Senescence is a tumor suppressor mechanism activated in stressed cells to prevent the replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving ageing 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. This study aimed to identify flavonoids with more potent senolytic activity.
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 chemotherapeutic flavonoid was tested in mice modelling a progeroid syndrome carrying a p16INK4a-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 the results translated.
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-and-run 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.
The natural product fisetin has senotherapeutic activity in mice and human tissues. The late-life intervention was sufficient to yield a potential health benefit. These characteristics suggest the feasibility of translation to human clinical studies.
This study identifies the flavonoid polyphenol fisetin as having greater senotherapeutic activity in cultured cells than quercetin. In addition, fisetin had potent senotherapeutic activity in vivo. Treatment of progeroid and aged wild-type mice acutely or intermittently with fisetin reduced senescence markers in multiple tissues and a subset of cell types in adipose tissue. Importantly, chronic administration of fisetin to wild-type mice late in life improved tissue homeostasis suppressed age-related pathology, and extended median and maximum lifespan. This result, similar to a recent report on the combination of D ± Q, is the first to document the extension of both health span and lifespan by a senolytic with few side effects, even though the administration was started late in life.