Pharmacology of Senolytics: Targeting Cellular Aging in Chronic Diseases

Abstract

Cellular senescence is a state of irreversible cell cycle arrest characterized by the secretion of pro-inflammatory mediators collectively termed the senescence-associated secretory phenotype (SASP). Although senescence plays a physiological role in tissue repair and tumor suppression, the accumulation of senescent cells during aging contributes to chronic low-grade inflammation and the pathogenesis of several age-related diseases. Senolytics, a novel class of pharmacological agents, selectively eliminate senescent cells and represent a promising therapeutic approach to delay aging and mitigate chronic disorders. This review provides an overview of the pharmacological basis of senolytics, highlighting their mechanisms of action, therapeutic potential, and current challenges. Small molecules such as dasatinib, navitoclax, and FOXO4-DRI peptides, as well as natural compounds including quercetin, fisetin, and curcumin, have demonstrated senolytic activity by targeting anti-apoptotic pathways, modulating mitochondrial function, and reducing SASP-mediated inflammation. Preclinical studies show their efficacy in cardiovascular disease, diabetes, osteoarthritis, neurodegeneration, and cancer, while early clinical trials suggest benefits in idiopathic pulmonary fibrosis and frailty. Despite their promise, limitations such as off-target effects, biomarker identification, and long-term safety remain critical barriers. Future perspectives include personalized senolytic therapy, integration with senomorphics, and nanotechnology-based delivery systems. Senolytics thus hold significant potential in transforming pharmacological management of chronic diseases.