Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes

Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged beta cells resemble those preceding the development of diabetes, the contribution of beta cell aging and senescence remains unclear. We generated a beta cell senescence signature and found that insulin resistance accelerates beta cell senescence leading to loss of function and cellular identity and worsening metabolic profile. Senolysis (removal of senescent cells), using either a transgenic INK-ATTAC model or oral ABT263, improved glucose metabolism and beta cell function while decreasing expression of markers of aging, senescence, and senescence-associated secretory profile (SASP). Beneficial effects of senolysis were observed in an aging model as well as with insulin resistance induced both pharmacologically (S961) and physiologically (high-fat diet). Human senescent beta cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D.