MicroRNA-loaded extracellular vesicles: Mechanisms and therapeutic potential in senescence and aging.
Article
Millares-Cangiani, Justin T, Rayo Parra, Juan D, Grand, Zachary A et al. (2026). MicroRNA-loaded extracellular vesicles: Mechanisms and therapeutic potential in senescence and aging.
. Mechanisms of Ageing and Development, 234 112269. 10.1016/j.mad.2026.112269
Millares-Cangiani, Justin T, Rayo Parra, Juan D, Grand, Zachary A et al. (2026). MicroRNA-loaded extracellular vesicles: Mechanisms and therapeutic potential in senescence and aging.
. Mechanisms of Ageing and Development, 234 112269. 10.1016/j.mad.2026.112269
Cellular senescence is a biological process characterized by stable cell cycle arrest that contributes to tumor suppression and tissue remodeling but can also promote aging-associated dysfunction when senescent cells persist and accumulate. Senescent cells influence neighboring and distant tissues through the senescence-associated secretory phenotype (SASP), of which extracellular vesicles (EVs) are an increasingly recognized component. This review examines how microRNAs (miRNAs) carried by EVs regulate senescence and ageing. miRNAs are key post-transcriptional regulators of senescence, particularly within the p53/p21Cip1 and p16INK4a/Rb tumor suppressor pathways. Selective sorting into EVs allows these molecules to act over long distances. EV-miRNAs have dual roles: anti-senescent miRNAs such as miR-17-5p, miR-146a and miR-378a-3p promote rejuvenation, whereas pro-senescent miRNAs including miR-34a, miR-21 and miR-27a propagate ageing. Hypothalamic neural stem cell-derived miRNAs maintain transcriptional homeostasis and suppress senescence across the brain, and their age-related decline contributes to neurodegeneration. miRNAs in small EVs from young plasma rejuvenate multiple organ systems and extend lifespan in mice, while adipocyte-derived miR-27a spreads metabolic dysfunction to distant tissues. Together, EV-miRNAs are an emerging component of the intercellular networks regulating cellular senescence and aging, and their selective sorting, intercellular transfer, and modulation of senescence-associated pathways provide opportunities for therapeutic development and biomarker discovery.
