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

eLife

Pritika Narayan¹  Matthew J Grant¹  Russell G Snell¹  Reuben R Hore²  Nan Wang³  Xiangdong William Yang⁴  Timothy A Hore⁵  Oscar J Ortega-Recalde⁵  Michael Garratt⁵  Victoria J Sugrue⁵  Donna M Bond⁵  Joseph Alan Zoller⁶  Karen E Sears⁷  Amin Haghani⁸  Steve Horvath⁸  Ake T Lu⁸  Skye R Rudiger⁹  C Simon Bawden⁹ 

[1] Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand;Blackstone Hill Station, Becks, RD2, Omakau, New Zealand;Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, United States;Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, United States;Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, United States;Department of Anatomy, University of Otago, Dunedin, New Zealand;Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, United States;Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, United States;Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States;Livestock and Farming Systems, South Australian Research and Development Institute, Roseworthy, Australia;

关键词: castration;    epigenetic clock;    DNA methylation;    sheep;    aging;    androgens;    Human;    Mouse;    Other;   

DOI  :  10.7554/eLife.64932

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY