Exosomes and small microvesicles are key regulators of non-cell autonomous intercellular communication in senescence

Senescence is a cellular phenotype present in health and disease, characterized by an irreversible cell cycle arrest and an inflammatory response, denominated senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behaviour of neighbouring cells and altering the microenvironment; yet, this role has been mainly attributed to soluble factors. Here, we show that both the soluble factors and extracellular vesicles (EV) (comprised of exosomes and small extracellular vesicles) are capable of transmitting paracrine senescence to nearby cells. Analysis of the individual cells internalizing sEV, using a Cre-reporter system, suggest a positive correlation between sEV uptake from senescent cells and paracrine senescence. Interestingly, we find exosome biogenesis increased during senescence in vivo. sEV protein characterization by Mass Spectrometry (MS) followed by a functional siRNA screen identify the Interferon Induced Transmembrane Protein 3 (IFITM3) as partially responsible for transmitting senescence to normal cells. Altogether, we found that sEV are part of the SASP and contribute to paracrine senescence