Deciphering the emerging interrelationship between cellular senescence and extracellular vesicles: Implications for...

Cellular senescence is emerging as one of the leading underlying mechanisms of ageing. Senescent cells are observed in most tissues and organs with advancing age, which augments tissue dysfunction and inflammatory disorders. Extracellular vesicles (EVs) are nanoscale sacs released by almost all cells, which carry cell-type dependent molecular cargo that can exhibit pharmacological effects in recipient cells. Since senescence represents a global phenomenon in an organism, and EVs are released by various cell types, this review attempts to delineate their intricate interactions in regulating various facets of cellular senescence and age-related diseases, as well as potential diagnostic avenues, research gaps, and challenges. EVs released by senescent cells are biophysically different and can not only promote bystander senescence in healthier cells but can also accelerate the development of age-dependent chronic disorders by promoting a pro-tumorigenic and pro-inflammatory environment. Conversely, EVs isolated from healthy cells, typically stem cells, can suppress senescence, promote inflammatory homeostasis, and improve lifespan in vivo. Novel non-mammalian sources of EVs, including the gut microbiota and dietary plants, are also being recognised with potentially senescence-modulatory effects. A previously unknown role of EVs in modulating immune cell response during senescence is also developing, and EVs-based biomarkers are identified with the aim of early prediction and diagnosis of senescence. However, several challenges remain at the technical and translational end of EVs, and future research should focus on the identification of EVs in senescent cell subtypes and immune cells, understanding non-mammalian sources of EVs in modulating senescence, and establishing the safety of EVs to fully comprehend their pathological, therapeutic, and diagnostic potential in regulating cellular senescence.