Embryonic stem cell-derived extracellular vesicles delay cellular senescence by inhibiting oxidative stress

The accumulation of cells that permanently exit the cell cycle and undergo senescence is a hallmark of aging and predisposes organisms to disease. Emerging evidence suggests extracellular vesicles (EVs) released by pluripotent embryonic stem cells (ESCs) possess therapeutic/regenerative properties with the potential to significantly impact cellular senescence and aging-related disorders. However, the critical next step for taking advantage of the potential benefits offered by ESC-derived EVs will be to unravel the molecular mechanisms responsible for their unique functional effects, which thus far have not been fully defined. Toward that goal, we now identify a signaling pathway essential for EVs shed by ESCs to potently block fibroblasts and astrocytes from undergoing senescence. It starts with the extracellular matrix protein fibronectin that coats the surfaces of EVs, enabling the vesicles to bind integrins on cells and trigger the activation of FAK and AKT. This leads to the inhibition of GSK3β activity and stabilization of the transcription factor Nrf2, which counteracts the effects of oxidative stress that would otherwise drive cellular senescence. These findings define a signaling pathway used by ESC-derived EVs to extend cellular lifespan, highlighting their potential application in anti-aging strategies.