Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age‐Related Disease

Abstract

Aging is increasingly recognized as a systems‐level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter‐organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age‐related 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‐sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non‐pharmacological 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‐control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber‐type–specific and age‐dependent 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‐control 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‐pharmacological approach to preserve mitochondrial quality and functional resilience during aging.