Greater Fitness in Humans Implies a Younger Epigenome and Transcriptome

Exercise improves health and life expectancy in humans, so it shouldn't be all that surprising to find studies in which assessments of the epigenome and transcriptome show signs of greater youth in people with greater aerobic fitness. It is in fact somewhat surprising that early epigenetic clocks were insensitive to the state of physical fitness. In the study noted here, the researchers do not use any of the existing epigenetic or transcriptomic clocks, and instead build their own assessment of the youthfulness of epigenetic and transcriptomic profiles as compared to chronological age. The findings are interesting, but specific to muscle tissue rather than the body as a whole.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (nā€‰=ā€‰3,176).

We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse.

We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.


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