Extracellular vesicles in cellular aging

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The progressive decline in cellular metabolic function and replicative capacity is a hallmark of aging and a central determinant of human lifespan. These changes are highly conserved across all cell types and species and modifiable: accelerated in disease, but amenable to reprogramming to delay senescence and extend lifespan. We, and others, have shown that large EVs released through outward membrane blebbing (ectosomal pathway) induce senescence. Conversely, our preliminary data suggest that small EVs arising from endosomal pathways preserve function and replicative capacity. This research program explores the role of EVs in cell-cell communications in aging with the goal of discovering novel approaches to optimize cellular aging throughout life. Over the next five years we will test the specific hypothesis that senescent cells undergo a phenotypic shift from release of endosomal-derived EVs which preserve cell function to ectosomal-derived EVs which induce secondary senescence and progressive cellular aging. We will focus on three research questions: 1. Do aging cells undergo a shift from endosomal EV secretion to ectosomal EV secretion? We will examine models of replicative senescence, stress-induced premature senescence, and fibroblasts from individuals with progeria and compare the phenotype of EVs released into the extracellular environment. We quantify EV levels and assess changes in individual EV subpopulations. We will correlate levels of specific EV subpopulations (exosomes, ARRDC1-mediated microvesicles [small ectosomes], and microvesicles [large ectosomes]) with senescent signaling in cells and assess dysregulated pathways that may be responsible for aberrant EV secretion. 2. Do EVs regulate cellular aging pathways in target cells. We will assess the effects of EV subpopulations on cellular aging pathways in target cells. We will test whether EVs from senescent populations induce secondary senescence as well as whether EVs from young/healthy cells can inhibit senescence. We will seek to identify candidate proteins responsible for EV signaling by proteomics. 3. Can aging cells be reprogrammed to endosomal EV secretion, attenuating secondary senescence? Finally we will test whether it is possible to reprogram cells to retain their ability to secrete endosomal EVs. We will test 3 approaches. 1) Induction of endosomal EV formation, 2) Inhibition of ectosomal EV formation, and 3) Redirection of EV formation from ectosomal to endosomal pathways by targeting a novel molecular switch (diacylglycerol kinase ?) recently identified in collaboration with Dr. Stephen Gee. Our proposed research program will enhance understanding of the human ageing process at the cellular level. If successful, this project may identify novel targets for therapeutic intervention to inhibit cell senescence and delay aging. This, in turn could help mitigate the effects of aging and age-related morbidities in a rapidly aging Canadian population.