endemic for malaria, as heterozygous sickle cell anemia patients have innate partial resistance to this disease (Allison 1954). Hereditary disease and hereditary resistance to malaria find an evolutionary compromise.
Huntington’s disease – a genetic disease of the nervous system. The variations in the number of CAG repeats in the HTT gene increase the fertility and reduce the risk of some types of cancer (Möncke-Buchner et al. 2002).
Cystic fibrosis – a genetic systemic disease transmitted as a recessive trait is fatal in homozygous individuals. The mutations causing it at the same time lead to an increase in fecundity (Knudson et al. 1967).
Beta-thalassemia – a hereditary blood disease. Mutations that cause it, in heterozygous individuals, lead to malaria resistance (Cao and Galanello 2010).
The lack of CAG repeats in the AR gene (androgen receptor) can, on the one hand, lead to ovarian cancer in women and to prostate cancer in men (which mostly elderly people face). The same lack of repeats, on the other hand, leads to increased fertility in women and reduced risk of breast cancer and in men to improved spermatogenesis and reduced risk of Kennedy disease (a hereditary neurodegenerative disease affecting motoneurons, manifested by 40–50 years). There is evidence that the lack of CAG repeats in the AR gene in men leads to the appearance of phenotypic traits that increase reproductive capacity (Carter and Nguyen 2011).
A large-scale study (Byars et al. 2017) showed a relation between the loci increasing the incidence of coronary artery disease (CAD) and the reproductive traits of both women and men. The positive impact on the reproduction ability of the CAD loci demonstrates that they have pleiotropic antagonistic features and at the same time explains their high prevalence in the human population. CAD, which begins at an early age with an accumulation of arterial plaques and can end in death later, is a by-product of increased fitness in the early stages of human development.
Alzheimer’s disease, a neurodegenerative disorder, is not only eliminated by evolution but, on the contrary, is becoming more common. Multiple reasons for the phenomenon of human susceptibility to Alzheimer’s disease (AD) are proposed; these are the rapid evolution of the human brain, and the short life spans of human ancestors (due to which AD was not removed by natural selection), etc.
One possible explanation for maintaining AD in the population is antagonistic pleiotropy (Fox 2018). AD susceptibility genes may have a pleiotropic effect, performing adaptive functions in other processes or at other stages of the development of the organism. In particular, the APOE-ε4 allele, according to modern concepts, is the most important genetic risk factor for AD in developed countries (Liu et al. 2015). This same allele has a variety of antagonistic pleiotropic effects – it protects against hepatitis C-associated liver damage, cardiovascular stress, miscarriage, and age-related macular degeneration and protects against malaria, etc.
There are suggestions that AD may be associated with the selection of genes associated with the activity of the neurons of the cerebral cortex. The presence of these genes increases learnability early on but also increases the risk of AD (Bufill and Blesa 2006).
Not only nuclear but also a mitochondrial genome can be the bearer of pleiotropic traits. In Benedictis et al. (1999), the incidence of nine haplotypes in centenarians (over 100 years old) and the control group (age 25–78 years) of men and women from northern Italy was studied. In male centenarians, the incidence of haplogroup J was 23%, while in the control group it was 2%. It can be assumed that haplogroup J carries a gene or genes that negatively affect their carriers early in life but are favorable for them at an older age. It should be noted that such an effect on fitness is directly opposite to what is usually implied in the classical antagonistic pleiotropy aging theory.
The above cases of antagonistic pleiotropy were obtained in human studies, but similar work was carried out in other species. The DTS-3 gene regulates the biosynthesis of ecdysone, which plays an important role in the early development and sexual reproduction of fruit flies. Mutation in it leads to a decrease in both the ecdysone titer and the fertility of the females (but not the males) as compared to the wild-type individuals. In (Simon 2003) it was shown that the average life span of females of ecdysone-deficient heterozygous DTS-3/+ line exceeds the life span of the wild-type line by 42%.
An experimental study of evolution is possible in Drosophila, unlike humans, including the possibility of verifying the validity of Williamsʼ theses regarding the expected consequences of the theory of antagonistic pleiotropy. The results of an evolutionary experiment on the adaptation of flies of D. melanogaster to a depleted diet environment (Yakovleva et al. 2016) are consistent with the assumption that antagonistic pleiotropy plays a significant role in the evolution of females. At the same time, the changes that occurred in the males are probably more due to the accumulation of harmful recessive mutations with a late effect.
Future Directions of Research
One of the starting points of the theory of antagonistic pleiotropy concerns the dynamics of the probability of reproduction (see above). In (Jones et al. 2014), survival, fecundity, and mortality curves were analyzed in a standardized form for 44 species: 11 mammals (including 3 Homo sapiens communities), 12 other vertebrates, 10 invertebrates, and 12 plants and chlorophytes. As expected, in many species, mortality increases and fertility decreases with age. However, there are species for which this rule is not met. Among considered species, all possible combinations of growth and fall in fertility and mortality can be found, including fertility increasing with age with decreasing mortality. This is typical, for example, for turtles (Gopherus agassizii) or mangroves (Avicennia marina) (Skulachev and Skulachev 2014). Based on the analyzed data, it is not possible to speak of any shape of graphs of the dynamics of fertility and mortality as of “usual behavior” and about the rest as of exceptions. Also, there is no rank correlation between the average life span of a species and the rate of aging. This situation is right when processing all data and when considering only plants or only mammals (Jones et al. 2014).
Since the balance between fertility and mortality is a crucial issue in the theory of antagonistic pleiotropy, it is desirable to compare these data with its predictions. A comparative analysis of the correspondences of the predictions of various theories of aging, including the theory of antagonistic pleiotropy, with empirical data is made in the paper (Libertini 2017). The data refer to the existence of non-aging species, increased longevity with reduced nutrition, differences in the rate of aging, age-related decline in fitness, etc. Expansion of this list is possible, for example, with data on the geroprotective effect of hypothermia, mitochondria-targeted antioxidants (Skulachev et al. 2011), etc.
Examples of antagonistic pleiotropy in many cases have to some degree sexual dimorphism (haplotype J in humans, woc gene in Drosophila). Perhaps this phenomenon is systemic and should be analyzed.
Antagonistic pleiotropy may be due not only to the nuclear but also to the mitochondrial genome, but the molecular basis of this remains unknown.
The existence of antagonistic pleiotropy in a large number of genes in different species has long been beyond doubt. The addition of another gene to this list certainly complements the picture, but this is not evidence of the correctness of the antagonistic pleiotropy aging theory. Its author wrote: “Senescence should always be a generalized deterioration, and never due largely to changes in a single system” (Williams 1957). Spatial relationship between such pleiotropic genes and regulatory or significant chromosomal regions such as centromeres, rDNA clusters, and telomeres (Libertini 2014) can give a better proof of the antagonistic pleiotropy aging theory, because a study in this direction may shed light on the control of expression and mechanism of involvement of such genes in the aging.
Antagonistic pleiotropy, proposed in (Williams 1957), is an evolutionary theory of non-programmed aging, suggesting the presence of genes that are beneficial for the organism in the early stages of development but have adverse effects at older ages. Aging is the consequence of the effects of these genes. The theory presupposes a connection between the favorable and unfavorable effects so strong that the positive effect helps to prevent the elimination of the pleiotropic gene by evolutionary processes. The evidence in support of this theory is still insufficient.
Preparation of this work was supported by the Russian Science Foundation (Project No. 16-16-04032).
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