An Example of High Dose Fisetin Exhibiting Senolytic Effects in Mice

Fisetin is perhaps the most intriguing of the first generation senolytic compounds, those capable of selectively destroying senescent cells in old tissues and thus producing rejuvenation to a meaningful degree. Senolytics have been demonstrated in animal studies to reverse many age-related conditions to a greater degree than any other approaches. Why is fisetin intriguing? Because in mice, it appears to be about as effective as the dasatinib and quercetin combination, yet it is a widely used dietary supplement.

Supplement dosing of fisetin in humans is not that much lower than the lowest demonstrated senolytic dose in mice. Senolytics are highly effective as treatments for inflammatory age-related conditions in mice, and starting to show similar effects in human trials. Should we expect that no older individual ever took enough fisetin to notice that it has profound effects on common inflammatory age-related conditions at higher doses? Is it realistic to think that strong medicines can be hiding in plain sight in this way for years upon years? The alternative explanation is that fisetin, unlike datastinib and quercetin, only effectively destroys senescent cells in mice. Which seems equally implausible, given what is known of the biochemistry of cellular senescence.

Questions regarding fisetin will be resolved (hopefully) at some point in the near future, given that human clinical trials of fisetin as a senolytic drug are presently ongoing, targeting frailty, cartilage degeneration, kidney disease, and osteoporosis. It is also worth looking at the materials on fisetin put together by the Forever Healthy Foundation, an extensive review of the evidence to date.

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease, which is characterized by the aberrant accumulation of extracellular matrix (ECM) in the lung parenchyma and deterioration of lung function. Both clinical observations and epidemiological investigations indicate that IPF is an aging-associated disease, since IPF occurs primarily in middle-aged and elderly people (median age at diagnosis is around 65 years), and the incidence rises remarkably with advancing age.

Cellular senescence is pivotal for phenotype of aging. The characteristics of senescent cells include growth arrest, enlarged cell morphology, elevated activity of SA-β-Gal as well as increased expression of cell cycle inhibitors, such as p16 and p21. Dysfunctional re-epithelialisation, following repetitive micro-injury, initiates the process of pulmonary fibrosis (PF). Increasing evidences have implicated that accelerated senescence of alveolar epithelial cells, a main cause of epithelial dysfunction, plays an important role in IPF pathogenesis. Senescent alveolar epithelial cells not only lose the ability of regeneration and repair, but also exert deleterious effects on neighboring cells by secreting a variety of proinflammatory cytokines, pro-fibrosis factors, growth factors, matrix metalloproteinases, and chemokines, described as senescence-associated secretory phenotype (SASP).

Fisetin (FIS), a natural non-toxic flavonoid, is present in various plants, fruits, and vegetables. Previous research has demonstrated that FIS has anti-inflammatory, anti-fibrosis, anti-oxidant, and anti-aging properties. Senolytic drugs, dasatinib and quercetin (D + Q), can attenuate experimental PF via selective depletion of senescent alveolar epithelial cells. More encouragingly, a recent first-in-human open-label clinical trial has suggested that short-term administration of D + Q could improve the physical dysfunction in IPF patients. Both FIS and quercetin belong to the flavonoid class, and FIS exhibits stronger senotherapeutic activity in cultured cells than quercetin, and can extend lifespan in mice. These traits remind us that FIS may have protective effect in PF. However, the role of FIS in PF has not been elucidated.

Bleomycin (BLM)-induced PF is the most frequently used animal model. Treatment with BLM can also induce alveolar epithelial cell senescence in vitro and in vivo. In this study, BLM was used to reproduce PF in mice and induce alveolar epithelial cell senescence to investigate the effect and mechanism of FIS in experimental PF. We found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype. FIS may be a promising candidate for patients with pulmonary fibrosis.

Comments

Thanks for your Fisetin senolytic review!

