Unique Human and Mouse β-Cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors
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Abstract
The aging of pancreatic β-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging β-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to β-cell failure. In this study, we defined the β-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent β-cells and a chemically induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the β-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. Multiple SASP factors were transcriptionally upregulated in models of β-cell senescence, aging, insulin resistance, and T2D. Single-cell transcriptomic analysis of islets from an in vivo mouse model of reversible insulin resistance indicated unique and partly reversible changes in β-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent β-cells and its potential implication in health and disease.
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Proteomics analysis of senescent and non-senescent mouse and human pancreatic islet cells confirmed SASP protein secretion and led to description of a unique SASP in β-cells.
“The secretion of SASP protein factors has been confirmed through proteomics analysis of senescent (SA-β-gal+) and non-senescent (SA-β-gal–) mouse and human pancreatic islet cells183, leading to the description of a unique SASP in β-cells.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [183]
In the reversal group, exercise training reduced p16Ink4a mRNA levels by 73%.
“but decreased p16Ink4a mRNA levels, a marker of late senescence, by 73% (Fig. 2i)”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [22]
The sample sizes used are similar to those in the authors' earlier publications.
“No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in our previous publications8,22,49.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [22]
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“The secretion of SASP protein factors has been confirmed through proteomics analysis of senescent (SA-β-gal + ) and non-senescent (SA-β-gal – ) mouse and human pancreatic islet cells 183 , leading to the description of a unique SASP in β-cells.”
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Self-citation
- Authors
- Midha, A., Pan, H., Abarca, C., Andle, J., Carapeto, P., Bonner-Weir, S., & Aguayo-Mazzucato, C.
- Affiliations
- Joslin Diabetes Center (US)
- Islet Cell and Regenerative Biology Section, Joslin Diabetes Center, Boston, MA
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2021-03-05
- Volume
- 70
- Issue
- 5
- Pages
- 1098-1116
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC8173799
- OpenAlex
- W3135681041
- Cited by
- 58
- References
- 59
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 14 · 2023: 10 · 2022: 9 · 2021: 2
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institutional Startup Funds
- National Institutes of Health (P30 DK036836, DK110390)
- Thomas J. Beatson Jr. Foundation (2020-010)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- β-cell senescence, senescence-associated secretory phenotype, pancreatic beta cells, type 2 diabetes, insulin resistance, paracrine signaling, DNA damage, islet heterogeneity, beta-cell subpopulations, inflammation, extracellular matrix remodeling, cellular stress response
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, DNA Damage, Humans, Signal Transduction, Biomarkers, Cellular Senescence, Insulin-Secreting Cells, Mice
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