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Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter\u2010organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age\u2010related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context\u2010sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non\u2010pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality\u2010control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber\u2010type\u2013specific and age\u2010dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality\u2010control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non\u2010pharmacological approach to preserve mitochondrial quality and functional resilience during aging.<\/jats:p>","DOI":"10.1002\/iub.70127","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:34:46Z","timestamp":1787132086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age\u2010Related Disease"],"prefix":"10.1002","volume":"78","author":[{"given":"Peng","family":"Ran","sequence":"first","affiliation":[{"name":"Department of Arts and Physical Education Huanghe University of Science and Technology  Zhengzhou Henan 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