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

Cell Metab. 2019 Jul 2;30(1):129-142.e4. doi: 10.1016/j.cmet.2019.05.006. Epub 2019 May 30.


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.

Keywords: SASP; beta cells; glucose metabolism; insulin resistance; insulin secretion; senescence; senescence signature; senescence-associated secretory profile; senolytic therapies; type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / therapeutic use
  • Animals
  • Body Weight / physiology
  • Cells, Cultured
  • Cellular Senescence / physiology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Flow Cytometry
  • Glucose / metabolism*
  • Humans
  • In Vitro Techniques
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Sulfonamides / therapeutic use


  • Aniline Compounds
  • Sulfonamides
  • Glucose
  • navitoclax