Fisetin as a Senolytic and Anti-Aging Molecule

Ball and Stick Model for Fisetin A Molecule

Fisetin Molecule (above) Ball-and-stick. For 3D Jsmol File

Molecular formula C₁₅H₁₀O₆

Molar mass 286.2363 g/mol

Fisetin Molecular Structure

Overview of Fisetin

Fisetin (3,3′,4′,7-tetrahydroxyflavone, above) is a polyphenol which is a bioactive flavonol molecule found in fruits and vegetables such as strawberry, apple, persimmon, grape, onion, and cucumber at concentrations in the range of 2–160 μg/g.

Fisetin, like other polyphenols  such as resveratrol, is a sirtuin-activating compound and has been shown in laboratory studies to extend the life of simple organisms like yeast, worms, and flies.  see: A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol .

 In lab studies it also has been shown to be an anti-proliferative agent, interfering with the cell cycle in several ways.--

--Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols

--The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

Fisetin, like some other flavonoids, has been found in lab studies to be a topoisomerase inhibitor, which may turn out to be a carcinogenic activity or an anti-cancer activity - further research is needed. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells.

Fistein has been shown to be an effective senolytic agent in wild-type mice, with effects of increased lifespan, reduced senescence markers in tissues, and reduced age-related pathologies. A clinical trial in the U.S. is currently underway as of October 2018 to show effectiveness in humans. (Clinical Trials.gov -- Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women (AFFIRM) ).

In studies conducted on cells in a laboratory, fisetin inhibits the activity of several pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin 6, and Nuclear factor kappa B.  It has also been shown in lab studies to upregulate glutathione, an endogenous antioxidant. Fisetin Boosts Cellular Glutathione .

Fisetin suppressed PI3K/Akt and mTOR signaling

Novel inhibitors of PI3-K, Akt, and mTOR are now passing through early phase clinical trials. This review article looks at the effect of fisetin on the PI3-K/Akt/mTOR pathway as studied in different cancer cell models...." See: Inhibition of Akt/mTOR Signaling by the Dietary Flavonoid Fisetin

Below dock model showing fisetin binding to mTOR protein.

"...Hypothetical model of the mTOR molecule in complex with fisetin. (i and iii) Blind docking of fisetin to the mTOR target was performed with autodock 4 by setting grid sizes that included the entire mTOR molecule. The structure consists of four stacked alpha helices. The grid size for the docking site was expanded to include the entire mTOR molecule and fisetin was docked. Using autodock 4, fisetin bound to two sites on the mTOR target..." From Dual inhibition of phosphatidylinositol 3‐kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin

Fisetin has shown anti-cancer activity in studies on cells and model animals conducted in laboratories, and appears to block the  PI3K/AKT/mTOR pathway. See: Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management.

Abstracts:

Fisetin is a senotherapeutic that extends health and lifespan

Background --Senescence 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.

"... 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.

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..." -

--Of the 10 flavonoids tested, fisetin was the most potent senolytic.

- Source

Clinical Trials

October 2018 --Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women -70-90 yrs Old (AFFIRM)

Dietary Fisetin -- Experimental: Treatment Fisetin 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months vs placebo.

Start Date -February 6, 2018--- Completion Date - June 30, 2020