“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.”

BUFFALO, NY — July 23, 2026 — A new research paper was published in Volume 18 of Aging on July 8, 2026, titled “TM4SF1 is a surface marker of senescent pancreatic β-cells.”

The study was led by first author Ana Beathriz Leite Lorente from Joslin Diabetes Center and Harvard Medical School, and São Paulo State University (UNESP), Brazil, and corresponding author Cristina Aguayo-Mazzucato from Joslin Diabetes Center and Harvard Medical School. 

Type 2 diabetes is characterized by insulin resistance and the progressive loss of pancreatic β-cell function. With aging and metabolic stress, senescent β-cells accumulate within the pancreas, producing less insulin while releasing inflammatory signals that contribute to disease progression. Although eliminating these dysfunctional cells has emerged as a promising therapeutic strategy, a major challenge has been identifying markers that distinguish senescent β-cells from healthy cells with sufficient precision. This study identifies transmembrane 4 L six family member 1 (TM4SF1) as a highly selective surface marker of senescent β-cells, providing a promising candidate for the future development of more selective therapies for type 2 diabetes. 

In this study, the researchers searched for cell-surface proteins that specifically identify senescent β-cells. Using RNA sequencing, flow cytometry, immunofluorescence, and analyses of both mouse and human pancreatic tissue, they compared TM4SF1 with the previously established senescence marker urokinase-type plasminogen activator receptor (uPAR/PLAUR). Their findings showed that TM4SF1 is expressed predominantly in senescent β-cells while exhibiting much lower expression in non-senescent β-cells and other tissues, making it a more β-cell-specific surface marker than uPAR.

The researchers demonstrated that TM4SF1 expression closely tracked established markers of cellular senescence, including p21 (CDKN1A) expression, HMGB1 nuclear exclusion, and senescence-associated β-galactosidase activity. In mouse models exposed to a high-fat diet, TM4SF1 levels increased alongside β-cell senescence and declined following treatment with the senolytic compound ABT263, further supporting its value as a reliable indicator of senescent β-cells. 

To further evaluate its performance, the investigators used a p21 fluorescent reporter mouse model that enabled direct visualization of p21-positive cells. A larger proportion of p21-positive β-cells expressed TM4SF1 than uPAR, and TM4SF1 showed substantially greater sensitivity for identifying this population. However, uPAR showed greater specificity in the reporter-model analysis. Considered together with its high expression in pancreatic tissue and relatively low expression in other tissues, these findings suggest that TM4SF1 is a sensitive and comparatively β-cell-selective marker that complements existing senescence markers.

The study further demonstrated that TM4SF1-positive β-cells are functionally impaired. Higher TM4SF1 transcript levels were associated with lower insulin content and a reduced glucose-stimulation index in human islets. In a separate functional experiment, TM4SF1-positive cells isolated from human islets secreted significantly less insulin in response to glucose stimulation than TM4SF1-negative cells. In addition, TM4SF1 expression increased with donor age and strongly correlated with CDKN1A (p21) expression, linking this surface marker to the progressive accumulation of dysfunctional β-cells during aging and type 2 diabetes.

“The identification of a surface marker with higher tissue-specificity for senescent pancreatic β-cells could improve studies on this cell population and could eventually be used for immunological targeting.”

The discovery has important therapeutic implications. Current senolytic approaches often target molecules expressed in many tissues, raising concerns about unintended effects on healthy cells. Because TM4SF1 appears to be more specific to senescent pancreatic β-cells than existing surface markers, it may provide a more selective target for next-generation approaches such as antibody-based therapies or chimeric antigen receptor (CAR) T-cell therapies designed to selectively eliminate dysfunctional β-cells while preserving healthy pancreatic tissue.

Overall, this study identifies TM4SF1 as a highly selective surface marker of senescent pancreatic β-cells in both mice and humans. By enabling more precise identification and potential targeting of dysfunctional β-cells, these findings provide an important step toward developing targeted senotherapies that could preserve insulin secretion and slow the progression of type 2 diabetes.

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

Corresponding author: Cristina Aguayo-Mazzucato – [email protected]         

Keywords: aging, senescent β-cell, type 2 diabetes, transmembrane 4 l six family member 1, urokinase-type plasminogen activator receptor

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