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Fisetin a powerful senolytic that extends health and lifespan

Senescent cells are defective older cells that are no longer functioning as they should. Most are cleared out and recycled by our immune systems, but as we age, more and more of these defective cells build up.

Sometimes called “zombie cells”, they cause significant harm by secreting molecules that cause inflammation to surrounding cells, leading to more impairment.

Increased systemic inflammation is now recognized as a leading contributor to all age related disease and aging itself. Clearing out of senescent cells can lower systemic inflammation and turn back aging to some degree.

https://www.ebiomedicine.com/article/S2352-3964(18)30373-6/fulltext

This new study found that Fisetin is more effective than any currently know senolytic compound, destroying 25-50% of senescent cells. The dose used equates to 500 mg per day for five days for a 60kg human.

A Phase 2 human trial is underway now, using 20 mg/kg a day for 2 days.

This current research with Fisetin was exciting because it is:

  • very effective at clearing senescent cells
  • a well studied natural product with very good safety profile
  • has many well documented health benefits
  • not required to use daily
  • has already passed phase 1 safety tests in humans

Killing Zombie cells is attracting big investors

Therapies to kill these zombie cells is attracting big money investors. San Francisco based Unity biotech received $385m from a group including Jeff Bezos and Peter Thiel, and just went public in May for $700m.

New startups like eattle based Oisin Biotech raised $4m, while Netherlands based Cleara Biotech was formed in June with $3m funding.

They are all focusing on drug combinations that can be patented, which clearly makes business sense as demonstrated by the flow of dollars into this burgeoning field.

Senescent cell clearance and NAD+ boosting therapies

Supplements to restore NAD+ levels are generating a lot of excitement among researchers working to extend Healthspan.  Researchers looking to uncover WHY NAD+ levels drop have found increased systemic inflammation consumes more and more NAD+ as we age.

Increasing NAD+ levels thru supplementation is being shown to have many health benefits, but likely has limits as the increased inflammation will eventually overwhelm any supplementation therapy.

Senescent cells are like little factories, spewing poisons that greatly increase inflammation in surrounding cells. Minimizing systemic inflammation by killing these zombie cells will make it easier to restore NAD+ levels.

How to try Fisetin for killing senescent cells

Fisetin has been widely used for it’s cancer fighting and numerous other health benefits (below), normally at 100-200mg per day.

This new research has spurred much self experimentation among the “bio-hackers”  at Longecity.org, so you might want to read there if you are interested in trying this yourself.

Most users on that forum are trying  1,000 to 2,000 mg per day, for 2-5 days.  The Phase 2 human study with Fisetin used 20 mg per kg of body weight for 2 days.

Quotes from this study:

 the first to document extension of both health span and lifespan by a senolytic with few side effects, even though administration was started late in life.

Taken together, these data establish the natural product fisetin as a potent senotherapeutic

 

demonstrate that reducing the senescent cell burden in mice even late in life is sufficient to have a significant health impact.

Taken together, these studies demonstrate that senolytic compounds can have significant effects on chronic degenerative diseases and age-related pathology.

Thus, new and improved senotherapeutic drugs and combinatorial approaches are needed to eliminate senescent cells safely from multiple organs or even within a single tissue [28–30,42].

Fisetin was most effective at reducing senescent markers.

Fisetin treatment extended the health and lifespan in WT mice even when treatment was initiated in aged animals.

Importantly, no adverse effects of fisetin have been reported, even when given at high doses.

 

 22–24-month-old mice were treated with 100 mg/kg fisetin for 5 consecutive days by oral gavage, or vehicle only.

The short-course treatment with fisetin resulted in a significant reduction in the fraction of senescent cells in each of these populations (Fig. 4C).

This resulted in an extension of median as well as maximal lifespan (Fig. 5A-B).

improved pancreatic and liver homeostasis (Fig. 5C).

Brain, kidney, liver, lung, and forepaw tissue sections … had reduced age-related pathology in the fisetin diet group compared to the control diet (Fig. 5D).

 

 

4. Discussion
Aging is a complex process involving numerous pathways and both genetic and environmental components [64–69]. The biological processes that drive the aging process contribute to the etiology of most chronic diseases including: 1) chronic, “sterile” inflammation; 2) macromolecular changes in proteins, carbohydrates, lipids, mitochondria, and DNA; 3) stem cell and progenitor dysfunction; and 4) increased cellular senescence [5,70]. These processes are linked in that interventions that target one appear to attenuate others. For example, senescent cells accumulate with age and at sites of pathogenesis in chronic diseases [5,70]. Reducing senescent cell burden can lead to reduced inflammation, decreased macromolecular dysfunction, and enhanced function of stem/progenitor cells [1,3,19]. Adult stem cells also become dysfunctional with age, displaying evidence of senescence [71].

