Fisetin

Fisetin is a flavonoid naturally occurring in plants, fruits, and vegetables that has gained attention for its potential role as a senotherapeutic agent for age-related chronic diseases. ^[1] It is a flavonol found in fruits and vegetables such as apple, grape, strawberry, cucumber and onion. ^[2] Fisetin shares distinct antioxidant properties with other plant polyphenols and shows potential as an anti-inflammatory, chemopreventive, chemotherapeutic and senotherapeutic agent. ^[3]

As a senotherapeutic, fisetin targets senescent cells, which accumulate with age and disease and drive systemic chronic inflammation through their senescence-associated secretory phenotype. ^[1] Fisetin was among the first senolytic drugs discovered using a hypothesis-driven approach, transiently disabling the anti-apoptotic pathways that let senescent cells survive despite their inflammatory phenotype. ^[4] As a polyphenol it also exhibits SIRT1-activating effects shared with resveratrol and quercetin, and cytoprotective activity that protects functional macromolecules against stress. ^{[5] [3]}

Only two studies have demonstrated that senolytics extend lifespan in mice, namely fisetin and the combination of dasatinib plus quercetin. ^[6] Evidence for fisetin as a senotherapeutic comes from in vitro studies, animal models, and early phase I/II trials in various patient populations. ^[1] Beneficial effects of fisetin on osteoporosis and osteoarthritis have been demonstrated in in vitro and in vivo preclinical animal studies, though reports remain limited. ^[7] Further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify reliable outcome measures in human trials, and optimize dosing. ^[1]

Targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. ^[1] A major limitation is fisetin's limited water solubility, low absorption, and poor bioavailability, which has driven the use of nanotechnology and structural modification to improve its therapeutic potential. ^[8] Because senescent cells take weeks to reaccumulate, senolytics such as fisetin can be administered intermittently in a hit-and-run approach, but it remains too early to use senolytics outside of clinical trials. ^[4]