Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Open accessAbstract
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.
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Mouse models of insulin resistance induced by high-fat diet and S961 show elevated SA-β-gal activity and expression of Cdkn1a, Cdkn2a and SASP factors Il1a, Il6, Tnf, Ccl3, Ccl4, Ccl5, Cxcl1 and Cxcl10.
“Mouse models of insulin resistance induced by a high-fat diet and the insulin receptor antagonist S961 exhibit elevation of SA-β-gal activity, and expression of Cdkn1a, Cdkn2a and the SASP factors Il1a, Il6, Tnf, Ccl3, Ccl4, Ccl5, Cxcl1 and Cxcl10 (ref. 182).”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [182]
The Results section, “Insulin resistance accelerated the appearance of senescent β-cells” (page unavailable), reports increased β-gal-positive cells and aging and SASP gene-expression indices after both S961 treatment and high-fat diet. The Methods section defines those indices to include p21, p16, Il1a, Il6 and TNFα, but not Ccl3, Ccl4, Ccl5, Cxcl1 or Cxcl10; it also does not establish that every listed gene rose individually in both models. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSenescent cells themselves are critically involved in T1D and T2D, and the deletion of senescent beta cells prevents diabetes.
“Concerning age-related diseases, senescent cells themselves are critically involved in T1D and T2D, and the deletion of senescent beta cells prevents diabetes (57, 298), indicating that even in T1D in which tissue-specific T cells are involved (299–301), local initiators originating from senescent beta cells play critical roles.”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [298]
The Discussion (page unavailable) reports that deleting p16Ink4a-positive cells improved glucose homeostasis and β-cell function in mouse models of aging and insulin resistance, supporting a role for senescent β-cells in T2D-related dysfunction. It does not show that deletion prevents diabetes. For T1D, the Discussion describes senolysis as a possible application and cites Thompson et al. (2019) for evidence of senescent β-cells in a T1D mouse model; it does not establish a critical role in T1D. (LLM, conf=0.89)
Experimental — accuracy not yet measuredBeta-cell senescence has a key role in the development of type 2 diabetes.
“We have previously shown that β-cell senescence has a key role in the development of the disease.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [8]
In mice, clearing senescent cells improves glucose responsiveness, cellular transcriptional identity and blood glucose levels.
“in contrast, clearance of senescent cells improved glucose responsiveness, cellular transcriptional identity and blood glucose concentrations8.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [8]
Senescence of pancreatic beta cells is a contributor to type 2 diabetes mellitus.
“Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM).”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [8]
Insulin resistance accelerates beta-cell senescence.
“We have previously shown that insulin resistance accelerates β-cell senescence8.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [8]
In mice, senescence causes beta-cell dysfunction and reduces expression of critical identity and functional genes.
“In mice, senescence led to β-cell dysfunction and downregulation of critical identity and functional genes”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [8]
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 [8]
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Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
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Senolytics for Cancer Therapy: Is All that Glitters Really Gold?
Carpenter, V. J., Saleh, T., & Gewirtz, D. A. (2021) · Cancers · doi:10.3390/cancers13040723 · Cited by 124 · see citing works
Xu, P., Wang, M., Song, W.-M., Wang, Q., Yuan, G.-C., Sudmant, P. H., Zare, H., Tu, Z., Orr, M. E., & Zhang, B. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00507-7 · Cited by 114 · see citing works
Effects of exercise on cellular and tissue aging
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Self-citationSanborn, M. A., Wang, X., Gao, S., Dai, Y., & Rehman, J. (2025) · Nature Communications · doi:10.1038/s41467-025-57047-7 · Cited by 82 · see citing works
“Targeted clearance of senescent cells with senolytics can mitigate disease severity and increase healthspan 7 – 10 , but their elimination may exacerbate disease in some contexts 11 .”
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Self-citationContext‐dependent roles of cellular senescence in normal, aged, and disease states
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Alpha cell dysfunction in type 1 diabetes is independent of a senescence program
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- Authors
- Aguayo-Mazzucato, C., Andle, J., Lee, T. B., Midha, A., Talemal, L., Chipashvili, V., Hollister-Lock, J., van Deursen, J., Weir, G., & Bonner-Weir, S.
- Affiliations
- Joslin Diabetes Center (US)
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 30
- Issue
- 1
- Pages
- 129-142.e4
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6610720
- OpenAlex
- W2947927825
- Cited by
- 469
- References
- 55
- Citations by year
- 2026: 51 · 2025: 68 · 2024: 71 · 2023: 72 · 2022: 73 · 2021: 71 · 2020: 48 · 2019: 13 · 2018: 1
- FWCI
- 49.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Diabetes Research and Wellness Foundation
- National Institutes of Health (P30 DK057521, P30 DK036836, R01 DK093909, R01 DK110390, 2UC4DK098085)
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- β-cell senescence, senolysis, type 2 diabetes, insulin resistance, senescence-associated secretory phenotype, senolytics, navitoclax, high-fat diet, beta-cell function, aging, glucose metabolism
- MeSH terms
- Aniline Compounds, Animals, Body Weight, Cells, Cultured, Diabetes Mellitus, Type 2, Flow Cytometry, Glucose, Humans, Insulin Resistance, Mice, Inbred C57BL, Sulfonamides, Cellular Senescence, Insulin-Secreting Cells, Mice, In Vitro Techniques
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