Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late- life exercise mitigates epi -genetic 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 aero -bic 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 struc-ture, 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.