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

Cristina Aguayo-Mazzucato, Joshua Andle, Terrence B. Lee, Ayush Midha, Lindsay Talemal, Vaja Chipashvili, Jennifer Hollister-Lock, Jan van Deursen, Gordon Weir, Susan Bonner-Weir

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)129-142.e4
JournalCell Metabolism
Volume30
Issue number1
DOIs
StatePublished - Jul 2 2019

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Aguayo-Mazzucato, C., Andle, J., Lee, T. B., Midha, A., Talemal, L., Chipashvili, V., Hollister-Lock, J., van Deursen, J., Weir, G., & Bonner-Weir, S. (2019). Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes. Cell Metabolism, 30(1), 129-142.e4. https://doi.org/10.1016/j.cmet.2019.05.006