The Rejuvenation Now Risk-Benefit Analysis of Fisetin as a Senolytic Therapy

The Forever Healthy Foundation's Rejuvenation Now program is engaged in the production of detailed analyses of risk and reward for presently available treatments that may act to slow or reverse aging. I think this is helpful, as a great deal of information exists, but is very scattered, and there is far too much uninformed hype out there. Putting all of the facts together in one place, coupled to a sober assessment of what those facts mean, is a good use of resources. This is particularly true given that senolytic therapies presently exist, and, to the degree to which these treatments successfully clear senescent cells with minimal side-effects, should be expected to produce sizable benefits to health for all old people who use them. Those old people just need to be told, so that they can make an informed choice about their own health.

One of the potential senolytic therapies of interest is a cheap and readily available supplement, fisetin. This is interesting because animal data shows it to be about as good as the dasatinib plus quercetin combination. One might ask how a supplement can be readily available for years, and yet no-one noticed that if you take the whole bottle at once, it significantly reverses inflammatory age-related conditions. Perhaps that is in fact the case, but as the analysis from the Forever Healthy Foundation notes, we just don't know. Human trials are ongoing, and we might expect initial publications from the research groups involved over the next year. This will clarify whether or not fisetin happens to be unusually effective in mice only.

In a sense, either outcome would be surprising. The important parts of the biochemistry of senescent cells, when it comes to the operation of senolytic drugs, are essentially the same between mice and humans. The dasatinib and quercetin combination has been shown to work in humans much as it does in mice when it comes to destroying these cells. Yet fisetin has been readily available and widely used as a supplement for a while, without the sort of attendant murmuring one might expect given the sizable benefits it should produce if it is as senolytic in humans as it is in mice. We shall see what the story is when the clinical trial data for fisetin emerges. Meanwhile, many more self-experimenters are using fisetin than are using the far more proven dasatinib and quercetin combination, given that fisetin is much more easily obtained.

Fisetin Senolytic Therapy Risk-Benefit Analysis

Senolytics are agents that selectively induce apoptosis of senescent cells. Fisetin is a flavonoid polyphenol found in many types of fruits and vegetables that is believed to act as a senolytic in addition to its numerous other known benefits. Although natural senolytics are less potent, compared to the targeted senolytics, they have lower toxicity and are thus, likely to be more readily translatable to clinical medicine. This risk-benefit analysis focuses on the risks and benefits of using fisetin as a senolytic rather than its more common use as a supplement.

There are currently three phase 2 clinical trials underway and the first data is expected to be reported in about a year. The data from the phase 1 trials has not been published. All trials are being conducted by the same investigators at the Mayo clinic using the same treatment protocol. Only two papers directly related to the use of fisetin as a senolytic were identified, neither of which were conducted in humans. The other 5 studies included in the table relate to pharmacokinetics, risk, and lifespan extension.

To the best of our knowledge, there haven't been any studies published on the pharmacokinetics of fisetin in humans. Only one animal study on fisetin has reported any form of toxicity from fisetin use and the authors concluded that the elevations in ALT/AST levels (indications of liver toxicity) were in large part due to the vehicle used to administer the fisetin (DMSO). However, the fisetin + vehicle group showed significantly higher elevations than the vehicle alone group indicating that high doses of fisetin may additionally burden the liver because of its poor bioavailability. At a lower dose (112 mg/kg), fisetin didn't significantly increase apoptosis or lead to liver toxicity. Intermittent dosing and use of a form of fisetin with increased bioavailability are likely to mitigate the risk of liver toxicity.

Fisetin has been shown to decrease senescent cell biomarkers as well as the numbers of senescent cells in a variety of tissues, including ex vivo, human adipose tissue as well as in vivo, in mice. The primary risk mitigation strategy is to wait to commence therapy until clinical trial data has been published that describes the possible benefits and adverse effects. At the current time, the only form and dose that has been tested in phase 1 clinical trials is the so-called "Mayo Protocol". The Mayo Protocol consists of taking 20 mg/kg of oral fisetin on two consecutive days and repeating the same dose, one month later.

