Fight Aging!

It seems likely that researchers will still be debating the well-established difference in life expectancy between men and women long after the first rejuvenation therapies make that difference irrelevant. Of the many possible contributing causes, it at least seems reasonable to rule out the sociological explanations based on behavioral differences, given that sex differences in life span are observed in many species. That still leaves a great many possibly contributing mechanisms, and the observed outcome may well result from the combination of many individually small effects rather than any one dominant single cause.

Today's open access paper might be taken as an argument for that combination of small effects. The researchers note that genetic associations with longevity are stronger for women in their data set. This supports a viewpoint on the evolution of human longevity that looks something like the grandmother hypothesis, in that selection pressure emerged for women to live longer, driven by the support they provided to the reproductive fitness of their immediate descendants. Thus altered forms of a large number of diverse mechanisms of metabolism were selected to produce that outcome. Men were dragged along as many mechanisms relevant to life span are extremely similar between sexes, but did not obtain the full effect as their longevity was not under direct selection in the same way.

Genetic associations with longevity are on average stronger in females than in males

In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians.

Our results beg the question of why are genetic associations with longevity on average stronger in females than in males? The fact that females take much more care for childbearing and offspring than males may shed light on answering this question. Studies related to age-specific manifestation of genetic load suggest that fertility serves as the major factor of Darwinian natural selection for the accumulation of genetic mutation driving population survival and growth. The grandmother hypothesis proposed that postmenopausal longevity in human evolved from grandmothers' assistance with childcare, which prolonged females' lifespan.

A study reported that female centenarians were four times more likely to have children in their forties than females who lived only to age 73. Other studies (including analyses based on the CLHLS datasets) also found that females' late childbearing after ages 35 or 40 is positively and significantly associated with longevity. A study indicated that the longevity advantage of females over males may be a by-product of genetic evolution that maximizes the length of time during which females could bear and take care of children and contribute to human reproduction. The reproductive function of females might serve as a driving force for positive selection on the human genome and the related physiological features, such as immune response and metabolism. During periods of stress such as starvation, females use available amino acids to create deposits in the liver to support reproduction; conversely males slow down anabolic pathways and reserve carbohydrate stores for eventual use by the musculature.

Sex differences in genetics also affect innate and adaptive immunity. Various studies have reported a more progressive decline in immunity and dysregulated inflammatory response with increase of age in males than in females. In the current study, our pathway analysis revealed neuronal system, glycosaminoglycan biosynthesis-heparan sulfate, NABA ECM glycoproteins, and cell-cell junction organization are male-specific pathways, and neuroactive ligand receptor interaction is the female-specific pathway. Interestingly, it is previously reported that reductions of heparan sulfate biosynthetic gene function increased lifespan in Drosophila parkin mutants.