Fisetin to Clear Senescent Cells
Following studies with mice that showed significant senolytic clearance of senescent cells following large doses of the readily available flavenoid supplement Fisetin, my wife and I (ages 79 and 84) decided to try it. We have just completed two sets of massive Fisetin doses.
We had Life Extension blood-work done in October before the start, and we will have more again next week to observe any changes. The first set of Fisetin doses was on October 22-25 with 800 mg/day for three days followed by 600 mg on the fourth day, for a total of 4 g. I didn't notice much in the way of effects. Perhaps some reduction of small aches and pains and some increase in energy and mental acuity.
For the second set of doses done November 22-26, since we experienced no negative side effects in the first set we decided to increase the dosage a bit and to add 10 mg of BioPerine, a supplement that is reputed to magnify the effects and potency of flavenoids. For five days starting on Thanksgiving we took 500 mg of Fisetin and 10 mg of BioPerine twice per day, for a total of 5 g of Fisetin.
This time. I did experience one negative side effect. A few months ago, about 2 AM in the morning I awoke from a deep sleep and experienced a severe episode of vertigo. I turned over in bed, and the the whole room seemed to tilt. Suddenly, I didn't know which way was up. I staggered to the bathroom and vomited. The symptoms tapered off and disappeared in a few days, but it was a very distributing experience.
On the 2nd day of our 2nd Fisetin series, I experience a recurrence of that vertigo in the middle of the night, not as bad as my initial experience but still rather disturbing. I tolerated this mild vertigo and continued the treatment. My wife had no similar symptoms, and after my last dose I experienced no further vertigo symptoms.
On the positive side, following the second set of dosages I did feel very well, and very sharp and alert. This past weekend I ran my Shetland Sheepdog Taliesin in an AKC Canine Agility Trial in Mt. Vernon, WA, and we did very well, qualifying in 7 runs out of 15 and getting various colored placement ribbons. I was feeling quite sharp, and I even invented a new dog-handling technique that fixed an ongoing problem we were having.
Next week we will do the blood-work again, and I'll report any changes.
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Karl Thanks. I am aware of that study. I looking for the dosage that Life Extension is using in its study wherein they use Fisetin and dasatinib and quercitin. I've attached a slide from the video where Bill Falloon mentions it. The slide is at 29:30 of the video which is at :
https://www.youtube.com/watch?v=fPH0sBfUK5U&feature=youtu.be
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Karl life extension is conducting the study from the slide so they must have dosages. But just haven't published them yet to my knowledge.
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For group informational purposes. I completed my first experiment with fisetin this weekend. I weigh 157 lbs. Took 2 grams of Swanson fisetin and 2 capsules of Life Extension Senolytic Activator. No particular reason to add that other than I had ordered ten boxes some time ago, so I had it and just threw it into the mix. I took this same cocktail over three days. No dramatic effects were experienced. Noticeably, a parallel to fasting where you feel a bit "charged" or mildly antsy and just want to do something. I do have some non-arthritis joint pain in my back and hip and I was surprised to note that it eliminated that short term. The following day it was back again. Alleviated with second and third doses also. This leads me to suspect an analgesic mechanism rather than a curative effect. Also, just to note previously I had taken 8 of the LEF senolytic activator capsules and felt like I had five cups of coffee, short-lived jitters. But no pain relief.
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Dorian Gray thanks for the feedback. I would think it will take awhile to see the positive effects.
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Dan said:
For example during a fast, at day 5 is when it's clinically been measured that heavy senolytic activity occurs.What's your evidence for this? I'm not aware of any evidence for fasting actually killing senescent cells, let alone a specific time-course.
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Latest Senolytic Sessions with Fisetin
It has been 6 months since we last did senolytics with Fisetin and D+Q, and our body load of senescent cells has probably built up again, so it's time for more sessions. This time, in the lead-up to this, I've been experiencing lower back pains and a "wry-neck" problem on the right side of my neck that interferes with sleeping and limits the amount I can turn my head while driving. Popping Advil and Tylenol doesn't help much. These are likely to be aspects of age-related inflammation (I'm 85), so I was curious as to whether the new senolytic session would have any impact on these symptoms.
Yesterday and today my wife Pauline and I took 10 mg of BioPerine at 8 AM followed by 2 grams of Fisetin powder stirred into warm Trader Joe's extra-virgin olive oil at 9 AM. The olive oil was put in a shot glass, heated in the microwave for 30 seconds, then put on a small digital scale while the yellow Fisetin powder was spooned in until an added weight of 2 grams was reached. The result was stirred until the yellow powder was either dissolved or suspended in the oil, forming an unsavory-looking opaque green liquid. This was drunk as thoroughly as possible, and the residue in the glass was scooped out with bread fragments and eaten, until the glass was clean.
My observation this afternoon is that my back pains are gone and my stiff neck is much better, but not completely gone. I also feel more energetic and alert. This time (see previous reports above) there were no flu-like symptoms or other observed negative side effects, at least so far.