Here, we demonstrate that when tested against a panel of other flavonoids, fisetin had the most potent senotherapeutic effects in several cell types in vitro and showed strong anti-geronic effects in vivo. We demonstrated that acute (oral) or chronic (dietary) treatment of progeroid and WT mice with fisetin reduces markers of senescence and senescence-associated secretory phenotype in multiple tissues (Fig. 3A-D, 4A, 5F-I).

Our findings reveal that fisetin targets multiple, but not all types of senescent cells in vivo. Furthermore, by reducing the percent of senescent cells, fisetin reduces expression of senescence markers in multiple organs as measured by qPCR. This results in improved tissue homeostasis and reduction in multiple age-related pathologies, consistent with effects on a fundamental aging process.

The fact that fisetin reduced the fraction of senescent T and NK cells could help amplify the beneficial effects of fisetin, since healthy immune cells are important for clearing senescent cells [72,73]. Similarly, fisetin reduces markers of inflammation and oxidative stress (Figs. 3F-G and 5L-M), consistent with prior literature [45]. This too could contribute to the reduction in senescence markers. The decrease in these markers was observed in tissues harvested several days after completion of fisetin administration.

Since the rapid and terminal half-lives of fisetin are 0.09 and 3.1 h respectively [74], these improvements did not depend on continued presence of circulating fisetin. This is more consistent with fisetin causing removal of senescent cells

Chronic exposure to fisetin improves healthspan and extends the median and maximum lifespan of mice. Importantly, in our study fisetin supplementation was initiated in mice N20 months old.

 

 

Fisetin has anti-cancer activity and appears to block the PI3K/AKT/mTOR pathway [80]. We previously found that transiently disrupting the PI3K/AKT pathway by RNA interference leads to death of senescent cells [30], as with other SCAPs that defend senescent cells from their own proapoptotic SASP [28,29]. Fisetin, like some other flavonoids, is a topoisomerase inhibitor, which may also contribute to its anti-cancer activity [81]. It increases the catalytic activity of hSIRT1 at least in vitro [76].

 

Other biological activities include anti-hyperlipidemic [84–86], anti-inflammatory [85], and neurotrophic [87] effects, some of which could be mediated through a reduction in the senescent cell burden, particularly since when administered intermittently, fisetin alleviated dysfunction despite its short elimination half-life, more consistent with elimination of senescent cells than action on a receptor or enzyme requiring continuous drug presence.

 

Given that fisetin is a natural product found in common foods and available as an oral dietary supplement and has no reported adverse side effects [45], our pre-clinical data suggest that fisetin should be imminently translatable and could have a significant benefit to the health of elderly patients.

 

Fisetin Snapshot

Fisetin is a flavonol, a chemical that belongs to the flavonoid group of polyphenols. Fisetin is a type of plant pigment that gives color to many fruits and vegetables (R, R1).

  • Great for reducing inflammation
  • Improves brain function and memory
  • Great antioxidant
  • Natural pain killer
  • Increases the master antioxidant – Glutathione
  • Maintains stable blood sugar
  • Good for a diverse array of conditions

 

Previously Documented Health Benefits of Fisetin

Note that there are very few trials of fisetin with humans and nearly all of the studies listed here are done on animals.

1) Fisetin is Good For Your Brain

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Fisetin Encourages New Brain Growth

Out of a number of studied flavanoids, fisetin was found to be the most effective at causing new brain growth (R).

One of the reasons fisetin possesses so many brain-boosting effects is because it is able to cross the blood brain barrier (R).

Fisetin Improves Memoryshutterstock_247872679

Fisetin supplementation increases the strength of long term memory pathways (by modifying ERK signaling and increasing BDNF), so it might be useful for memory disorders like Alzheimer’s (RR1).

Fisetin Protects Against Brain Degeneration

Fisetin has been shown to regulate a number of pathways (e.g. antioxidant & mitochondrial function) that are implicated in age-related decline in brain health (R).

One mechanism by which fisetin might protect against degenerative brain conditions is by activating certain transcription factors such as Nrf2that increase the cellular levels of glutathione – a key cellular antioxidant that has protective effects on nerve cells (RR1).

