The genetic architecture of aging: sexual antagonistic pleiotropy of p53 and foxo

Current theories suggest that aging results from pleiotropy of gene function – that is, the ability of the same gene to be beneficial in one context but deleterious in another context^[1]. The declining force of natural selection as a function of age is predicted to result in the accumulation of inherited alleles with late-acting deleterious effects (“mutation accumulation”). If these same alleles produce positive effects earlier in life they can be maintained by positive selection despite their late-acting deleterious effects (“antagonistic pleiotropy” AP; Figure 1A). Because the sexes share most of the same genes, yet are under different selective pressures, alleles may accumulate that are relatively deleterious to one or both sexes, because they have been selected for sex-specific functions (“sexual antagonistic pleiotropy” SAP; Figure 1B)^[2]. The prediction from these models is that genes affecting aging should tend to have developmental stage-specific and sex-specific effects, and so far the data appear to support this prediction. For example, quantitative trait loci (QTLs) affecting Drosophila life span have developmental stage-specific and age-specific effects that are often opposite in males and females^[3].

Figure 1.

Gene pleiotropy in aging. A. Antagonistic pleiotropy refers to genes that have a beneficial and selectively advantageous effect in young animals, but that contribute to aging in old animals. B. Sexual antagonistic pleiotropy refers to genes that respond to sex-specific selective pressures, resulting in a benefit to one sex and a detrimental effect in the other sex, or a detriment to both sexes. C. Model for SAP of p53 and foxo in adult flies. The black arrows and bars summarize the effects of wild-type p53 over-expression on life span in males and females. The opposite effects on longevity of p53 over-expression in nervous system relative to tissue-general over-expression suggest that signals from nervous system may act to repress the effects on longevity caused by the peripheral tissues. In females, relatively greater levels of IIS act through InR and chico to repress Foxo activity. In males, the relatively greater Foxo activity interacts with p53 to alter the effect of p53 in peripheral tissues from a negative effect on longevity to a positive effect on longevity. Therefore, in a foxo null background, the effects of p53 over-expression on life span become reversed in males, becoming like the pattern in females.

Recently Waskar et al reported that Drosophila p53 has developmental stage-specific and sex-specific effects on adult life span that are indicative of SAP^[4]. For example, tissue-general over-expression of wild-type p53 (isoform A) in adult flies caused decreased life span in females and increased life span in males, and mutations of the endogenous p53 gene also had sex-specific effects on life span. In addition to being sex-specific, the effects of p53 on fly life span were also tissue-specific: over-expression of wild-type p53 in nervous system caused increased life span in females and decreased life span in males –i.e, opposite of the pattern observed upon tissue-general expression^[5]. The opposing effects on life span caused by p53 over-expression in nervous tissue versus peripheral tissues suggests a model involving inter-tissue signaling, which is known to be important in regulating longevity^{[6, 7]} (Figure 1C). Consistent with the observation of SAP of p53 function in Drosophila, in humans p53 mutations have sex-biased effects on cancer incidence, and certain p53 alleles have been linked to human longevity^[8].

The Drosophila foxo gene has recently been found to interact with p53 transgenes to affect life span in a sex-specific manner^[5]. In females nervous-system-specific over-expression of p53 increased life span in a foxo null background, demonstrating that p53 can regulate life span independent of foxo. However, in males the foxo null mutation caused the tissue-specific effects of p53 on life span to become reversed in sign, becoming like the pattern in females. This indicates that foxo acts in males to create the sexual-dimorphism in tissue-specific p53 life span effects (Figure 1C). Consistent with the idea of greater Foxo activity in males, the Foxo target genes l(2)efl and 4EBP were expressed at higher levels in males than in females, in a foxo-dependent manner^[5]. In general agreement with these observations, a recent study of 1,332 P-element induced mutations revealed that sexually antagonistic effects on life span are common, and identified a specific mutation of the foxo gene that increases life span in males but not females^[9].

IIS negatively regulates life span across several species, including C. elegans, Drosophila and mammals, and in C. elegans this has been shown to result from IIS repression of Foxo activity^[6]. In Drosophila, mutation of the IIS pathway components chico^[10] and Insulin-like receptor (InR)^[11] caused greater increases in life span in females than in males, indicating that IIS limits life span to a greater extent in Drosophila females than in males. Moreover, tissue-specific over-expression of Foxo is reported to increase fly life span, with greater increases generally observed in females relative to males^[7]. These results are consistent with a model involving greater levels of IIS activity and Foxo inactivation in Drosophila females, resulting in relatively greater Foxo activity in males (Figure 1C). The greater Foxo activity in males then interacts with p53 to cause the sexual dimorphism in p53 life span effects in adult flies.

Taken together the data support a model in which IIS favors aging, at least in part, by promoting sexual differentiation and the SAP of p53 and foxo^{[2, 4, 5]}. In the future it will be of interest to determine if asymmetry in IIS between the sexes might underlie the SAP of genes in addition to p53 and foxo, and whether other pathways known to promote aging, such as TOR, RAS, oxidative stress, etc., might also act to promote sexual differentiation and the SAP of p53 and foxo and/or other genes.

Abbreviations

IIS

insulin/IGF1-like signaling

AP

antagonistic pleiotropy

SAP

sexual antagonistic pleiotropy