A few minor corrections/clarifications:
- 100 mg/kg/day in mice would actually scale to 8 mg/kg in humans (HED = mouse dose / 12.3: see Nair and Jacob Basic Clin Pharm 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/)
- Fisetin showed senolytic effects at 60 mg/kg day in in Ercc1-/∆ mice when taken with food, which would scale to ~5 mg/kg in humans (see Yousefzadeh et al. EBioMed 2018, https://www.ebiomedicine.com/article/S2352-3964(18)30373-6/fulltext)

Posted by: Edward F Greenberg at January 7th, 2021 6:07 PM

@Edward F Greenberg: Thanks, I removed the incorrect line.

Posted by: Reason at January 7th, 2021 7:16 PM

Mayo in their first trial on women give it 20 mg/1 kg body mass. For women it's 1500 mg. I tried it and for male a bit more is needed cause a prostate captures it so efficient and fast that you must add additional at least 500mg or more per 100 kg mass (effective 25mg/ 1kg), even after you find a solvent to let the body absorb any of it. And it's side effects with tendrils for some would require special additional pretreatment and post treatment, or very seldom usage at minimal effective dosage. And it's still too weak a senolytic to have any meaningful lasting effect alone. Fisetin is more effective as senotherapeutic against SASP than as a senolytic. And senoterapeutic effects are registered worldwide for a long time since the invention of strawberries (as a crossbred of different strains of wild strawberry) as noticeable elongation of life length in countries where they become popular.

Posted by: SilverSeeker at January 8th, 2021 6:49 AM

Fisetin poorly absorbed from the gut. Help is required to transport it from the gut lumen to the blood stream. Best vehicle is a nanoscale lipovesicle into which the fisetin needs to be loaded first

Posted by: JLH at January 8th, 2021 1:10 PM

How about taking fisetin with olive oil? Would that help bioavailability?

Posted by: Matt at January 8th, 2021 4:54 PM

Maybe use NaNots instead of Fisetin. It seems much more promising:)

Posted by: Robert at January 8th, 2021 8:22 PM

Is fisetin a good Senolytic for humans? I could play the devil's advocate and point out that mice are terrible aging models for humans. What works for them doesn't have to work for the humans since humans might already have compensatory systems letting us live many decades.

For example, there are insects which in their butterfly form have no digestive apparatus and die after mating and laying eggs. For them having the equivalent of glucose IV injections could easily extend their lifespan many times over. Obviously, there will be close to zero chance to translate such a treatment to humans.
I do hope that one of the Senolytics in the next couple of years will turn out to be safe and effective in humans, but

Posted by: Cuberat at January 9th, 2021 10:46 AM

About the fisetin bio availability. It has terrible solubility in water, alcohols and oil. DSMO call dissolve it but it can make something harmless 100 times more potent and turn it into poison. Here somebody mentioned a food grade solvent which works but I will have to check my links and notes.

Without special solvents my self experiments didn't yield anything convincing. But it was hardly a scientifically rigours setup. I have got 50% powder from pirebulk. It stains and tastes bitter and a bit gross, so already has the hallmarks of a good placebo. I tried to mix it with vodka and a bit of oil. Vodka is more fun, oil let's it pass smoother. I was taking up to 2 tablespoons per day supplemented by same or double dose of quercetin. For all experiments I have nothing which cannot be explained by placebo effect. Of course my fisetin batch might be bad or fake. It might be just not absorbed at all. At the time I was 43/44 probably not that old to have a sizeable ScC burden (I do feel the effects of the age, though).

Posted by: Cuberat at January 9th, 2021 10:46 AM

@Reason: Thanks for the correction.

One additional point: you state that humans use fisetin "at doses that are 1/10th to 1/30th of the lowest demonstrated senolytic dose."
- The lowest demonstrated senolytic dose (60 mg/kg mice, 5 mg/kg humans) would be about ~300 mg/day for a 60 kg human.
- Humans routinely take fisetin at 100-200 mg/day, so:
- Humans actually are currently using fisetin as a supplement at doses 1/3rd to 2/3rd of the lowest demonstrated senolytic dose.