Comments

They're doing a great job. But I read that only people who are over 50 can benefit from these therapies. It's really frustrating for 30s because basically you can only wait to get old before taking anti-aging therapies, it sounds weird. I thought preventing damage before they appear was a better approach. Even thought I'm "only" 33 I will still take these therapies.

Posted by: Jonathan Weaver at September 19th, 2019 2:39 PM

@Jonathan Weaver i agree, im 32 and i am currently taking life extensions senolytic activator (bio quercetin and theaflavins formula) which is reccomended for over 35s. am awaiting the mayo clinics data from their study with fisetin before i use or reccomend that

Posted by: scott at September 19th, 2019 2:54 PM

I've already done both rounds of the Mayo Protocol, sounds like I need to go pop some milk thistle....

Posted by: August at September 19th, 2019 7:50 PM

Someone needs to make liposomal fisetin commercially.
Liposomal Fisetin

Posted by: gwood at September 19th, 2019 10:52 PM

As a man, this first antiwrinkle effect I noticed right after the third day of 2.0-2.0-2.5 gram series (2 gram at first day and second, 2,5g at third), ie. 25mg/1kg. The earlier 3 day series (1g-1g-1,5g, 1.5-1.5-2.0g for 3 days) gave no visible effect. This supplement was always sold with the guideline to not exceed 1 capsule (100mg daily), 25 fives LESS than minimal oral dose giving effect on humans. The fruit with most content (160mg/1kg) is strawberry. Who would eat 20 kg of strawberries at once? And, since strawberries gained popularity on Europe in the XVIII-XX centuries, societies that started wide consumption of this fruit, soon after enjoyed its benefits already centuries before supplement come into existence already, ie. 10-15 years longer mean life. Today it's consumption in natural products is uncomparably far greater from natural products than from supplement, and the extension on mean life (by more than a decade) already took place before.

Posted by: SilverSeeker at September 20th, 2019 7:06 AM

I see no mention among the listed risks (or anywhere else in the analysis) of fisetin's potential genotoxicity as an inhibitor of topoisomerases. Is this an oversight, an intentional omission, or has that worry somehow been put to rest and no one told me?

Posted by: Mike Guetta at September 26th, 2019 1:43 AM

My main concern about Fisetin is in regards to telomeres. In mice studies, it seemed to reduce telomeres if they weren't under severe oxidative stress.

The following is a comment I found on another site by someone named Brien:

"Fisetin could have potential negative effects on antiaging through its effects of shortening telomeres by causing cells to go through more cell divisions. Maybe it wouldn't be detrimental if the enzyme telomerase were activated at the same time to renew the telomere numbers or counteract the shortening effect, but I also came across this one animal study on fisetin that no one seems to be mentioning. Fisetin in mice at 1 micromolar blood levels actually shortened telomeres after a period of time in normal mice. Those mice which were subjected to increased oxidative stress did not show reduced telomeres relative to the control with oxidative stress. But if we think about how so many antiaging enthusiasts take a lot antioxidants, then if they don't have a higher than normal amount of oxidative stress maybe Fisetin could shorten telomeres. Since some cells go through increased divisions every 30 to 60 days to replace senescent cells, or maybe when taking a senolytic like fiestin it would happen sooner, it makes sense what a lot of people are saying to just take it for a short time, like 5 days at 500 to 700 mg per day to get the senolytic blood levels. Then maybe at the same time or shortly thereafter take telomerase upregulating nutraceuticals such as high dose melatonin, Ginkgo biloba, milk thistle, and cycloastragenol/ astragaloside-4. Even tocotrienols, vitamin D, and Omega 3 upregulate telomerase. I found studies on all of those, though the shortcomings admittedly are that many are just cell or animal studies, though the ones for Vit D and Omega 3 were actually human studies. It still is a gamble unless people take blood tests of their telomere end cap numbers which is available now from testing labs for those willing to pay the money. Otherwise it is a shot in the dark.
Here is the excerpt about Fisetin in the conclusion section:
Chronic fisetin treatment of HF at physiological concentrations resulted in shorter telomeres compared to control cells, indicating reduced telomere stability and enhanced biological aging of these cells. Under the assumption that it is healthy, fisetin is often added to nutritional supplements at relatively high concentrations. Since the biological effects of regular consumption of high doses of fisetin (and also flavonoids in general) are not known, thorough safety evaluation is warranted with respect to these nutritional supplements. Chronic minocycline treatment also enhanced telomere shortening. This implies that precaution should be taken when minocycline is subscribed as a chronic treatment.
However, under conditions of chronic oxidative stress, both fisetin and minocycline appeared to reduce the rate of telomere shortening. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844163/
part of abstract:
"Therefore we evaluated the effect of chronic PARP-1 inhibition (by fisetin and minocycline) in human fibroblasts (HF) cultured under normal conditions and under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide (t-BHP). Results showed that PARP-1 inhibition under normal culturing conditions accelerated the rate of telomere shortening. However, under conditions of chronic oxidative stress, PARP-1 inhibition did not show accelerated telomere shortening. We also observed a strong correlation between telomere length and subtelomeric methylation status of HF cells. We conclude that chronic PARP-1 inhibition appears to be beneficial in conditions of chronic oxidative stress but may be detrimental under relatively normal conditions.""

