Exercise-Induced Extracellular Vesicle-Associated miRNAs in Cognitive Aging of Older Adults: A Narrative Review

Cognitive aging involves chronic neuroinflammation, microglial dysregulation, vascular dysfunction, oxidative stress, and impaired neuroplasticity, and physical activity is one of the few modifiable interventions known to influence all of these processes simultaneously. The molecular mechanisms linking peripheral exercise adaptations to the aging brain, however, remain incompletely defined. This review examines exercise-responsive, EV-associated miRNAs as candidate mediators of this communication across four mechanistic domains: inflammatory signaling (miR-146a, miR-155, miR-223), microglial regulation (miR-124), neurotrophic and synaptic signaling (miR-132, miR-206), and vascular/blood-brain barrier function (miR-126). For each candidate, we distinguish evidence obtained by direct demonstration of an exercise-responsive, EV-associated change from evidence obtained by triangulating separate, non-vesicular, or non-exercise studies-a distinction largely absent from the existing literature. We also evaluate EV-miRNAs as candidate biomarkers of individual exercise responsiveness, separating analytical validity and biological association, for which evidence exists, from predictive validity and clinical utility, for which it does not. Standardized EV characterization, longitudinal exercise interventions, and integration with neuroinflammatory, neurovascular, and cognitive outcomes are needed before these candidates can be considered validated biomarkers of brain health in aging.