Fisetin protects nerve cells from oxidative stress. Oxidative death is one of the many factors associated with cognitive decline, stroke, Alzheimer’s, and Parkinson’s disease (R).

Moreover, Fisetin limits the accumulation of harmful compounds (phosphorylated tau) that accumulate in the brain and cause Alzheimer’s disease (R).

Fisetin is a potentially useful supplement for decreasing inflammation in microglia – immune cells that exert neurotoxic effects and are often activated in neurodegenerative conditions (R).

2) Fisetin Has Anti-Inflammatory Properties

Fisetin inhibits the activity of lipoxygenases (enzymes that act on fatty acids), thereby reducing the production of pro-inflammatory compounds(eicosanoids) and their by-products (RR).

High blood sugar in diabetics can cause inflammation of the blood vessels and lead to serious damage. These inflammatory processes are inhibited by treatment with fisetin (possibly via inhibition of the HMGB1 signaling pathway) (R, R1).

Fisetin can relieve allergic reactions by inhibiting inflammatory cytokine production (IL-4 and IL-13) by Basophils (R).

Fisetin was found to be an effective treatment for Eczema in animals as it reduced the presence of inflammatory cytokines, eosinophils, mast cells and T-cells (CD4+ & CD8+) that are typically found in atopic dermatitis skin lesions (R).

3) Fisetin May Prevent and Treat Cancer

Fisetin induces cell death and inhibits the growth of various types of cancers(e.g. melanoma, pancreatic cancer, colon cancer, lung cancer and prostate cancer) (R).

Fisetin inhibits the pathways responsible for cell growth and survival that are overactive in cancer patients (R).

Fisetin inhibits the ability of cancer cells to invade healthy tissues (R).

Fisetin inhibits cell proliferation and causes programmed death of chronic myeloid leukemia (white blood cell cancer) cells and possibly other leukemias(R, R1).

Treatment with fisetin was able to kill acute monocytic leukemia cells by increasing levels of nitric oxide and Ca(2+) and activating pathways of apoptosis (cell death) (R).

Fisetin might exert anti-cancer effects by inhibiting the mTOR pathway (R).

Fisetin is such a promising anti-cancer agent because it appears to inhibit and kill cancers without severely affecting the surrounding normal cells – probably because it is able to identify the unique cell-signaling pathways used by cancer cells (R, R1,R2).

4) Fisetin Improves Blood Flow & Lowers Blood Pressure

Fisetin lowers the clumping together (coagulation) of blood cells in mice and, thus, lowers the chance of blockages (R)

By inhibiting Ca(2+) signaling, Fisetin helps reverse vasoconstriction caused by the release serotonin and phenylephrine (R).

Fisetin was able to reverse bad circulation in mice caused by a high fat diet (R).

A rodent study found that Fisetin relaxes drug-induced contraction of blood vessels and, thus, lowers blood pressure. This action occurs regardless of blood vessel function (R).

5) Fisetin May Help Treat Diabetes

Fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and, therefore, may have potential therapeutic use for the treatment of diabetic complications (R).

Diabetic mice fed a diet high in Fisetin stayed diabetic, but the kidney abnormalities normalized (R).

Fisetin administration normalized the increased levels of lipid content in blood, liver and kidney in drug-induced diabetic rats (R).

In diabetic mice, Fisetin reduced the expected formation of cataracts (R).

Fisetin increases HDL and lowered LDL in diabetic rats (R).

6) Fisetin May Extend Lifespan

A number of studies have found that fisetin activates SIRT-1, a gene that has been repeatedly associated with long lifespan; in fact, it is often referred to as the longevity gene (R, R1, R2).

Dietary supplementation with a strawberry extract (which is said to have the highest levels of fisetin) improved the performance of rats in a rodent model of accelerated aging (R).

7) Fisetin May Lower Body Weight

In mice, fisetin supplementation reversed the weight gain caused by a high fat diet (R).

Mice that underwent fisetin treatment had less weight increase than mice that did not undergo treatment (R).

Fisetin prevents diet-induced obesity by regulating cell growth (R).

8) Fisetin Protects Skin From Sun Damage

Fisetin lowers the expression of various genes associated with skin aging (COX-2, MMP-1, MMP-3, MMp-9) that are usually induced by UVB exposure (R).

Fisetin inhibits UVB-induced collagen degradation – a key factor in skin aging (R).

Fisetin reduced  the cellular levels of UV-induced reactive oxygen species, prostaglandin E2, and nitric oxide generation (R).

 

 

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