Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci

Abstract

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 it may drive androgen-dependent hypomethylation in divergent mammalian species. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

DNA methylation aging and transcriptomic studies in horses

“…This negative result echoes the same finding for blood samples from cats 29 . By contrast, castration was found to slow epigenetic aging in ear samples from sheep 40 .…”

“…These relationships require validation in new data and also a consideration for a potential confounding effect of horse breeds. f The overlap of castration methylation signatures between horse blood and sheep ears 40 . Although we considered the top 1 thousand significant CpGs in sheep (500 in each direction), we only found one overlapping CpG.…”

“…We used results from a recent study evaluating the effects of castration on DNAm patterns in ear punch samples from sheep 40 to investigate if commonality exists between observed methylation loss or gain following castration from these two divergent species. EWAS comparisons of the top 500 age-related CpGs revealed a single CpGs (adjacent to ARX 3’UTR) that gained methylation following castration in both horse blood and sheep ears (Horse blood: p = 3.49e−6, false discovery rate = 0.008, sheep ear: p = 3.14e−17, FDR = 4.6e−15, Fig.…”

Variability in Global DNA Methylation Rate Across Tissues and Over Time in Sheep

“…Aging has been reported to have a profound effect on DNA methylation in many tissues and cell types ( Rakyan et al, 2010 ; Teschendorff et al, 2010 ; Horvath, 2013 ; Issa, 2014 ). In sheep, like in other species, an epigenetic clock has been described that is capable of estimating chronological age and of detecting accelerated rates of aging ( Sugrue et al, 2021 ). However in our study, the time series only covered the first 6 months of life of the lambs and this was probably too short to detect a major effect of aging on GDMR.…”

Androgen Elevation Accelerates Reproductive Senescence in Three-Spined Stickleback

“…Given this connection between any physiological cost paid to enhance current reproductive success at the expense of future reproductive success, we may expect physiological regulators balancing these investment decisions. Hormones, and in particular sex hormones, have gathered considerable attention in this regard (Hau, 2007;Regan et al, 2019;Bell, 2020;Garratt et al, 2020;Sugrue et al, 2021). In sexual signaling studies, testosterone specifically has attracted considerable attention for several reasons.…”