Fight Aging!

The well-known difference in longevity between genders, in which females live longer than males, is not peculiar to our species. It is present in most gendered species examined to date, which strongly suggests that these differences in the pace of aging arise quite robustly from the interaction of evolutionary pressures with gender roles in mating and reproduction. Males can achieve reproductive fitness by investing resources into mating sooner rather than later, while for females greater fitness arises through investing resources to retain the capacity to mate successfully over time. The male candle burns brighter and less long. This is an overly simple summary of a complicated and much debated area of research, however.

The research reported here is an interesting addition to the literature on this topic. Some years ago the scientific community engineered mouse lineages with a mix of sex chromosomes and gonads, so as to obtain physically male mice with female sex chromosomes, and vice versa. Most mammals have two sex chromosomes, X and Y, producing XX chromosome females and XY chromosome males. This allows researchers to split out the contribution of sex chromosomes versus gonads for most gender differences, and determine relative level of importance. Here the researchers have chosen to focus on differences in the pace of aging, running a lifespan study on mice with different combinations of sex chromosomes and gonads. Unsurprisingly, both female sex chromosomes and gonads provide a modest survival advantage. The sex chromosome effect is larger, however, which might not be the expected outcome for many observers.

This is all, of course, a matter of purely scientific interest rather than a matter of relevance to the future of aging. The introduction of rejuvenation therapies will make any of the existing disparities in aging irrelevant, and the mechanisms that produce gender differences in longevity have no role to play in the development of rejuvenation therapies. These therapies will work through repair of the molecular damage that causes aging, which is exactly the same in both genders. When it becomes possible for everyone to use medical science to live decades longer in good health, few people will care about evolved difference that might add or subtract a few years from human life spans.

Female XX sex chromosomes increase survival and extend lifespan in aging mice

Women live longer than men around the world, regardless of culture or socioeconomic status. Female longevity is also observed in the animal kingdom due to causes that may be extrinsic, intrinsic, or both. Extrinsic causes of sex difference in invertebrates can signal antagonistic survival strategies: female pheromones reduce male lifespan in Drosophila, and male secretions shorten hermaphrodite lifespan in C. elegans. Intrinsic effects - operating within the organism - underlie longer life in organisms following removal of reproductive cells or organs in C. elegans hermaphrodites, male and female dogs, and possibly men as suggested by a study of eunuchs. Nonetheless, causes of intrinsic sex difference in lifespan remain largely unknown. The pervasive nature of female longevity in humans, even in early death during severe epidemics and famine, suggests a role for innate biology in the survival gap between the sexes. Here, we sought to identify intrinsic causes of female longevity in mammalian lifespan.

Sex chromosomes or gonads cause intrinsic sex differences in mammals, but whether they directly contribute to increased female lifespan is unknown in mammalian aging. To dissect these etiologies, we used four core genotypes (FCG) mice. In mice and humans, the Sry gene normally resides on the Y chromosome and codes for a protein (testicular determining Y factor) that induces development of testes and perinatal masculinization. In FCG mice, Sry resides instead on an autosome, enabling inheritance of Sry - and thus male, testicular phenotype - with or without the Y chromosome. The genetic manipulation of SRY generates XX and XY mice, each with either ovaries (O) or testes (T): XX(O), XX(T), XY(O), XY(T). Gonadal hormone levels in FCG mice with the same gonads are comparable, regardless of their sex chromosomes. In FCG model mice, a sex difference with a main effect that statistically differs by genotype (XX vs. XY) is sex chromosome-mediated; one that differs by phenotype (ovaries vs. testes) is gonadal sex-mediate. Examples of age-relevant FCG mouse studies show that XX improves blood pressure regulation and attenuates experimental brain injuries.

To explore sex-based differences in lifespan, we generated and aged over 200 mice from the FCG model on a congenic C57BL/6J background and investigated aging-dependent mortality from midlife to old age (12-30 months). We first examined whether mortality in "typical" females (XX,O) and males (XY,T) recapitulates the pattern of female longevity. Indeed, aging females (XX,O) lived longer than aging males (XY,T). We next measured main effects of sex chromosomes and gonads on survival in aging. XX mice with ovaries or testes lived longer than XY mice of either gonadal phenotype, indicating a main effect of sex chromosomes on lifespan. Mice with ovaries (XX and XY) tended to live longer than those with testes (XX and XY), suggesting a gonadal influence on lifespan. Collectively, these data indicate that the XX genotype increases survival in aging - and suggest a protective effect of ovaries.