We're doing AKC competition dog agility with our Shetland Sheepdog Taliesin at a facility north of Seattle this weekend, so I will also be able to observe how the senolytics affects our performance (which was a mediocre 7 Qs out of 16 runs last weekend). We plan one more Fisetin session tomorrow, followed by two D+Q+F+P sessions, to be done in the next two weeks.
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Followup on Above
At the dog agility competition I mentioned, we did better than in the previous competition with 9 qualifications (Qs) out of 18 runs and 3 more near misses (2 clean but overtime runs and 1 tail hitting last bar). Still some lower back pain after sitting too long, but wry neck is gone.
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Anyone have any ideas where to get dasatinib without a prescription? I do not live in Florida or another state where the Florida doctor can ship. The anti aging site was hacked and bonhoa health will not ship to US or EU.
Thanks
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I've tried several combinations of Fiestin with various supplements. Initial trial was with Fisetin and Qurecetin. 2 grams of each, twice a day for three days. Learned that Quercetin has no senolytic value so switched to using Fisetin with Echinacea as an immune system booster on the assumption that it would increase microglia activity. No immediate changes noted. Third trial, added Lecithin to the combination on the assumption that an emulsifier would increase the adsorption of Fisetin. Noted improvements in cogitative functions, ambition, physical condition over next several weeks. Now seems to have leveled off. Wish someone would devise a simple means of measuring the senescent cells concentration and / or removal effectiveness.
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RAW My feeling is that even if it is true that quercetin is not senolytic, it might be valuable to take it along with the fisetin. My reasoning is that it has a "a moderate to strong inhibitory effect on CYP3A4 activity activity." "cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology."
For this reason, even if it is only a sacrificial substance, it may increase the bioavailability of Fisetin when taken with it by reducing the effect of the CYP3A4 enzymes. -
Dan Nave
Who says that "quercetin is not senolytic"? My understanding is the in the initial in vitro tests with cell cultures, both quercetin and dasatinib were found to show senolytic effects, but when they were combined into the D+Q cocktail, the senolytic effect was considerably stronger than the sum of the two individual effects.
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JGC Quercetin was originally used with Dasatinab because it appeared to enhance the effectiveness of Dasatinab. (I don't recall which research group published the information) Once Fisetin was discovered to be a more effective senolytic than Dasatinab, it became apparent that Quercetin didn't help Fisetin penetrate the intestinal wall and didn't have any synergistic effect with Fisetin.
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RAW
Read the link in my post above and the link that it provides. The work was done by the Mayo Clinic and other institutions, and is as I described it. Fisetin is better, but Quercetin has senolytic properties, particularly for the cells that line blood vessels. There has been speculation and self-experiments with F+Q, but I am not aware of any studies in which the synergy of Fisetin + Quercetin has been rigorously investigated.
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JGC Thanks very much for the information and the link. I've been absolutely swamped with unrelated issues for the last several weeks and haven't had time to follow up on much of the information that's available. I'll probably be in the 'body shop' for hip replacement and other repairs for the next several weeks and recovering for a while after that. Hope to be back online in a couple of weeks.
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Fisetin + Hydroxypropyl-Beta-Cyclodextrin?
Some of you may understand more about the arcane subject of biochemistry and molecular structure than does a simple-minded nuclear physicist like me, so perhaps you can answer a question about Cyclodextrins.
Beta-Cyclodextrin
Cyclodextrins are a family of non-toxic glucose-based molecules (alpha, beta, gamma, ...) shaped like doughnuts. They are hydrophylic (water-seeking) on the outside and hydrophobic and lipophylic in the doughnut hole. I have read that these properties can be used to increase the bioavailability of water-insoluble supplements like the flavenoid curcumin. It's a bit more complicated than that, however, because beta-cyclodextrin, which is about the right size for transporting such insoluble molecules, is so tightly bound that it also has water solubility problems. Fortunately, this can be fixed by hanging a propylene molecule on the basic beta-cyclodextrin molecule to make water soluble hydroxypropyl-beta-cyclodextrin.
The supplement manufacturer Nature's Essentials of Suwanee, GA actually sells boosted versions of the supplements Tumeric/Curcumin, Resveratrol, and Melatonin that have hydroxypropyl-beta-cyclodextrin included for increased bioavailability. I have bought and am taking these boosted supplements daily. Unfortunately, Nature's Essentials does not sell versions of the senolytic flavenoids fisetin and/or quercetin that have been similarly boosted.
So my question is, if I buy some hydroxypropyl-beta-cyclodextrin powder, mix it with fisetin or quercetin powder, and take this as a senolytic, will that have the desired boosted bioavailibility? Or does one have to do some further chemistry to thread the flavenoid molecule into the doughnut hole?
