Kirkland JL1, Tchkonia T2.
J Intern Med. 2020 Jul 19. doi: 10.1111/joim.13141. [Epub ahead of print]
Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin, and Navitoclax were discovered using a hypothesis-driven approach. SC accumulate with aging and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality, and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighboring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to re-accumulate, senolytics can be administered intermittently – a «hit-and-run» approach. In pre-clinical models, senolytics delay, prevent, or alleviate frailty, cancers, and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, hematological, metabolic, and skin disorders as well as complications of organ transplantation, radiation, and cancer treatment. As anticipated for agents targeting the fundamental aging mechanisms that are «root cause» contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation, and alleviate frailty in humans. Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, eye diseases, and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.