Posted by: Alex at December 27th, 2019 8:35 AM

Need feedback from someone. I have fisetin in a package... states 20 grams. I'm confused. Is this the volume of the package or the true volumn of the fisetin contained within. My daily dosage would be 1.36 grams total... daily for two days. According to the study. Not sure... how much I'm taking.. little confused by the math. How many grams of fisetin in 1 tbsp? Thanks help appreciated

Posted by: Charmaine d St. Croix at January 12th, 2020 8:25 AM

Mike,

My understanding is there are two kinds of topoisomerase inhibitors,
acting at different steps of the topo lifecycle.

- topoisomerase "poisons" which inhibit the religation step. That is,
when topo has cut a DNA strand and is bound to the cut site, a
"poison" prevents it from reconnecting the DNA and
detaching. Inhibiting topo at this step results in proliferation of
strand breaks all over the genome resulting in DNA damage when
replication/transcription/etc machinery tries to walk over the strand
break/binding site, and either cell death or cancer.

- so-called "catalytic inhibitors" which act during other parts of the
cycle, preventing topo from cutting DNA. Inhibiting topo here just
causes lots of free topo to accumulate, floating around not doing
anything, resulting in a *reduction* of DNA strand breaks. This can
lead to failure of cellular replication due to topo not doing its job
(because the DNA is all tangled up and can't be separated).

Fisetin is the latter, a catalytic inhibitor of topo(I) and (II). This
means it can kill replicating cells (although from the studies it
doesn't seem like it does this enough to matter at the doses which are
used) but it won't cause cancer.

In terms of effects, these two types of inhibitors are kind of
opposites: if you are dosed with a topoisomerase poison, you might get
cancer, but you can prevent it by also taking a topoisomerase
catalytic inhibitor, which prevents topo from cutting DNA in the first
place. This is why they tested the effect of fisetin in [1] by dosing
cells with a topo(II) poison, seeing a proliferation of strand breaks,
then additionally dosing them with fisetin to see that the strand
breaks are prevented.

References:

[1] https://www.ncbi.nlm.nih.gov/pubmed/20025993 "The dietary
flavonoids myricetin and fisetin act as dual inhibitors of DNA
topoisomerases I and II in cells."

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961513/#!po=10.6061
"Topoisomerase II and leukemia"

Posted by: nshepperd at January 22nd, 2020 10:09 AM

I have been taking one Fisetin every day. Each tab is 100mg. It is difficult to find it (at least online) to find Fisetin at all. And it only comes in 30 caps per bottle at about $15/bottle. Reading this article makes me wonder is it possibly effective at 100mg/day or do I need to take 6 over two days (for my weigh avg. of 115 lb.) or is it really unknown at this point?

