Senolytic drugs: from discovery to translation

Abstract

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.

Keywords: dasatinib; fisetin; quercetin; senescent cell anti-apoptotic pathways; senolytics; unitary theory of fundamental aging processes.

Figure 1

Cellular senescence: causes, mechanisms and consequences. A number of factors can combine to cause a cell to enter the senescent cell fate, as opposed to apoptosis or necrosis, through transcription factor cascades that can involve p16^INK4a, Rb, p53, p21^CIP1 or others. Note that not every senescent cell exhibits increased p16^INK4a, Rb, p53 or p21^CIP1. It can take up to 6 weeks for a cell to become a fully senescent, nondividing cell. This indicates that senescent cells can be removed intermittently, rather than having to treat with agents continuously to remove these cells. Some, but not all senescent cells can develop a SASP. This SASP is a ‘root cause contributor’ to the stem cell, progenitor, tissue and systemic dysfunction that predispose to multiple disorders, which account for the bulk of morbidity, mortality and health costs.

Figure 2

Helper (H) and (D) senescent cells. D‐senescent cells have a pro‐inflammatory, pro‐apoptotic, tissue‐damaging SASP and are susceptible to senolytics. H‐senescent cells do not have a SASP and do not up‐regulate SCAPS and are not cleared by senolytics. H‐ senescent cells appear to promote stem and progenitor cell determination into appropriate lineages and functions and have a beneficial impact on tissue homoeostasis.

Figure 3

Early clinical studies of senolytics: Balancing benefit and risk. Since senolytic drugs are at the forefront of a completely new potential therapeutic paradigm – targeting fundamental ageing processes to delay, prevent or alleviate age‐related phenotypes, multiple diseases, geriatric syndromes and reductions in physical resilience – a careful risk‐benefit balance must be struck within first‐in‐human senolytic drug clinical trials, since potential short‐ and long‐term side‐effects from clearing senescent cells are not yet fully known.