There are functional benefits to exercise in muscle, even when performed late in life, but the contributions of epigenetic factors to late-life exercise adaptation are poorly defined. Using reduced representation bisulfite sequencing (RRBS), ribosomal DNA (rDNA) and mitochondrial-specific examination of methylation, targeted high-resolution methylation analysis, and DNAge™ epigenetic aging clock analysis with a translatable model of voluntary murine endurance/resistance exercise training (progressive weighted wheel running, PoWeR), we provide evidence that exercise may mitigate epigenetic aging in skeletal muscle. Late-life PoWeR from 22–24 months of age modestly but significantly attenuates an age-associated shift toward promoter hypermethylation. The epigenetic age of muscle from old mice that PoWeR-trained for eight weeks was approximately eight weeks younger than 24-month-old sedentary counterparts, which represents ~8% of the expected murine lifespan. These data provide a molecular basis for exercise as a therapy to attenuate skeletal muscle aging.

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Published in Aging Cell, e13527.

© 2021 The Authors

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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The authors wish to thank Drs. Keith Booher and Kai Chang of Zymo Research and Drs. John McCarthy and Charlotte Peterson of the University of Kentucky Center for Muscle Biology for their support and encouragement, as well as their grant funding (National Institutes of Health AR060701 and DK119619).

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All sequencing data are made available through GEO: GSE175410, and processed raw data are presented in supplemental tables.

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Supporting information: Figures, tables, and supplementary material