Castration Delays Epigenetic Aging in Male Sheep
Castration is known to extend life in male sheep. Researchers here show that epigenetic clocks constructed for this species show the expected slowing of epigenetic aging following castration. This is a way to dig deeper into the question of how it is that females live longer than males in mammalian species, an exploration of which mechanisms are important in determining that outcome. It is also a way to further explore how epigenetic clocks relate to biological aging. Since the clocks are constructed by machine learning approaches applied to epigenetic data, it remains far from clear as to what exactly they measure under the hood, meaning which of the processes of aging are driving changes in specific epigenetic marks used in the clocks.
In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age and identifying novel factors influencing the aging rate using only DNA methylation data. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens.
Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Comparable sex-specific methylation differences in MKLN1 also exist in bat skin and a range of mouse tissues that have high androgen receptor expression, indicating that it may drive androgen-dependent hypomethylation in divergent mammalian species. In characterizing these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.