Research Paper|Volume 18|pp 815—832

TM4SF1 is a surface marker of senescent pancreatic β-cells

Ana Beathriz Leite Lorente^1,², Sergio Vazquez^1,³, Kanako Iwasaki¹, Adedoyin Adebayo¹, Maya Jackson¹, Christopher Cahill¹, Summer Ryan¹, Brooke A. Sullivan¹, Susan Bonner-Weir¹, Cristina Aguayo-Mazzucato¹

¹Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02115, USA
²Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-689, São Paulo, Brazil
³Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA

Received: September 24, 2025Accepted: June 10, 2026Published: July 8, 2026

https://doi.org/10.18632/aging.206398

Copyright: © 2026 Lorente et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Senescent pancreatic beta (β)-cells accumulate with age and contribute to impaired insulin secretion and progression of type 2 diabetes mellitus (T2DM). Although the urokinase-type plasminogen activator receptor (uPAR; encoded by PLAUR) has been used as a surface marker of senescence in mice and humans, its broad expression across tissues limits therapeutic specificity. Here, we identify transmembrane-4-L-six-family member-1 (TM4SF1) as a selective surface marker of senescent β-cells.

Using RNA sequencing, flow cytometry, and immunofluorescence, we demonstrate that TM4SF1 is enriched in p21 (encoded by CDKN1A) senescent β-cells, with minimal expression in non-senescent β-cells or non-pancreatic cell types. TM4SF1⁺ β-cells exhibit reduced insulin content and impaired glucose-stimulated insulin secretion, linking this population to functional decline.

Importantly, compared to uPAR, TM4SF1 shows stronger concordance with canonical senescence markers and greater specificity for β-cells. These findings establish TM4SF1 as a robust and selective marker of senescent β-cells and support its potential as a target for β-cell-directed senotherapeutic strategies in T2DM.