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

By Victoria J Sugrue, Joseph Alan Zoller, Pritika Narayan, Ake T Lu, Oscar J Ortega-Recalde, Matthew J Grant, C. Simon Bawden, Skye R Rudiger, Amin Haghani, Donna M Bond, Mike Garratt, Karen E. Sears, Nan Wang, Xiangdong (William) Yang, Russell Snell, Timothy A Hore, Steve Horvath

Posted 17 Nov 2020
bioRxiv DOI: 10.1101/2020.11.16.385369

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 using only DNA methylation data. These clocks have been used to identify novel factors influencing the aging rate, but few studies have examined the performance of epigenetic clocks in divergent mammalian species. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), and using 185 CpG sites can predict chronological age with a median absolute error of 5.1 months from ear punch and blood samples. 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. Many of these androgen sensitive demethylating sites are regulatory in nature and located in genes with known androgen-dependent regulation, such as MKLN1, LMO4 and FN1. Comparable sex-specific methylation differences in MKLN1 also exist in mouse muscle (p=0.003) but not blood, indicating that androgen dependent demethylation exists in multiple mammalian groups, in a tissue-specific manner. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging. ### Competing Interest Statement SH is a founder of the non-profit Epigenetic Clock Development Foundation which plans to license several patents from his employer UC Regents. These patents list SH as inventor. TAH and DMB are a shareholders and directors of Totovision Ltd, a small agricultural and biotechnology consultancy. The other authors declare no conflicts of interest.

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