Posted by: Edward F Greenberg at January 9th, 2021 11:09 AM

@Edward F Greenberg: Further updated, thanks.

Posted by: Reason at January 9th, 2021 12:40 PM

People are usually scared by side effects, so no one sane exceeds maximum dose cautioned in the leaflet. Side effects, when you take some medicine too much, teach people fast never to exceed those doses stated as maximum dose... I take sylimarin for more than a quater of a century, and never exceeded daily dose stated on the package. Only after I've read in pubmed that it was proved to be safe and effective in dose of 2-3 grams of silibinin at combatting some viruses (like hepatitis C) I tried such a big dose for the first time...

And with fisetin, I went to doses up to 5 gram of fisetin at once (I would go to 10-15 grams a dose but it was too expensive...) and the only effects were weak and were fading away within week or two. So it definitely has some effect (by my very subjective feeling 10-20 times stronger than quercetin), but senomorphic effects is all what I subjectively felt. Maybe some objective biochemical analysis would draft the difference, but objectively the only thing you feel in the longer term is tendon pain here and there even at the dose 50 times larger than maximum dose stated on the package... If you have medical history on tendons, start with supplementing calcium and magnesium first and control their level by laboratory examination frequently, because it's seems this effect is caused in significant part by number of new osteoblasts created by fisetin and the calcium they used up, since supplementing calcium and magnesium ameliorated most of this effect.

Posted by: SilverSeeker at January 10th, 2021 2:52 PM

@Edward F Greenberg where did you get this from: "The lowest demonstrated senolytic dose ([...] 5 mg/kg humans)"?

The Mayo clinic is still conducting their trial, trying to prove that the lowest working senolytic dose for human females is 20mg/kg, and their result are neither officially or unofficially published :<. They definitely must have made the scaling from mouse to human some way (measuring level of fisetin in the blood maybe? and level of some metabolites indicating senescent cells killed maybe?), but their trial is still ongoing and I can't find the source with the method they did for this dose scaling.

Posted by: SilverSeeker at January 12th, 2021 5:25 AM

@Edward There are ongoing fisetin trials at Mayo Clinic, like this one, where they use 20mg/1kg of body mass of fisetin for women: https://clinicaltrials.gov/ct2/show/NCT03325322 to prove that this dose is enough to cause removal of any senescent cells in humans and still safe. There are also earlier long time ago completed small scale studies on pulmonary cancers where minimal effective and still safe dose established for humans was 1500mg fisetin + 1500mg wogonin. Fisetin alone was not effective enough no matter the dose. Senescent cells in many tissues are identical to cancer cells (except the only difference that they don't divide), so doses established as safe for human and effective for cancer should be effective against pre-cancer (senescent) cells too. These mouse-human tables are very rough initial estimates, and with fisetin these estimates are even worse than usual.

Posted by: SilverSeeker at January 22nd, 2021 11:11 AM

@SilverSeeker: I agree that the mouse:human conversions are rough at best. I would disagree with extrapolating fisetin's anti-lung cancer effects to its general whole-body senolytic activity.

Senescent cells vary widely in their susceptibility to senolytics. Navitoclax only induces apoptosis in senescent lung cells at ~1000-3000 nM (Pan et al. Int Jour Rad Onc 2017); it takes 500X LESS navitoclax (~5-10 nM) to induce comparable apoptosis in senescent HUVEC (Zhu et al. Aging Cell 2016). Even if you assume, as you indicate:
- Lung cancer cell activity = senescent lung cell activity
- Fisetin anti-lung cancer activity = 1500 mg/day in humans

Then we would expect Fisetin to start showing senolytic activity against other cell types at ~500x lower concentrations (~3 mg/day).

Ultimately, I agree that more human studies are needed. It could go either way.