As for Strawberries? I've been told I have silent acid reflux. That means berries are high on the acidic scale. So amongst other foods I have avoided them when possible.

Posted by: Ellen at February 8th, 2020 11:36 AM

@Ellen
There's an option to bye a bag at purebulk but they seems to not ship to all countries. They do ship to US, and probably to Canada.
Another option is bottles from Amazon.
The most common fisetin is doctor's best 30 pils of 100mg. A bit pricey and not always available.

I did self experimentation with a questionable scientific value. I was taking 2-3 100mg pill with Quercetin pills 500mg. I was taking it throughout the day since it has poor solubility, and I didn't want to use stronger solvents. Besides, it seems fisetin has a half-life of about 6 hours in the body, so spreading the dose might keep a higher concentration and better bio availability. And it was plain simpler to take pills on schedule than mixing solvents and measuring powder.

The immediate effect was that I've got diarrhea, which most likely sent some 50 USD down the drain.

Posted by: Cuberat at February 8th, 2020 2:05 PM

And here's the aftermath . Very subjective, inconclusive and not scientific.
It is speculated that killing senscencent cells impairs wound healing for some time. Lo and behold on the next day I fell on ice and got bad scratches. I would not say it took longer than usual to heal (4-7 days). That would indicate that there was no measurable effect. I had a tendon trauma from an earlier accident a month earlier. It got better. Could be unrelated to the senolitics, though. I didn't have any flu -like symptoms as many people report.( And even if I had it cold be a seasonal cold)
What is interesting, a week after the dose I had an itch (a pre-existing irritation) that I was scratching until bleeding. The scratch was very tiny. Yet the blood wasn't stopping. So there was some strong anti coagulation effect. Almost 5 days later... Mind that I don't have hemophilia, so that is highly unusual. That would indicate that there was some effect, but probably not from the fisetin. No other noticable effects neither positive nor negative.

Posted by: Cuberat at February 8th, 2020 2:11 PM

Hello,
56 y.o., female.
A week ago i have started 0.8 g twice a day for 3 days. Didn't notice any inconvénient side effect.
On second day i got surprised by the brigthness of day light. 3rd day, i could smell and taste much more stonger sents.
Since few days, i expérience much bitterness in vegetables and fruits.
Energy ok, sleep may be better, memory/blurs seems better.
I intent to continue next months same doses.
Sd

Posted by: Sd at February 22nd, 2020 5:43 PM

45 y.o. male.

I tried 30 100mg pills spread over 12 hours coupele with about 2g Quercetin. ( I got diarrhea of that many pills, so initially I thought there was no effect at all)

However, one or more noticable effect was that I had long bleeding about week after... from a very tiny scratch. A month after a much larger scratch coagulated within a couple of minutes. The previous snatch was bleeding at least for half an hour and I stopped it by pressing the wound for a few minutes. So i have my personal confirmation about increased risk of bleeding.

No obvious major improvement that I noticed. I had a tendon trauma that got much better but that could be unrelated and it just healed anyway.
Basically no dramatic improvements like grey hair turning dark again. On the other hand, there were no age deteriorations like back pain and such for the couple of months.

Either 44 is too young for fisetin, or its effects are muted due to either bad bioavailability or incomplete protocol...

Posted by: Cuberat at February 22nd, 2020 6:43 PM

Hello, 54yo man. Plan, w fasting, going to take 200mg fisetin w 1000mg Quercetin and Milk thistle. Plan to repeat once a week. At bedtime will take melatonin,D/K2, and extra fish oil. The dose may be too low to pick up any benefits, but risk/cost and side effects should be low. Also, on days following anti-senokytic seems reasonable to hold anti-oxidants active in cell compartments active in macrophage activity- although quercetin has anti-oxidant properties - so this is a bit infusing when trying to consider what is happening at a cellular and immune surveillance level. Any comments?

Posted by: QuartzSand at March 24th, 2020 10:30 AM

Fisetin might well also be a CD38 inhibitor. So a long-term, lower-dose schedule may have some benefit aside from a senolytic effect. CD38 is a NAD-ase -- the levels of which go up as you age while NAD+ levels go down.

