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 (n = 3176). 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.
|Number of pages||15|
|Early online date||2 May 2023|
|Publication status||Published online - 2 May 2023|
Bibliographical noteFunding Information:
This work was supported by Sarah Voisin's National Health & Medical Research Council (NHMRC) Early Career Research Fellowship (APP11577321) and by Nir Eynon's NHMRC Career Development Fellowship (APP1140644). The Gene SMART and LITER studies were both supported by the Collaborative Research Network for Advancing Exercise and Sports Science (201202) scheme awarded to VGC and KJA from the Department of Education and Training, Australia. Mr Nicholas Harvey was supported by a Ph.D. stipend also provided by Bond University CRN‐AESS. This research was also supported by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia – Queensland Node project (LRG). Work at Ulster was supported by an Interdisciplinary Award. We also greatly acknowledge Erika Guzman at the ATGC/IHBI/QUT for performing the HMEPIC assays in the LITER study. The EPIK study was supported by the Research Foundation Flanders (FWO G.0898.15). Open access publishing facilitated by Victoria University, as part of the Wiley ‐ Victoria University agreement via the Council of Australian University Librarians.
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
- cardiorespiratory fitness
- DNA methylation
- exercise training
- human skeletal muscle
- mRNA expression