Senolytic drugs: from discovery to translation.
J L KirklandTamara TchkoniaPublished in: Journal of internal medicine (2020)
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 ageing 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 neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to reaccumulate, senolytics can be administered intermittently - a 'hit-and-run' approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment. As anticipated for agents targeting the fundamental ageing 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.
Keyphrases
- cell cycle arrest
- induced apoptosis
- oxidative stress
- cell death
- clinical trial
- idiopathic pulmonary fibrosis
- endoplasmic reticulum stress
- bone marrow
- pi k akt
- type diabetes
- healthcare
- cardiovascular disease
- mesenchymal stem cells
- sars cov
- stem cells
- mental health
- public health
- small molecule
- randomized controlled trial
- postmenopausal women
- high throughput
- cell therapy
- risk factors
- health information
- systemic sclerosis
- bone mineral density
- drug delivery
- mild cognitive impairment
- radiation therapy
- community dwelling