Faculty Opinions recommendation of Fisetin is a senotherapeutic that extends health and lifespan.

Background: Senescence(definition) is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA.Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches.We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease.The goal of this study was to identify flavonoids with more potent senolytic activity.Methods: A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively.The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16 INK4a -luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan.Human adipose tissue explants were used to determine if results translated.Findings: Of the 10 flavonoids tested, fisetin was the most potent senolytic.Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-andrun senolytic mechanism.Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity.Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.Interpretation: The natural product fisetin has senotherapeutic activity in mice and in human tissues.Late life intervention was sufficient to yield a potent health benefit.These characteristics suggest the feasibility to translation to human clinical studies.