Senescent cell heterogeneity: The impact of targeting senescent endothelial cells in obesity

Masayoshi Suda

1,2,*

Tamar Tchkonia

1,2

James L. Kirkland

1,2,*

*Correspondence to: James L. Kirkland, Center for Advanced Gerotherapeutics, Cedars-Sinai Health Sciences University, West Hollywood, CA 90048, USA; Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Health Sciences University, Los Angeles, CA 90048, USA. E-mail: James.Kirkland@csmc.edu
Masayoshi Suda, Center for Advanced Gerotherapeutics, Cedars-Sinai Health Sciences University, West Hollywood, CA 90048, USA; Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Health Sciences University, Los Angeles, CA 90048, USA. E-mail: Masayoshi.Suda@csmc.edu

Geromedicine. 2026;2:202610. 10.70401/Geromedicine.2026.0036

Received: February 18, 2026Accepted: September 02, 2026Published: September 02, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Cellular senescence is increasingly becoming recognized as a key contributor to many age-related disorders and diseases and senotherapeutics, which are therapies that target senescent cells (SCs) have indicated benefit in multiple preclinical models, including models of obesity, metabolic syndrome/diabetes, and their complications. Importantly, SCs are not a uniform population. They differ by originating cell type, stimuli through which senescence was induced, time since induction of senescence, and the tissue and microenvironment in which senescent cells are located, including the composition and magnitude of the senescence-associated secretory phenotype (SASP). Recent studies have indicated that senescent cell populations comprise cells that release inflammatory SASP factors and less inflammatory senescent cells that release growth factors. Senolytics, agents that eliminate senescent cells, preferentially remove the more inflammatory senescent cells while sparing the less inflammatory senescent cells that arise during processes such as acute wound healing. In another study, senescent cell heterogeneity was investigated in adipose tissue impacted by obesity, with a focus on senescence marker expression and cell-type specificity. p16⁺ senescent endothelial cells were a key source of SASP factors within adipose tissue, but p21⁺ senescent preadipocytes and immune cells also contributed substantially to the inflammatory milieu. Identifying and selectively targeting the more pathogenic, pro-inflammatory senescent cell populations may be facilitated by single-cell-level analyses to elucidate the extent of senescent cell heterogeneity and markers of different senescent cell subpopulations. Appreciating diversity of senescent cells may be critical, since refining senotherapies based on specific SC subtypes may lead to development of individualized and personalized therapies, potentially improving upon existing more broad-spectrum strategies.

Keywords

Cellular senescence, senescent cell heterogeneity, endothelial cells, p16^Ink4a, p21Cip1, senolytics, SASP factors, senotherapeutics

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Suda M, Tchkonia T, Kirkland JL. Senescent cell heterogeneity: The impact of targeting senescent endothelial cells in obesity. Geromedicine. 2026;2:202610. https://doi.org/10.70401/Geromedicine.2026.0036