Antagonistic Pleiotropy Model Research Articles

Are some conventional measures of the rate of ageing consistent with antagonistic pleiotropy?

Several measures of the rate of ageing have been proposed in the literature. But are they all equally good? In this work, three of these measures are considered: ωG and the parameter b for the Gompertz model, and ωW for the Weibull model. It is shown that ωG and ωW may fail to detect genuine changes in the rate of ageing when this rate varies in response to the fixation of antagonistic–pleiotropic mutations with effects on survival, while the parameter b never fails to detect such changes. It is suggested that ωG and ωW are inconsistent with the antagonistic pleiotropy model for the evolution of ageing. Hence, they should not be used to test any prediction that this model is supposed to entail about the evolution of the rate of ageing, notably, Williams' prediction according to which the higher the level of environmental mortality, the higher the evolutionarily favoured rate of ageing.

P53 and aging: A fresh look at an old paradigm

Apoptosis and cellular senescence, two key tumor suppression mechanisms, are thought to be antagonistically pleiotropic. Antagonistic pleiotropy holds that functions that are advantageous for a young and reproductively fit organism (eg. cancer protection and proper development) can be deleterious when that same organism becomes old (eg. loss of stem cell proliferation and tissue degeneration leading to diseases associated with age) [1]. This theory predicts that in an older animal (or human), the activity of tumor suppressors would be associated with enhanced aging phenotypes. However, confirmation of a direct connection between apoptosis, senescence and aging remains elusive [2]. In fact, at least in the case of p53 there is mounting data challenging the antagonistic pleiotropy model. Multiple lines of evidence from animal models suggest that a functional p53 pathway favors prolonged survival. Aging mice show a decrease in p53 activity correlated with increased tumor incidence as well as an overall reduction in longevity [3]. On the other hand, mice with an extra gene dosage of Arf and p53 show significant tumor protection, decreased oxidative damage and delayed aging [4]. Animals expressing the p53S18A mutation present with accelerated aging, and cells from these mice undergo early senescence [5]. As phosphorylation of p53 at Ser18 (Ser15 in humans) is associated with activation, these results highlight a requirement for intact p53 signaling in longevity [6]. In the nematodeCaenorhabditis elegans, mutations that lead to longevity preferentially antagonize tumor growth, likely due to an increase in DAF-16/p53-dependentapoptosis [7]. The mTOR pathway is intimately connected with organismal aging. In fact inhibition of mTOR either by treatment with rapamycin or by the inhibition of upstream signaling molecules, extends lifespan in yeast, worms and flies suggesting that this pathway may be one of the main mechanisms that decrease lifespan [8]. p53 is able to regulate activity of mTOR following DNA damage or oncogenic stress by activation of PTEN, AMP kinase and TSC-2, each of which signals to diminish the activity of mTOR (Figure ​(Figure1)1) [9,10]. p53 may also function downstream of mTOR by activating antioxidant genes and thus protecting cells against increased ROS levels in cells, one of the consequences of heightened mTOR activity [11-13]. Figure 1. Signaling circuitry connecting Mdm2 with the regulation of longevity and metabolism. As the ability of p53 to increase longevity becomes more evident, we should consider the role of its negative regulator, Mdm2, if not in the process of aging directly, at least in its effects on the activity of mTOR. Growth factor and oncogene signaling activate PI-3 kinase and its downstream effector AKT, a protein kinase that activates mTOR via inhibition of TSC-1 protein. AKT also phosphorylates Mdm2 leading to enhanced Mdm2 ubiquitin ligase activity and more rapid degradation of p53 (Figure ​(Figure1)1) [8,14]. Additionally, AKT stimulates FOXO phosphorylation, which results in FOXO nuclear exportation and ubiquitin dependent proteasomal degradation [15]. FOXO proteins have conserved abilities to increase longevity in worms and flies [16]. Indeed, Mdm2 was reported to function as an E3 ubiquitin ligase to promote FOXO degradation, following activation of AKT, thus forging an additional link between Mdm2 and changes in longevity [17]. Additionally, mTOR is able to positively regulate Mdm2 through an increase in translation of Mdm2 mRNA. Consistently, an increase in p53 dependent apoptosis in the liver of mouse embryos treated with Rapamycin in utero is attributed mTOR's ability to control translation of Mdm2 [18]. However, because the interplay between apoptosis and aging is likely to be highly context specific, it is important to note that mice expressing only ~30% of the wild type Mdm2 levels do not have an aging phenotype, while exhibiting clear enhancement in tumor protection [19]. It would be of interest to look at the effects of nutrient deprivation on the mice carrying an Mdm2 hypomorphic allele. In conclusion, as our notion of p53 function in aging and senescence changes, it is very tempting to imagine that just a slight inhibition of Mdm2 function in cells could both prolong full tumor surveillance mechanisms of p53, and in some circumstances increase longevity. Numerous molecular inhibitors of Mdm2 are in various stages of development with the goal of reactivating p53 activity in cancer [20]. The idea that controlled pharmacological modulation of Mdm2 function might also have positive consequences in extension of human lifespan could be an unexpected benefit and an additional incentive for design of new compounds targeting Mdm2.

