Distinct senescent β-cell senotypes differentially drive islet aging and dysfunction

Area of Science:

• Endocrinology
• Gerontology
• Cell Biology

Background:

• Biological aging affects glucose metabolism and is a key risk factor for type 2 diabetes (T2D).
• Cellular senescence in the human endocrine pancreas and its role in aging are not well understood at the single-cell level.
• Senolytic therapies show promise, but heterogeneity of senescent cells requires further investigation.

Purpose of the Study:

• To investigate the heterogeneity and functional roles of senescent cells in the aging human pancreas at a single-cell resolution.
• To identify distinct subpopulations of senescent cells (SnCs) and their specific characteristics.
• To provide a framework for developing targeted senescence therapies for T2D.

Main Methods:

• Single-cell-resolved spatial proteomics and transcriptomics on intact human pancreas (26 donors, ages 20-80).
• Multiplexed single-cell RNA sequencing and functional assays on dispersed human islets (14 donors, ages 34-69).
• Identification and characterization of senescent cell subpopulations based on gene expression (CDKN1A, CDKN2A).

Main Results:

• Two distinct senescent cell subpopulations (SnCs) were identified: CDKN1A⁺ and CDKN2A⁺.
• CDKN1A⁺ SnCs showed loss of beta-cell identity, reduced insulin secretion, and a pro-inflammatory senescence-associated secretory phenotype (SASP), correlating with increased islet immune infiltration.
• CDKN2A⁺ SnCs maintained transcriptional identity and function with lower inflammatory signaling.

Conclusions:

• Human pancreatic senescence is heterogeneous, with distinct senotypes.
• An adaptive (CDKN2A⁺) and a maladaptive (CDKN1A⁺) senescence program exists in the pancreas.
• These findings offer a mechanism-guided approach for developing senescence-targeted therapies for T2D.