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


Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [Email]


Type 2 diabetes (T2D) is an age-related disease. Although changes in function and proliferation of aged β cells resemble those preceding the development of diabetes, the contribution of β cell aging and senescence remains unclear. We generated a β cell senescence signature and found that insulin resistance accelerates β 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 β 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 β cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of β cells as a preventive and alleviating strategy for T2D.


SASP,beta cells,glucose metabolism,insulin resistance,insulin secretion,senescence,senescence signature,senescence-associated secretory profile,senolytic therapies,type 2 diabetes,

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