Skeletal Muscle Aging Is a Significant Contributor to Systemic Aging

Abstract

Skeletal muscle aging is a conserved biological process characterized by progressive declines in muscle mass, strength, regenerative capacity, and metabolic adaptability, contributing to impaired mobility, frailty and age-related diseases. Beyond its canonical role in locomotion, skeletal muscle functions as an endocrine and metabolic organ that actively regulates organismal aging through myokines, metabolites, extracellular vesicles, thermogenic activity, and dynamic communication with distant organs. In this review, we summarize the intrinsic mechanisms driving skeletal muscle aging, including protein turnover imbalance and anabolic resistance, myosteatosis, denervation and motor unit loss, and cellular composition remodeling. We also discuss how aging skeletal muscle influences systemic aging through bidirectional interactions with metabolic organs, brain, cardiovascular system, and bone via endocrine signaling and interorgan communication. Finally, we highlight emerging interventions targeting skeletal muscle aging, including exercise, nutritional strategies, pharmacological approaches, and other novel therapies. Understanding skeletal muscle as both a target and regulator of systemic aging provides a framework for developing strategies to promote healthy aging and reduce the burden of age-associated diseases.