Senolytic-resistant senescent cells have a distinct SASP profile and functional impact: The path to developing senosensitizers

Authors: TRIPATHI, UTKARSH - Mayo Clinic; SUDA, MASAYOSHI - Cedars-Sinai Medical Center; KULSHRESHTHA, VAGISHA - Mayo Clinic; PIATKOWSKI, BRYAN - Mayo Clinic; PALMER, ALLYSON - Mayo Clinic; GIORGADZE, NINO - Mayo Clinic; INMAN, CHRISTINA - Mayo Clinic; GASEK, NATHAN - University Of Connecticut; XU, MING - University Of Connecticut; JOHNSON, KURT - Mayo Clinic; PIRTSKHALAVA, TAMAR - Cedars-Sinai Medical Center; CHAIB, SELIM - Cedars-Sinai Medical Center; LANGHI PRATA, LARISSA - Cedars-Sinai Medical Center; ZHU, YI - University Of Texas Health Science Center; KADHAYA-PILLAI, RENUKA - University Of Washington; TULLIUS, STEFAN - Brigham & Women'S Hospital; WYLES, SARANYA - Mayo Clinic; MAJJI, RAMBABU - Texas Children'S Hospital; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); ALLISON, DAVID - Children'S Nutrition Research Center (CNRC); TCHKONIA, TAMAR - Cedars-Sinai Medical Center; KIRKLAND, JAMES - Cedars-Sinai Medical Center

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/18/2025
Publication Date: 1/1/2026
Citation: Tripathi, U., Suda, M., Kulshreshtha, V., Piatkowski, B.T., Palmer, A.K., Giorgadze, N., Inman, C., Gasek, N., Xu, M., Johnson, K.O., Pirtskhalava, T., Chaib, S., Langhi Prata, L.P., Zhu, Y., Kadhaya-Pillai, R., Tullius, S.G., Wyles, S.P., Majji, R., Yalamanchili, H.K., Allison, D.B., Tchkonia, T., Kirkland, J.L. 2026. Senolytic-resistant senescent cells have a distinct SASP profile and functional impact: The path to developing senosensitizers. Aging Cell. 25(1). Article e70358. https://doi.org/10.1111/acel.70358.
DOI: https://doi.org/10.1111/acel.70358

Interpretive Summary: As we get older, and especially when we carry excess body weight from poor diet — our bodies accumulate what are sometimes called "zombie cells." These are cells that have stopped working normally and stopped dividing, but they refuse to die. Instead, they sit in tissues and release a constant stream of inflammatory signals that damage everything around them, contributing to diabetes, heart disease, cancer, and physical decline. Drugs called senolytics were developed to selectively clear these harmful cells, and they have shown real promise. But we discovered something important: a significant portion of these cells resist being cleared, even by the best available drugs. These resistant cells were not identical to the ones that could be eliminated, they had a different pattern of signals, less inflammatory but richer in growth-promoting factors, and they behaved differently when studied in living animals. In obese mice, senolytic treatment preferentially cleared the most inflammatory subset, leaving the resistant ones behind. This tells us that not all zombie cells are the same, and that clearing some while leaving others may explain why treatments work only partially. The next step is developing what we call senosensitizers, agents that could convert resistant cells into ones that can be eliminated. Because obesity and poor diet are among the primary forces that drive zombie cell accumulation in the first place, understanding the full molecular identity of these resistant cells, including how their gene messages are processed could reveal new nutritional or pharmacological strategies to reduce the chronic inflammation that underlies so many diet-driven diseases.

Technical Abstract: 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 antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic 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 the 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**INK4a, p21**CIP1, senescence-associated Beta-galactosidase (SAbetagal), gammaH2AX, 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 proapoptotic 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.