Exercise and p21 Signaling in Central Nervous System Aging and Senescence: A Context- and Dose-Dependent Relationship

Physical exercise is a potent modifier of CNS aging, but its relationship with the cyclin-dependent kinase inhibitor p21 (CDKN1A) is neither uniformly suppressive nor equivalent to cellular senescence. Direct evidence remains sparse and preclinical. Sustained physiological exercise reduced hippocampal or cortical p21-associated signatures in models of metabolic distress, natural aging, and amyloid pathology. Conversely, acute treadmill exercise transiently increased hippocampal Cdkn1a, while spatial transcriptomics identified increased endothelial Cdkn1a during broader exercise-associated vascular rejuvenation. At the maladaptive extreme, excessive swimming produced sustained hippocampal p53-p21 activation accompanied by oxidative injury, apoptosis, senescence-associated β-galactosidase activity, and cognitive impairment. Genetic studies further indicate that endogenous p21 restrains exercise-responsive neural stem-cell activation, but they do not demonstrate that exercise itself reduces p21. To reconcile these findings, this review applies a four-axis interpretive matrix based on signal persistence, cellular and subcellular compartment, corroborating senescence-associated features, and functional consequence. The evidence is integrated into three states: physiological exercise associated with attenuation of persistent p21-related stress, transient or cell-specific adaptive p21 induction, and maladaptive exercise overload characterized by sustained p53-p21 signaling and tissue injury. Current findings therefore support exercise more strongly as a stress-preventive or senomorphic intervention than as a proven CNS senolytic or p21-targeted therapy. The central question is not simply whether exercise increases or decreases p21, but when, where, for how long, and within which cellular and molecular context the response reflects repair, quiescence, persistent senescence-like dysfunction, or progression toward cell death.