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Fisetin May Be An Effective Senolytic

5 days, 1 hour ago

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Posted on Oct 10, 2018, 2 p.m.

Senolytic compounds have been suggested in animal studies that show promise to possibly destroying enough senescent cells in mammals to be worth investigating for use as first generation rejuvenation therapies. Fisetin appears to reduce senescent cell load in many tissues by about 25-50%, which may translate to about 10 human years.

Senescent cells accumulating is one of the causes of aging; cells become senescent within the body every day, but with age are not cleared away effectively, a fraction remain and linger to cause significant harm through inflammatory signal molecules they secrete. If researchers could find a way to remove senescent cells, it may become possible that many inflammatory diseases and aspects of aging could be turned back to a certain degree. In terms of reliability and breadth of benefits research in animal studies using senolytic compounds are leading the pack above all other approaches to aging.

Researchers are working on testing some potential senolytic compounds in animal studies, but there is a larger body of candidates at present that are only accompanied by cell study data. A compound’s ability to destroy senescent cells selectively in petri dishes indicates potential, however there is a significant rate of failure in medical research and development for compounds with promising cell data, and many reasons as to why they may not work well enough with tissues or turn out to be infeasible for use in animals and humans.

The flavonoid Fisetin, a natural easily attainable and inexpensive product, is a senolytic candidate that only has cell study data which has exceeded expectations in animal studies that reduced the amounts of these damaged cells in the body, and appears to be just as effective in mice studies as any of the top senolytics including the chemotherapetics navitoclax and dasatinib. Fisetin dosing appears to  destroy 25-50% of senescent cells depending on organ and method of measurement, in aged mice with one time treatment of 100 mg/kg daily for 5 days.

Results suggest healthspans can safely be extended even towards the end of life. Many questions still need to be addressed including correct dosage. Typically approaches to scale up doses from mice studies to estimates in initial human trials leads to 500 mg per day for 5 days for a 60 kg human, but that amount has yet to be determined.

Flavonoid polyphenols were investigated for senolytic activity using senescent murine driven by oxidative stress and human fibroblasts driven by genotoxic stress. Top performers were then tested on model mice carrying a p16IKN4a-luciferase reporter and aged wild type mice to determine effects of fistein on senescence markers, age related histopathology, disease markers, lifespan, and healthspan, with human adipose tissue explants being used to determine whether results could translate. Of the top 10 flavonoids tested fistenin was observed to be the most potent senolytic. Fisetin decreased senescence in subsets of cells in murine and human adipose tissue demonstrating cell type specificity; acute or intermittent treatment of progeroid and old mice resulted in decreased senescence markers in multiple tissues consistent with senolytic mechanisms; and fisetin restored tissue homeostasis, reduced age related pathology, extended median and maximum lifespans in wild type mice in late life.

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