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Updated: Sep 15, 2025
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
A human and mouse subpopulation of senescent β-cells induces pathologic dysfunction through targetable paracrine
Kanako Iwasaki1, Priscila Carapeto1, Cristian Abarca1
1Joslin Diabetes Center/Harvard Medical School. Boston, MA.
Abstract:
Cellular senescence is a stress response mechanism marked by irreversible growth arrest, upregulation of antiapoptotic pathways, loss of cellular function, and remodelling of the cellular secretory profile. In both humans and mice, pancreatic β-cells undergo senescence with age and insulin resistance. Targeted removal of senescent cells in mouse models of diabetes improves glucose homeostasis, demonstrating the role β-cell senescence in diabetes progression. In contrast, β-cell senescence also promotes immune surveillance, promoting β-cell survival and function. Thus, a better understanding of senescent cells' phenotypic and functional heterogeneity is needed to develop effective therapeutic strategies. Herein, we show that subpopulations of senescent β-cells in mice and humans, which were identified through the expression of Cdkn1a (encoding p21 Cip1 ) and Cdkn2a (encoding p16 Ink4a ) by single-cell RNA sequencing (scRNA-seq), flow cytometry, spatial transcriptomics, and spatial proteomics, exhibit distinct transcriptional and functional identities. The predominant senescent β-cell subpopulation expressed Cdkn1a and was characterized by a lack of glucose responsiveness, high basal insulin secretion, and transcription of canonical SASP factors. The SASP of Cdkn1a-expressing β-cells had non-cell autonomous effects on neighbouring cells. A subset of four SASP factors from Cdkn1a + cells was sufficient to induce secondary senescence and β-cell dysfunction in vitro. JAK inhibitors (JAK1/2 and JAK1/3) counteracted secondary senescence induction and restored β-cell function in high-fat diet-fed mice and human islets from donors with or without type 2 diabetes.
Insights
Cellular senescence in pancreatic beta cells drives diabetes. Targeting specific senescent cell subpopulations with JAK inhibitors restored beta cell function in mouse and human models.
Area of Science:
- Cellular and Molecular Biology
- Endocrinology
- Immunology
Background:
- Cellular senescence, a state of irreversible growth arrest, impacts pancreatic beta-cell function.
- Beta-cell senescence is linked to aging and insulin resistance, playing a role in diabetes progression.
- Senescent cells exhibit heterogeneity, necessitating a deeper understanding for therapeutic development.
Purpose of the Study:
- To investigate the phenotypic and functional heterogeneity of senescent pancreatic beta-cells.
- To identify distinct subpopulations of senescent beta-cells and their secretory profiles.
- To explore therapeutic strategies targeting senescent beta-cells in diabetes.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) to identify senescent beta-cell subpopulations based on Cdkn1a and Cdkn2a expression.
- Flow cytometry, spatial transcriptomics, and spatial proteomics for detailed cellular characterization.
- In vitro and in vivo models using mice and human islets to assess beta-cell function and senescence induction.
Main Results:
- Two distinct senescent beta-cell subpopulations were identified, characterized by Cdkn1a and Cdkn2a expression.
- Cdkn1a-expressing senescent beta-cells showed impaired glucose responsiveness and high basal insulin secretion.
- Secretory factors from Cdkn1a+ cells induced secondary senescence and beta-cell dysfunction, impacting neighboring cells.
- JAK inhibitors (JAK1/2 and JAK1/3) effectively counteracted secondary senescence and restored beta-cell function.
Conclusions:
- Senescent pancreatic beta-cells are heterogeneous, with distinct subpopulations exhibiting unique functional and secretory profiles.
- The senescence-associated secretory phenotype (SASP) from specific beta-cell subpopulations can induce further beta-cell dysfunction.
- JAK inhibition represents a promising therapeutic strategy for restoring beta-cell function in diabetes by targeting senescent cells.
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