Exercise enhances aged chondrocyte health through microRNA-29-enriched extracellular vesicles.

Extracellular vesicles (EVs) have been proposed to be mediators of the health-promoting effects of exercise throughout the body, but how EVs communicate these beneficial signals to recipient cells remains unknown. Here we interrogated these mechanisms using articular cartilage as a model. Network propagation of EV microRNA perturbations on a cartilage-specific network identified microRNA-29 as an exercise-responsive regulator of cellular aging. Consistent with this prediction, a 3-month aerobic exercise intervention in older adults increased microRNA-29 levels in EVs relative to baseline EVs. In vitro studies revealed that these exercise-primed EVs epigenetically de-repressed the KL gene, which encodes the longevity-associated protein α-Klotho, and restored a more youthful chondrocyte phenotype. EVs engineered to express microRNA-29 recapitulated these anabolic effects in a KL-dependent manner. Intra-articular administration of exercise-primed EVs into aged mice enhanced cartilage health, thereby confirming physiological and potentially translational relevance. These findings elucidate mechanisms by which exercise transduces beneficial signals in EVs to promote health in distal tissues through regulation of KL.