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Home
Distinct Senescent Β-cell Senotypes Differentially Drive Islet Aging And Dysfunction.

Home
Distinct Senescent Β-cell Senotypes Differentially Drive Islet Aging And Dysfunction.

Related Experiment Video

Differentiation of Human Pluripotent Stem Cells into Insulin-Producing Islet Clusters

Differentiation of Human Pluripotent Stem Cells into Insulin-Producing Islet Clusters

Published on: June 23, 2023

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

Kanako Iwasaki, Hui Pan, Jonathan Dreyfuss

Biorxiv : the Preprint Server for Biology

|June 5, 2026

View abstract on PubMed

Summary

This summary is machine-generated.

Biological aging impairs glucose handling and increases type 2 diabetes risk. This study reveals two distinct pancreatic senescent cell types, one maladaptive and one adaptive, offering new therapeutic targets for diabetes.

Related Experiment Videos

Differentiation of Human Pluripotent Stem Cells into Insulin-Producing Islet Clusters

Differentiation of Human Pluripotent Stem Cells into Insulin-Producing Islet Clusters

Published on: June 23, 2023

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.