Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell metabolism, 2019-07, Vol.30 (1), p.129-142.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •β cell senescence signature reveals loss of identity and upregulation of SASP factors•Insulin resistance accelerates the appearance of senescent β cells•Clearance of senescent cells improves glucose levels, β cell function, and identity•In humans, β cell senescence increases with type 2 diabetes, age, and BMI Aguayo-Mazzucato et al. identify the signature of senescent pancreatic β cells and show that the population of senescent β cells is increased by insulin resistance but is partially reversible. Removing senescent cells improves insulin secretion, genetic identity, and glucose homeostasis. These findings provide insight into how β cell senescence contributes to type 2 diabetes, opening new therapeutic targets.