Senolytics

Senolytics are a class of drugs that selectively clear senescent cells, and the first senolytic drugs, Dasatinib, Quercetin, Fisetin and Navitoclax, were discovered using a hypothesis-driven approach. ^[1] Senolytics are drugs that specifically eradicate senescent cells, and they are distinguished from senomorphics, which are compounds that suppress the senescence-associated secretory phenotype (SASP) without killing cells. ^[2]

The most deleterious senescent cells are resistant to apoptosis and up-regulate anti-apoptotic pathways that defend them against their own inflammatory senescence-associated secretory phenotype, and senolytics transiently disable these pathways, causing apoptosis of the senescent cells with a tissue-destructive SASP. ^[1] Because senescent cells take weeks to reaccumulate, senolytics can be administered intermittently in a hit-and-run approach. ^[1] Senolytics remove senescent cells by inducing apoptosis and include inhibitors of anti-apoptotic proteins such as B-cell lymphoma-extra large, inhibitors of the forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. ^[3]

In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders, potentially alleviating over 40 conditions. ^[1] Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans, but until such studies are done it is too early for senolytics to be used outside of clinical trials. ^[1] Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senolytics, multiple clinical trials are under way to translate small-molecule senolytics and other senescence-targeting interventions into clinical use. ^[4] Senolytics eliminating senescent cells, for example dasatinib plus quercetin, are among recent aging-targeting strategies that have demonstrated lifespan extension and healthspan

Dosing intervals, whether intermittent or continuous, influence both the therapeutic efficacy and adverse events of senolytics, such as thrombocytopenia. ^[2] The efficacy and safety of senotherapeutic strategies, including senolytics, remain highly dependent on cell type, disease context, and agent specificity. ^[6] The safety of these treatments after long-term administration requires further study, and larger clinical trials are needed to translate these approaches to patient care. ^{[3] [7]}