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

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; Reuben R Hore; Michael Garratt; Karen E Sears; Nan Wang; Xiangdong William Yang; Russell G Snell; Timothy A Hore; Steve Horvath

doi:10.7554/eLife.64932

eLife (Jul 2021)

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

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,
Reuben R Hore,
Michael Garratt,
Karen E Sears,
Nan Wang,
Xiangdong William Yang,
Russell G Snell,
Timothy A Hore,
Steve Horvath

Affiliations

Victoria J Sugrue: ORCiD; Department of Anatomy, University of Otago, Dunedin, New Zealand
Joseph Alan Zoller: ORCiD; Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, United States
Pritika Narayan: Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand
Ake T Lu: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Oscar J Ortega-Recalde: Department of Anatomy, University of Otago, Dunedin, New Zealand
Matthew J Grant: Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand
C Simon Bawden: Livestock and Farming Systems, South Australian Research and Development Institute, Roseworthy, Australia
Skye R Rudiger: Livestock and Farming Systems, South Australian Research and Development Institute, Roseworthy, Australia
Amin Haghani: ORCiD; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Donna M Bond: Department of Anatomy, University of Otago, Dunedin, New Zealand
Reuben R Hore: Blackstone Hill Station, Becks, RD2, Omakau, New Zealand
Michael Garratt: Department of Anatomy, University of Otago, Dunedin, New Zealand
Karen E Sears: ORCiD; Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, United States
Nan Wang: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, United States
Xiangdong William Yang: ORCiD; 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
Russell G Snell: Applied Translational Genetics Group, School of Biological Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand
Timothy A Hore: ORCiD; Department of Anatomy, University of Otago, Dunedin, New Zealand
Steve Horvath: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

DOI: https://doi.org/10.7554/eLife.64932
Journal volume & issue: Vol. 10

Abstract

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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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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