Testing the antagonistic pleiotropy model of schizophrenia susceptibility by analysis of DAOA, PPP1R1B, and APOL1 genes

Schizophrenia is a common disease associated with reduced fertility. Therefore, the existence of common susceptibility alleles not removed by natural selection may be considered an evolutionary paradox. The antagonistic pleiotropy model, proposed to explain this paradox, states that an allele may be common because of its overall selective advantage, in spite of deleterious effects on specific traits. Recent work on DAOA, PPP1R1B, and APOL1 suggests that these genes present common alleles associated to increase risk of schizophrenia but conferring an overall selective advantage, related to better cognitive performance ( DAOA and PPP1R1B) or protection against pathogens ( APOL1). To test if these genes fit the antagonistic pleiotropy model, we searched for recent natural selection at these loci applying the long-range haplotype test on data from the HapMap Project; and performed case-control association analysis in a well-powered sample, including 301 schizophrenic patients and 604 controls from Spain. For DAOA and PPP1R1B, we genotyped the Single-nucleotide polymorphisms (SNPs) needed to replicate previous associations, while for APOL1, we genotyped 15 tagSNPs, and seven putative functional SNPs. We did not detect evidence of recent natural selection. Furthermore, we did not find significant associations. Thus, these genes do not fit the antagonistic pleiotropy model.

Drosophila melanogaster p53 has developmental stage-specific and sex-specific effects on adult life span indicative of sexual antagonistic pleiotropy

Truncated and mutant forms ofp53 affect life span in Drosophila, nematodes and mice, however the role of wild-type p53 in aging remains unclear. Here conditional over-expression of both wild-type and mutant p53 transgenes indicated that, in adult flies, p53 limits life span in females but favors life span in males. In contrast, during larval development, moderate over-expression of p53 produced both male and female adults with increased life span. Mutations of the endogenous p53 gene also had sex-specific effects on life span under control and stress conditions: null mutation of p53 increased life span in females, and had smaller, more variable effects in males. These developmental stage-specific and sex-specific effects of p53 on adult life span are consistent with a sexual antagonistic pleiotropy model.

What can genetic variation tell us about the evolution of senescence?

Quantitative genetic approaches have been developed that allow researchers to determine which of two mechanisms, mutation accumulation (MA) or antagonistic pleiotropy (AP), best explain observed variation in patterns of senescence using classical quantitative genetic techniques. These include the creation of mutation accumulation lines, artificial selection experiments and the partitioning of genetic variances across age classes. This last strategy has received the lion's share of empirical attention. Models predict that inbreeding depression (ID), dominance variance and the variance among inbred line means will all increase with age under MA but not under those forms of AP that generate marginal overdominance. Here, we show that these measures are not, in fact, diagnostic of MA versus AP. In particular, the assumptions about the value of genetic parameters in existing AP models may be rather narrow, and often violated in reality. We argue that whenever ageing-related AP loci contribute to segregating genetic variation, polymorphism at these loci will be enhanced by genetic effects that will also cause ID and dominance variance to increase with age, effects also expected under the MA model of senescence. We suggest that the tests that seek to identify the relative contributions of AP and MA to the evolution of ageing by partitioning genetic variance components are likely to be too conservative to be of general value.

Applying the genetic theories of ageing to the cytoplasm: cytoplasmic genetic covariation for fitness and lifespan

Two genetic models exist to explain the evolution of ageing - mutation accumulation (MA) and antagonistic pleiotropy (AP). Under MA, a reduced intensity of selection with age results in accumulation of late-acting deleterious mutations. Under AP, late-acting deleterious mutations accumulate because they confer beneficial effects early in life. Recent studies suggest that the mitochondrial genome is a major player in ageing. It therefore seems plausible that the MA and AP models will be relevant to genomes within the cytoplasm. This possibility has not been considered previously. We explore whether patterns of covariation between fitness and ageing across 25 cytoplasmic lines, sampled from a population of Drosophila melanogaster, are consistent with the genetic associations predicted under MA or AP. We find negative covariation for fitness and the rate of ageing, and positive covariation for fitness and lifespan. Notably, the direction of these associations is opposite to that typically predicted under AP.

