Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases

Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as a senotherapeutic agent for the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age and disease, in both circulating immune cell populations and solid organs and tissues. Senescent cells contribute to development of many chronic diseases, primarily by eliciting systemic chronic inflammation through their senescence(definition)-associated secretory phenotype. Here, we explore whether fisetin as a senotherapeutic can eliminate senescent cells, and thereby alleviate chronic diseases, by examining current evidence from in vitro studies and animal models that investigate fisetin’s impact on age-related diseases, as well as from phase I/II trials in various patient populations. We discuss the application of fisetin in humans, including challenges and future directions. Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. However, further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify relevant and reliable outcome measures in human trials, optimize dosing, and better understand the possible limitations of fisetin as a senotherapeutic agent. • Fisetin induced apoptosis in many, but not all, types of senescent cells in vitro . • Fisetin can reduce senescent cell numbers and attenuate pathology in animal models. • Ongoing clinical trials are evaluating the safety and efficacy of fisetin in humans. • Reliable, sensitive, and accessible measures of efficacy remain to be validated. • Fisetin's low bioavailability and rapid metabolism may hinder clinical translation.