Abstract
Cellular senescence, originally described as a finite proliferative arrest in cultured somatic cells, has since been recognized as a central mechanism underlying aging and the development of age-associated disorders. The progressive accumulation of senescent cells (SnCs) promotes chronic inflammation through the senescence-associated secretory phenotype (SASP) and circumvents immune-mediated clearance by upregulating pro-survival and immune checkpoint pathways. Early “first-generation” senolytics, including navitoclax (ABT-263) and the dasatinib–quercetin (D + Q) combination, provided proof-of-concept that selective removal of SnCs can alleviate certain fibrotic, metabolic, and cardiovascular pathologies in preclinical studies. However, these agents exhibited notable drawbacks, such as dose-dependent thrombocytopenia, variable therapeutic efficacy, and the emergence of resistance mechanisms. Consequently, current research has shifted toward precision senotherapy, though significant translational challenges remain. This review synthesizes three next-generation strategies developed to address limitations of early senolytic agents. (1) Immune-based senolysis: This approach applies immuno-oncology principles to counter immune evasion of SnCs. Strategies include blocking immunosuppressive ligands such as GD3 ganglioside, engineering chimeric antigen receptor (CAR) T cells to target senescence-specific surface markers like urokinase-type plasminogen activator receptor (uPAR), and exploiting metabolic vulnerabilities (e.g., glutaminolysis and ferroptosis) to sensitize SnCs to immune-mediated clearance. (2) Tissue-precision proteolysis-targeting chimeras (PROTACs): These agents recruit organ- or tissue-specific E3 ligases (e.g., von Hippel-Lindau (VHL)) to selectively degrade anti-apoptotic proteins such as BCL-xL. Localized activity may reduce systemic toxicity and mitigate dose-limiting effects observed with traditional inhibitors. (3) Microbiome–epigenetic interplay: This strategy modulates the gut–liver axis to enhance senolytic efficacy. Short-chain fatty acids (SCFAs), such as butyrate, epigenetically regulate drug transporter expression and suppress the SASP, while dietary interventions may create a microenvironment favorable to senolysis. These approaches offer potentially more targeted and personalized therapeutic options but face significant challenges, including immunopathology, manufacturing complexity, off-target effects, and long-term safety concerns. The ongoing shift from broad inhibition to precision reprogramming represents a promising but preliminary step in the treatment of age-related diseases.
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This work was supported by the National Natural Science Foundation of China (Grant No. 82172210) and the Xijing Hospital Advancement Program (Grant No. XJZT24CY38). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.
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Weidong Zhang: Conceptualization, Writing—Original Draft, Visualization, Literature Curation. Shijie Song: Writing—Review and Editing, Visualization. Yue Zhang: Writing—Review and Editing, Literature Curation. Yong Pan: Writing—Review and Editing, Validation. Dahai Hu: Conceptualization, Supervision, Funding Acquisition, Writing—Review and Editing. Yunchuan Wang: Conceptualization, Supervision, Funding Acquisition, Writing—Review and Editing.
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Zhang, W., Song, S., Zhang, Y. et al. Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming. npj Aging (2026). https://doi.org/10.1038/s41514-026-00355-z
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DOI: https://doi.org/10.1038/s41514-026-00355-z
