p21-senescent cells drive pancreatic islet dysfunction through targetable paracrine signaling in type 2 diabetes

Kanako Iwasaki; Priscila Carapeto; Cristian Abarca; Francesko Hela; Stephanie Sanjines; Sebastian Pena; Sandra Le; Hui Pan; Maya Jackson; Christopher Cahill; Ayush Midha; Juliana Alcoforado Diniz; Dylan Baker; Sergii Domanskyi; Sara Espinoza; Alejandro Pena; Francisco G. Cigarroa; Jillian L. Woodworth; Jeffrey H. Chuang; Vesna D. Garovic; James L. Kirkland; Tamara Tchkonia; Nicolas Musi; George A. Kuchel; Paul Robson; Cristina Aguayo-Mazzucato

doi:10.1172/jci.insight.197310

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Iwasaki, K. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Carapeto, P. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

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¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

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¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Sanjines, S. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Pena, S. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

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¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Pan, H. in: PubMed | Google Scholar |

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Jackson, M. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Cahill, C. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Midha, A. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Diniz, J. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Baker, D. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Domanskyi, S. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Espinoza, S. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Pena, A. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Cigarroa, F. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Woodworth, J. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Chuang, J. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Garovic, V. in: PubMed | Google Scholar |

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Kirkland, J. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Tchkonia, T. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Musi, N. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Kuchel, G. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Robson, P. in: PubMed | Google Scholar

¹Joslin Diabetes Center/Harvard Medical School, Boston, United States of America

²The Jackson Laboratory for Genomic Medicine, Farmington, United States of America

³Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁴UT Health San Antonio Transplant Center, San Antonio, United States of America

⁵Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, United States of America

⁶Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States of America

⁷UConn Center on Aging, UConn Health, Farmington, United States of America

Find articles by Aguayo-Mazzucato, C. in: PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.197310.
Copyright © 2026, Iwasaki et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 9, 2026 - Version history

Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodelling of the cellular secretory profile. In humans, pancreatic β-cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β-cell senescence to islet dysfunction remains unknown and thus, the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β-cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics, and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21⁺ β-cells induced secondary senescence in neighbouring cells, characterized by dysfunction and loss of identity. Janus kinase inhibitors (JAKi) counteracted the induction of secondary senescence and restored β-cell function in islets from humans with T2D and in high-fat diet-fed mice. These findings reveal the critical role of p21⁺ β-cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.

Version 1 (June 9, 2026): In-Press Preview

p21-senescent cells drive pancreatic islet dysfunction through targetable paracrine signaling in type 2 diabetes

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p21-senescent cells drive pancreatic islet dysfunction through targetable paracrine signaling in type 2 diabetes

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