ABSTRACT/SUMMARY The prevalence of obesity is rising to epidemic proportions. Obesity often leads to endocrine and metabolic derangements, and reduction in its complications could diminish morbidity and mortality, and produce large cost savings. Currently, bariatric surgery is considered the most effective treatment for sustainable weight loss. Obesity triggers cellular damage in multiple organs, partly via induction of premature senescence. This cellular program is characterized by a permanent cell-cycle arrest and altered cellular function, which prompts cells to acquire a senescence-associated secretory phenotype (SASP), a distinctive secretome that involves secretion of inflammatory cytokines and chemokines. Aberrant accumulation of senescent cells exhibiting the SASP phenotype exerts noxious effects on neighboring cells, and drives tissue injury and the aging phenotype. Mesenchymal stem cells (MSC), a ubiquitous cellular repair mechanism, may be injured by ambient risk factors. In obesity adipose tissue-derived MSC might develop cellular senescence (CS) and acquire a SASP phenotype, suggesting that obesity may impede endogenous cellular repair capacity. However, the effects of obesity on CS in human MSC, and the impact of MSC CS on their reparative capacity, remain unknown. Our hypothesis is that obesity evokes senescence in human MSC, which interferes with their capacity to repair injured kidneys. We hypothesize that this impaired MSC function is partly mediated by a phenotype shift in MSC-derived extracellular vesicles (EV) that drive their paracrine effects, but would be reversible upon senolytic pre-treatment of MSC, or following patient weight loss. We will use unique and novel model systems and techniques to pursue specific aims showing that: Specific Aim 1: In human subjects, obesity induces CS in adipose tissue MSC, and interferes with their repair capacity in injured mouse kidneys. Specific Aim 2: The functional impairment in adipose tissue MSC from obese human subjects is partly mediated by a phenotype shift in their membrane-derived EV. Specific Aim 3: MSC-CS and SASP in obese human subjects would be reversible upon bariatric surgery. The proposed studies may uncover novel mechanisms, involving impaired circulating and tissue cellular repair systems, which underlie complications of human obesity. Furthermore, they may establish a novel strategy to blunt this injurious cellular senescence, and thereby boost endogenous kidney repair capability.