Posted by: Edward F Greenberg at January 27th, 2021 6:15 PM

@Edward F Greenberg what we are seeking is not the smallest dose that kills (any) type of senescent cell (which are as diverse as cancer types or maybe more, taking into account that some differ significantly from later cancer cells) but the dose that kills as many and as diverse of them to meaningfully lower SASP. To get teraputic effect at least 2/3* to 3/4* of senescent cells must be removed. *this is yet still another unknown number

Combinations are promising in this respect that two or three very weak anticancer substances combined can kill wide senescent/cancer cell types that single one of them can't at any dose (like Q+D can and neither Q nor D can't), broading the range and ratio killed in safer ways. 1500mg with combination of 1500mg sth else doesn't mean that 1500mg alone can do anything. Wogonin is uncomparately safer to use than dasatinib. Dasatinib can't be legally bought in my jurisdiction anyway if you don't have prescription. Wogonin as a common supplement can be bought without such legal hassle as it is GRASS... just nobody makes it so it can't be too :<. More studies, more scientific research is needed, but nobody is funding it. Everybody incorporates a startup to have new senolytic that can be patented, but no basic scientific research. Pity.

Posted by: SilverSeeker at January 29th, 2021 10:06 AM

@SilverSeeker: agreed that more studies are needed. On the academic side, James Kirkland (Mayo), Pamela Maher (Salk Institute), and Miranda Orr (Wake Forest) are testing DQ and Fisetin in a number of preclinical models and a few clinical trials; I will be interested to see how they pan out!

Posted by: Edward Greenberg at January 31st, 2021 2:50 PM

Can anyone give me a ballpark conversion ratio for taking liposomal sublingual fisetin, compared to the dosages and ingestion methods discussed above? I want to try a few days of reaching a sufficient blood concentration to have the target effect. (I'll be using the Alive By Science product which is 75mg of fisetin per 2ml dose)

Posted by: Clay Townsend at March 4th, 2021 11:43 AM

Buying fisetin in this country, the USA, is a bad idea. However, there is one place I know of now, where the price begins to approach a reasonable one for the consumer, that is AliExpress.com, where a kilogram of 99% fisetin can be bought for less than $250. In this country, the USA, you are submitting to a system of market control, price fixing and price gouging. It costs less than $15 to manufacture a kilogram of fisetin.
I am new to this forum and this subject. Can anyone tell me why the mg/kg dose is "scaled down" for humans. Dosing of a particular nutrient is a difficult matter. Note that a 5mg sublingual tablet of B12, the most often sold potency, is 208,333% higher than the formerly used and still government recommended dose: politics. Self-styled authorities on dosing, repeating like a parrot, will tell you vitamin A can be toxic, therefore, don't exceed 10,000iu a day. But the effective dose for protecting the eyes, for the health of skin and for many other benefits is 30,000 to 40,000iu, and it is safe up to 75,000iu a day. I had to stumble across that particular bit of information in the writings of a very knowledgeable and trustworthy doctor. Be very skeptical about commonly accepted doses. It's difficult to find the toxic dose of a nutrient for humans. Admittedly, I have no training for it, but when I try I almost always fail. Perhaps someone can give me a few tips.
Since senescent cells accumulate continuously, wouldn't it better to take fisetin every day? How many studies showed a shortening of telomeres? Where they done in vitro or in vivo? It seems illogical to me that an unhealthy state, oxidative stress, would make telomeres more resistant to shortening than a health state. I think this is a question that deserves a lot more attention. Logic doesn't always give you the right answer in biochemistry, but it should not be dismissed.

Posted by: Jeffrey Averack at April 8th, 2021 3:38 AM

Does anyone know if Fisetin targets senescent cells in different tissues than Dasatinib? Do they have the same effect on senescent cells or are there some differences between the two?

Posted by: Chuck at May 11th, 2021 11:31 PM
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