Exercise-Derived Extracellular Vesicles Attenuate Aging-Associated Cellular Senescence

Aging is characterized by the accumulation of cellular senescence(definition), increased DNA damage, and reduced regenerative capacity, processes that are strongly influenced by systemic intercellular communication. Extracellular vesicles (EVs) are key mediators of interorgan communication and have been implicated in the transmission of aging-associated signals. Exercise is a well-established intervention that mitigates many age-related cellular deficits. However, whether exercise modifies EV mediated signaling in the context of aging remains poorly understood. Although EV-induced senescence-associated phenotypes have been previously described, the role of circulating EVs as intercellular communicators of aging, as well as their sensitivity to exercise, has not been fully defined. The objective of this study was to determine whether exercise alters EV-mediated regulation of aging-associated cellular senescence and to identify exercise-induced changes in EV protein cargo. We hypothesized that EVs from aged sedentary mouse donors promote cellular senescence, whereas EVs from exercised aged mouse donors attenuate aging associated cellular dysfunction. EVs were isolated from young mice (4 months), old sedentary mice (24 months), and old mice (24 months) subjected to 4 weeks of voluntary wheel running and applied to recipient cells. Senescence markers, proliferation, and DNA damage were assessed using p16INK4a, senescence-associated β-galactosidase (β-gal), BrdU incorporation, and γH2AX. EVs from old sedentary donors increased p16INK4a and β-gal expression and significantly decreased BrdU incorporation compared to controls, indicating enhanced senescence and reduced proliferative capacity. In contrast, EVs from exercised aged donors significantly reduced γH2AX and β-gal levels relative to sedentary aged EVs, indicating reduced DNA damage and functional senescence, while p16INK4a expression remained unchanged. In parallel with these in vitro studies, EV protein cargo was compared among young, old sedentary, and exercised aged groups. Together, these findings demonstrate that circulating EVs convey aging-associated signals and that exercise remodels EV-mediated communication to selectively mitigate key features of cellular aging, highlighting EVs as a potential mechanism underlying the systemic protective effects of exercise. Funding: The Allen Distinguished Investigator Program, Allen Philanthropies. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.