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 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.
Highlights
Age has a profound effect on DNA methylation in many tissues and cell types (Horvath, 2013; Issa, 2014; Rakyan et al, 2010; Teschendorff et al, 2010)
We developed the first epigenetic clock for sheep and show that it is capable of estimating chronological age with a median absolute error (MAE) of 5.1 months – between 3.5% and 4.2% of the average sheep lifespan
Improved survival has previously been reported in castrated sheep compared to intact males and females, at least part of which has been attributed to behavioral changes such as reduced aggression (Jewell, 1997)
Summary
Age has a profound effect on DNA methylation in many tissues and cell types (Horvath, 2013; Issa, 2014; Rakyan et al, 2010; Teschendorff et al, 2010). Despite being one of the earliest epigenetic clocks constructed, Horvath’s 353 CpG site clock is capable of estimating chronological age with a median absolute error (MAE) of 3.6 years and an age correlation of 0.96, irrespective of tissue or cell type (Horvath, 2013). Estimates generated by this and related epigenetic clocks are predictive of chronological age and biological age, allowing identification of pathologies as well as novel genetic and environmental factors that accelerate or slow biological aging. Irrespective of ethnic background, females and exceptionally long-lived individuals are found to have reduced epigenetic aging compared to males and other controls (Horvath et al, 2016; Horvath et al, 2015)
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