Late‐life exercise mitigates skeletal muscle epigenetic aging

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.