Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers.

Sep 5, 2025bioRxiv : the preprint server for biology

Senescent Cells Resistant to Senolytics Show Unique Secretions and Effects, Guiding Development of Senosensitizers

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Senolytics may selectively eliminate 30-70% of senescent cells associated with aging and physical dysfunction.

Senolytic agents disable protective pathways in senescent cells that prevent their death.
A JAK/STAT inhibitor, Ruxolitinib, reduced the pro-inflammatory secretions of senescent human preadipocytes but made them resistant to senolytic treatment.
In obese mice, senolytics decreased the number of pro-inflammatory senescent cells.
Senolytic-resistant cells showed increased markers of senescence but produced fewer inflammatory factors compared to senolytic-sensitive cells.
Transplanting senolytic-resistant cells into younger mice resulted in less physical dysfunction than transplanting the total senescent cell population.
Senolytic-sensitive and senolytic-resistant cells may convert into each other under certain conditions.

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The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16, p21, senescence-associated β-galactosidase (SAβgal), γH2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as "senosensitizers"), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible. INK4a CIP1

Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers.

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