Why do sexes differ in lifespan extension? Sex-specific pathways of aging and underlying mechanisms for dimorphic responses

Abstract

Males and females typically have different lifespans and frequently differ in their responses to anti-aging interventions. These sex-specific responses are documented in mice and Drosophila species, in addition to other organisms where interventions have been tested. While the prevalence of sex-specific responses to anti-aging interventions is now recognised, the underlying causes remain poorly understood. This review first summarises the main pathways and interventions that lead to sex-specific lifespan responses, including the growth-hormone/insulin-like growth factor 1 (GH-IGF1) axis, mechanistic target of rapamycin (mTOR) signalling, and nutritional and pharmacological interventions. After summarising current evidence, several different potential causes for sex-specific responses are discussed. These include sex-differences in xenobiotic metabolism, differing disease susceptibility, sex-specific hormone production and chromosomes, and the relative importance of different signalling pathways in the control of male and female life-history. Understanding why sex-differences in lifespan-extension occur should provide a greater understanding of the mechanisms that regulate the aging process in each sex, and will be crucial for understanding the full implications of these treatments if they are translated to humans.