Evolutionary genetics of ageing in the wild: empirical patterns and future perspectives

Summary 1 Classical evolutionary theory states that senescence should arise as a consequence of the declining force of selection late in life. Although the quantitative genetic predictions of hypotheses derived from this theory have been extensively tested in laboratory studies of invertebrate systems, relatively little is known about the genetics of ageing in the wild. 2 Data from long-term ecological studies is increasingly allowing quantitative genetic approaches to be used in studies of senescence in free-living populations of vertebrates. We review work to date and argue that the patterns are broadly consistent with theoretical predictions, although there is also a clear need for more empirical work. 3 We argue that further advances in this field of research might be facilitated by increased use of reaction norm models, and a decreased emphasis on attempting to discriminate between mutation accumulation and antagonistic pleiotropy models of senescence. We also suggest a framework for the better integration of environmental and genetic effects on ageing. 4 Finally, we discuss some of the difficulties in applying quantitative genetic models to studies of senescence outside the laboratory. In particular we highlight the problems that viability selection can cause for an accurate estimation of parameters used in the prediction of age-trajectory evolution.

Human ageing and telomeres.

Telomerase expression is repressed early in development in all normal somatic human tissues investigated to date, whereas activity and the expression of the RNA component for this enzyme are upregulated in almost all cases of malignant transformation and late-stage cancer. The telomere hypothesis of ageing and immortalization postulates that sufficient telomere loss on one or more chromosomes in normal somatic cells triggers cell senescence, whereas reactivation of the enzyme is necessary for cell immortalization. Measurements of telomere length and telomerase activity in cancer and during normal and accelerated human ageing in skin, blood, haemopoietic, skeletal muscle, vascular and CNS tissues support this model. Tissue culture studies of cell ageing and transformation have added to our understanding of telomere dynamics in these processes. Evolution of telomerase repression and mortality in somatic cells of long-lived organisms is consistent with antagonistic pleiotropy models in which cell senescence is a tumour suppressor mechanism: stringent repression of telomerase has a beneficial early effect in reducing the probability of cancer, but a deleterious, unselected late effect in its contributions to age-related disease.

Artificial Selection on Male Longevity Influences Age‐Dependent Reproductive Effort in the Black Field Cricket Teleogryllus commodus

Although the trade-off between reproductive effort and longevity is central to both sexual selection and evolutionary theories of aging, there has been little synthesis between these fields. Here, we selected directly on adult longevity of male field crickets Teleogryllus commodus and measured the correlated responses of age-dependent male reproductive effort, female lifetime fecundity, and several other life-history traits. Male longevity responded significantly to five generations of divergent selection. Males from downward-selected lines commenced calling sooner and reached their peak calling effort at a younger age. They called more per night and, despite living less than half as long, called more overall than males selected for increased longevity. Females from the downward-selected lines lived significantly shorter lives than females from the upward-selected lines but still produced the same number of offspring. Nymph survival, development time, and body size and weight at eclosion did not show significant correlated response to selection on male longevity, despite evidence for substantial genetic variation in each of these traits. Collectively, our findings directly support the antagonistic pleiotropy model of aging and suggest an important role for sexual selection in the aging process.

Quantitative genetics of age at reproduction in wild swans: support for antagonistic pleiotropy models of senescence.

Why do individuals stop reproducing after a certain age, and how is this age determined? The antagonistic pleiotropy theory for the evolution of senescence predicts that increased early-life performance should be accompanied by earlier (or faster) senescence. Hence, an individual that has started to breed early should also lose its reproductive capacities early. We investigate here the relationship between age at first reproduction (AFR) and age at last reproduction (ALR) in a free-ranging mute swan (Cygnus olor) population monitored for 36 years. Using multivariate analyses on the longitudinal data, we show that both traits are strongly selected in opposite directions. Analysis of the phenotypic covariance between these characters shows that individuals vary in their inherent quality, such that some individuals have earlier AFR and later ALR than expected. Quantitative genetic pedigree analyses show that both traits possess additive genetic variance but also that AFR and ALR are positively genetically correlated. Hence, although both traits display heritable variation and are under opposing directional selection, their evolution is constrained by a strong evolutionary tradeoff. These results are consistent with the theory that increased early-life performance comes with faster senescence because of genetic tradeoffs.

