Myokines in Aging: A Multi-Organ Network Perspective

Exercise training represents a well-established anti-aging intervention that counteracts the multisystem functional decline. Skeletal muscle, the primary effector of physical activity, functions as a potent secretory organ, releasing myokines and extracellular vesicles into circulation. These muscle-derived factors mediate extensive crosstalk between muscle and distant organs, thereby coordinating the multi-tissue adaptations that underline the systemic benefits of exercise. This review synthesizes current knowledge on how myokine networks counteract aging across key physiological systems-including the metabolic, cardiovascular, musculoskeletal, nervous, and immune systems-by modulating core aging-related processes such as chronic inflammation, metabolic dysregulation, and loss of tissue homeostasis. We highlight how diverse myokines converge on conserved signaling hubs to exert integrated protective effects and discuss the profound influence of sex and age on myokine action. Finally, we outline the translational potential of, and challenges to, harnessing this myokine network in clinical practice, proposing personalized exercise regimens and engineered myokine-based therapies as promising strategies for promoting healthy aging.