Apigenin, though, is more studied as a CD38 inhibitor, and is probably cheaper.

Posted by: cacarr at April 27th, 2020 2:42 PM

I have some thoughts on the bioavailability of fisetin. I found myself not being able to happily digest dairy anymore last year after fasting for a few weeks. That kinda bugged me. I got over it. Not sure whether it was a result of the extended fasting or the subsequent removal of all things dairy, but I sure can get away with using much lower doses of all supplements for desired results.

If my understanding is correct fisetin, rutin and naringenin are three functionally equivalent flavonoids. That being the case the effectiveness of fisetin could greatly be amplified if one were to consume a whole-food/plant-based vegan diet for a minimum of 72 hours before any protocols.

The reason for this is that these flavonoids are proteolytic in nature. They specifically target proteins. And they will get spent on the easier/closer proteins in the gut restricting their therapeutic systemic benefit in eliminating senescent cells.

I mentioned 72 hours above. That is the average transition time from nose to tail for those consuming an average western diet that includes any dairy. Your gut turns dairy into pectin. That's why cheese tends to slow most people down. Optimal transition for men is 32 hours for women 46 hours.

I've had a number of friends come to me for help regarding diet and the first thing I have them do before they supplement anything is to simply remove "all things dairy" from their diet for 30 days and then get back to me for the next step. Invariably they all come back to me 10-15 lbs. lighter and in much better spirits. And then from their it is much easier to make effective changes.

Once you get the thing(DAIRY) out of the way that is causing nutrient malabsorption the bacterial(probiotic) pathways are wide open.

Cheers MjL

Posted by: mjl(michael) at April 27th, 2020 10:10 PM

I purchased some fisetin and quercetin from purebulk. Divided the powder into capsules of 300mg, 4x for fisetin dose (1,200mg) and 3x for quercetin (900mg) for two days. Used it myself to confirm safety, my partner tried it as well. Neither noticed any side effects, positive or negative (both too young to expect much if any benefit). It was then passed to elders (55 and 65) to try out. I had initially intended to follow the self-experimentation protocol put together by Reason but due to issues with COVID I wasn't able to be around them before/after ingestion and still haven't been able to visit (they do have regular blood and heart tests done for age-related health issues which could at least give a partial answer). There were at least no side effects at least.

Posted by: JSC at August 31st, 2020 11:48 PM

-at least*

Posted by: JSC at September 1st, 2020 12:07 AM

@mjl(michael): what solvent do you use to dissolve fisetin? I make emulsion with butter milch, and combine it with quercetin and resveratrol, and visible effects on skin start at around 25mg/1 kg of weight of fisetin. PureBulk is too impure (too much tannins), max dose I can take without diarrhea is at most 1,5 gram.

Posted by: SilverSeeker at September 1st, 2020 5:34 AM

I am on the second day, of my second monthly round of fisetin 2500mg in a shot glass of Bariani green (high polyphenols) olive oil with 1TBL sunflower lecithin. I notice slight adrenal / anxiety feeling at about the 15 minute mark after consuming which fades after about another 30 mins.

Each time I would get sleepy at about 4 hour mark and take a 2-4 hour nap. Things I have noticed day following dosing are: reduced appetite, and some weight loss (5 lbs). I was concerned about the weight loss, but strength levels have remained constant or slightly improved so it seems to be primarily tissue that I don't need. No other striking improvements but I do appear leaner. I should measure body fat I suppose.

I am sensitive to blood thinners (per 23 and me, which is correct from my experience) but noticed no issues at all with this dosing. I am watchful for tendon issues, since I am sensitive to that, but nothing strikingly different there either.

I should note that I took 5 beet tablets as well as 2 lipase capsules to ensure proper fat digestion since this is a high fat load for me. So far no big belching.

I am considering trying to dissolve the fisetin in small chain triglycerides and see how that goes.

Posted by: jt at October 4th, 2020 10:17 AM

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