Sex-specific regulation of aging and apoptosis

Abstract

Genetic analysis of Drosophila, mice and humans indicates that gene alleles, mutations and transgenes that affect life span tend to do so differently depending on the sex of the organism. The likely reason for this is that the sexes are different genotypes (e.g., X/X vs. X/Y) and face quite different environments: e.g., to reproduce, males have to mate with females while females have to mate with males. Genes are subject to different genetic interactions and different gene-by-environment effects in male vs. female. The consequence is that through evolution certain genes are differently selected and optimized for each sex. Both the mitochondrial genome and the X chromosome are asymmetrically inherited in Drosophila and mammals; through evolution these genes spend relatively more time under selection in females and are therefore expected to be better optimized for function in the female than in the male. Consistent with this the Drosophila X chromosome has been found to be a hotspot for sexually antagonistic fitness variation. Old Drosophila and old mammals exhibit apoptosis-an observation consistent with the idea that the mitochondria are less functional during aging due to maternal-only inheritance. One feature of aging that is common to Drosophila and mammals is that females tend to live longer than males, and this may be due in part to sub-optimal mitochondrial function in males. The data support the conclusion that a significant part of the aging phenotype is due to antagonistic pleiotropy of gene function between the sexes. Liberal application of Occam's razor yields a molecular model for the co-regulation of sex, apoptosis and life span based on the on/off status of a single gene: Sxl in Drosophila melanogaster and Xist in humans. Aging may simply represent an ancient and conserved mechanism by which genes re-assort.