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JGC I prepared a fisetin-cyclodextrin complex last year. Note I used gamma-cyclo instead of beta-cyclo. It's a bit trickier than just mixing the two together. You first need to dissolve the fisetin and then allow it to complex with the cyclo. I did this using ethanol, but it takes a decent amount to dissolve a dose. I also added piperine. You then add this to an aqueous cyclo solution (50:50 was what I used) and allow time to complex. However, it's important to remove the ethanol afterwards unless you want alcohol poisoning. A potential problem is that fisetin is extremely temperature sensitive, so I used a rotary evaporator, which allows you to evaporate the ethanol at low temp. You could ingest at this point. I took it a step further and lyophilized the solution to create a powder, which I stored for a while before dissolving in some water and ingesting.
The dose I ingested was probably less than 400 mg fisetin (started w/ 500 mg but lost some during prep). I used ultra-pure compounds that were pretty expensive ($500 per dose!). I verified complexation in the lab using FT-IR. I was doing this on the side to see if it was effective and might be marketable, but the business relationship I was in didn't work out and I haven't done anything with this since. However, I recently gave my father a dose of fisetin mixed with olive oil (the cyclo is just too time consuming and needs scaled up equipment for bigger doses). He gets his bloodwork done a lot because he has leukemia (CLL), so I was really surprised when the very next test (a week after his last dose) he saw the biggest drop in lymphocytes he's ever had. Although an N of 1 means very little, his result raised my interest and I'm considering a making a large batch. Would love to hear your own experience.
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Jacques Mathieu
That's really interesting work, Jacques. I received my order of 25 g of 2-Hydroxypropyl-beta-cyclodextrin last week, but I haven't done anything with it yet. My plan was to first dissolve a stoichiometric quantity of 2.44 g of the cyclodextrin in water, then add 500 mg of fisetin powder and leave it overnight to combine with the cyclodextrin and dissolve. Do you think that would work, or would one absolutely need to use the ethyl alcohol, as you did?
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JGC it's hard to say. When I add the fisetin/ethanol to cyclo/H2O, I assume some precipitates out, but almost all is eventually complexed. Without a solvent I don't know if complexation will occur, or if the fisetin will just aggregate. You could test using a small amount first - if it's complexed it shouldn't leave much residue.
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Partial Answer
I found a paper by some researchers in Thailand in which they actually do a computer simulation to investigate how Fisetin threads through the hole in Beta-Cyclodextrin and how this effect the interaction with water. There are four possible configurations, and they calculate their relative probability of formation. Apparently cofigurations II and III are the most soluble because the "B" region is more enclosed. Here's a figure:
The bottom line seems to be that mixing Cyclodextrin and Fisetin in an aqueous solution does produce dual molecules with improved water solubility. They use unmodified Beta-Cyclodextrin, not Hydroxypropyl-Beta-Cyclodextrin, and they do not give any solubility values, but after all, its a simulation. On this basis, I just ordered some Beta-Cyclodextrin and some 2-Hydroxypropyl-Beta-Cyclodextrin from Amazon. I intend to do some self-experiments with the aqueous mix, and maybe try it with Quercerin also.
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Followup
My experiment with Hydroxypropyl-Beta-Cyclodextrin (HBC) and Quercetin was a failure. I dissolved the HBC in water, warmed it in the microwave, and then added a stociometrically correct amount of Quercetin. It made an opaque mustard-colored liquid that, after a few hours, resolved itself into a yellow transparent liquid with a thick layer of yellow powder on the bottom. Repeated heatings and stirrings made no change in the situation. Finally, it went down the sink.
It has been suggested that one should dissolve the Qurecetin (or Fisetin) in 200 proof alcohol before mixing with dissolved HBC. Partly because of the COVID-19 self-isolation, I haven't tried that yet.
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JGC fisetin is only soluble in ethanol to 5 mg/ml, so unless you find a way to remove it you would need to ingest 400 ml ethanol to get a 2 g dose of fisetin. I suspect that would kill most people. I used a rotary evaporator to keep temperature low as fisetin is very sensitive to temperature
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I received dasatinib today from antiaging.clinic - I paid via wire (which minimizes my risk as they did not receive my bank info. Via wire was the only method offered.
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I was able to get mine from Bonhoa.
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I don't think there's any evidence that piperine/BioPerine enhances the absorption of flavonoids generally — just curcumin. Or do you know of any? And the mechanism isn't really understood, so it's hard to make strong predictions. Bath1 Best Bathroom shower wall panels
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Philip V. Anstett
https://www.hindawi.com/journals/omcl/2015/854015/
Interactions between CYP3A4 and Dietary Polyphenols
https://www.ncbi.nlm.nih.gov/pubmed/12130727
Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4
I expect BioPerine is the same as piperine. You can Google it. Plenty of info on the net.
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Philip V. Anstett
It's deja vu all over again. If you scroll up to posts from one year ago, you will find that I already answered this question, as asked by Iðunn, and gave a reference.
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