The Role of Exercise in Regulating Histone Modifications and Non-coding RNAs in Muscle Aging and Sarcopenia

Sarcopenia, the progressive loss of skeletal muscle mass and function with age, is a major contributor to frailty and decreased quality of life in older adults. While physical exercise remains the most effective intervention, its molecular mechanisms of action are not fully understood. Emerging evidence highlights the central role of epigenetic regulation-including histone modifications and non-coding RNAs (ncRNAs)-in mediating both the pathogenesis of sarcopenia and the adaptive responses to exercise. This review synthesizes current findings on how aging disrupts the epigenetic landscape of skeletal muscle, fostering anabolic resistance, inflammation, and impaired regeneration. We explore how exercise reverses these effects by modulating histone acetylation, methylation, and the novel mark of lactylation, thereby reactivating key genes involved in muscle maintenance and repair. Additionally, we detail how specific microRNAs and long non-coding RNAs contribute to muscle plasticity, and how their dysregulation underlies age-related functional decline. Importantly, we emphasize the interplay between histone modifiers and ncRNAs, and the translational evidence from human trials supporting exercise as an epigenetic reprogramming agent. Although human evidence is limited compared to animal models, emerging clinical studies in older adults demonstrate that resistance and endurance training modulate histone acetylation/methylation and miRNA profiles, with dose-dependent benefits on muscle function and epigenetic markers (e.g., reduced epigenetic age acceleration via methylation clocks in active elderly). These insights offer promising avenues for therapeutic strategies aimed at extending healthspan and combating sarcopenia in aging populations.