Distinct senescent β-cell senotypes differentially drive islet aging and dysfunction
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.
Authors: Kanako Iwasaki, Hui Pan, Jonathan Dreyfuss, Maya Jackson, Sergii Domanski, Dylan Baker, Priscila Carapeto, Christopher Cahill, Sandra Le, Francesko Hela, Juliana Alcoforado Diniz, Giray Naim Erylmaz, Fan Wu, Pei-Hsun Wu, Bofei Yu, Denis Wirtz, Sara Espinoza, Alejandro Pena, Francisco G. Cigarroa, Gregory Abrahamian, Jillian L. Woodworth, Peter Adams, Duygu Ucar, Jeffrey H. Chuang, Vesna D Garovic, James L. Kirkland, Tamar Tchkonia, Nicolas Musi, George A. Kuchel, Paul Robson, Cristina Aguayo-Mazzucato
Institutions: Joslin Diabetes Center, Harvard University, The Jackson Laboratory for Genomic Medicine, Johns Hopkins University, Johns Hopkins Medicine, Cedars-Sinai Medical Center, The University of Texas at San Antonio Health Science Center, Sanford Burnham Prebys Medical Discovery Institute, UConn Health, Mayo Clinic
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Translational Geroscience Network, Effect of Aging on Preadipocyte Differentiation, Diabetes Research Center, The KAPP-Sen Tissue Mapping Center Collaborative, Three-dimensional maps of senescence in the human pancreas, Spatial mapping senescent cells across the mouse lifespan by multiplex transcriptomics and epigenomics, Elucidating and targeting beta-cell senescence and its SASP
OpenAlex ID: W7162677749