The Effect of Antagonistic Pleiotropy on the Estimation of the Average Coefficient of Dominance of Deleterious Mutations

We investigate the impact of antagonistic pleiotropy on the most widely used methods of estimation of the average coefficient of dominance of deleterious mutations from segregating populations. A proportion of the deleterious mutations affecting a given studied fitness component are assumed to have an advantageous effect on another one, generating overdominance on global fitness. Using diffusion approximations and transition matrix methods, we obtain the distribution of gene frequencies for nonpleiotropic and pleiotropic mutations in populations at the mutation-selection-drift balance. From these distributions we build homozygous and heterozygous chromosomes and assess the behavior of the estimators of dominance. A very small number of deleterious mutations with antagonistic pleiotropy produces substantial increases on the estimate of the average degree of dominance of mutations affecting the fitness component under study. For example, estimates are increased three- to fivefold when 2% of segregating loci are over-dominant for fitness. In contrast, strengthening pleiotropy, where pleiotropic effects are assumed to be also deleterious, has little effect on the estimates of the average degree of dominance, supporting previous results. The antagonistic pleiotropy model considered, applied under mutational parameters described in the literature, produces patterns for the distribution of chromosomal viabilities, levels of genetic variance, and homozygous mutation load generally consistent with those observed empirically for viability in Drosophila melanogaster.

Response of Sod-2 enzyme activity to selection for high voluntary wheel running.

The objective of this study was to examine the correlated response of anti-oxidant enzyme activity to selective breeding for increased voluntary wheel running in house mice. Activity of liver superoxide dismutase-2 (Sod-2), a free radical scavenger, was measured in four groups of mice. 'Active' individuals were housed in cages with attached wheels for 8 weeks beginning at weaning; 'sedentary' individuals were housed in cages with attached wheels that were prevented from rotating. Both of these treatments were applied to male and female mice from generation 14 of a replicated artificial selection experiment, which is composed of four lines selected for high wheel running and four randomly bred lines that serve as controls. In females, Sod-2 activity was significantly lower in selected vs control animals, regardless of presence/absence of a free-turning wheel. This difference suggests a trade-off between early-age voluntary wheel-running activity and Sod-2 activity. In males, Sod-2 activity was significantly affected by an interaction between selection group and activity group, with males from selected lines having lower Sod-2 activity relative to control males only in the sedentary treatment. These negative correlated responses of Sod-2 activity to selection on wheel running are discussed in the context of antagonistic pleiotropy models of aging and with respect to potential effects on lifespan.

Age-specific inbreeding depression and components of genetic variance in relation to the evolution of senescence.

Two major theories of the evolution of senescence (mutation accumulation and antagonistic pleiotropy) make different predictions about the relationships between age, inbreeding effects, and the magnitude of genetic variance components of life-history components. We show that, under mutation accumulation, inbreeding decline and three major components of genetic variance are expected to increase with age in randomly mating populations. Under the simplest version of the antagonistic pleiotropy model, no changes in the severity of inbreeding decline, dominance variance, or the genetic variance of chromosomal homozygotes are expected, but additive genetic variance may increase with age. Age-specific survival rates and mating success were measured on virgin males, using lines extracted from a population of Drosophila melanogaster. For both traits, inbreeding decline and several components of genetic variance increase with age. The results are consistent with the mutation accumulation model, but can only be explained by antagonistic pleiotropy if there is a general tendency for an increase with age in the size of allelic effects on these life-history traits.

Age-specific patterns of genetic variance in Drosophila melanogaster. II. Fecundity and its genetic covariance with age-specific mortality.

Under the mutation accumulation model of senescence, it was predicted that the additive genetic variance (VA) for fitness traits will increase with age. We measured age-specific mortality and fecundity from 65,134 Drosophila melanogaster and estimated genetic variance components, based on reciprocal crosses of extracted second chromosome lines. Elsewhere we report the results for mortality. Here, for fecundity, we report a bimodal pattern for VA with peaks at 3 days and at 17-31 days. Under the antagonistic pleiotropy model of senescence, it was predicted that negative correlations will exist between early and late life history traits. For fecundity itself we find positive genetic correlations among age classes > 3 days but negative nonsignificant correlations between fecundity at 3 days and at older age classes. For fecundity vs. age-specific mortality, we find positive fitness correlations (negative genetic correlations) among the traits at all ages > 3 days but a negative fitness correlation between fecundity at 3 days and mortality at the oldest ages (positive genetic correlations). For age-specific mortality itself we find overwhelmingly positive genetic correlations among all age classes. The data suggest that mutation accumulation may be a major source of standing genetic variance for senescence.

Evolutionary mechanisms of senescence.

This paper reviews theories of the evolution of senescence. The population genetic basis for the decline with age in sensitivity of fitness to changes in survival and fecundity is discussed. It is shown that this creates a pressure of selection that disproportionately favors performance early in life. The extent of this bias is greater when there is a high level of extrinsic mortality; this accounts for much the diversity in life-history patterns among different taxa. The implications of quantitative genetic theory for experimental tests of alternative population genetic models of senescence are discussed. In particular, the negative genetic correlations between traits predicted by the antagonistic pleiotropy model may be obscured by positive correlations that are inevitable in a multivariate system, or by the effects of variation due to deleterious mutations. The status of the genetic evidence relevant to these theories is discussed.