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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Fisetin in high doses just makes me feel sick, I don't get then when taking Quercitin .
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Jack Black https://senolyticstreatment.com/
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I was thinking of using LEF Quercetin tablets and alternating days with their Fisetin tablets. thoughts ??
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Kelly K To explain my comments above the reason I suggest not using Q at all regularly is the reasoning that it is chronic non-fatal toxicities that promote cancer. This idea is explained very well here; https://www.youtube.com/watch?v=nrqXKf3tprE
Then consider this review here; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ where Q was actually detrimental to mouse lifespan. If that is the case why would chronic administration benefit humans?
Aside from hit and run senolytics (alongside other compounds, Q doesn't seem to work alone) I am not aware of anything beneficial around Q, especially chronic dosing. Other forums has people talking about kidney damage. If you can direct me to anything to the contrary I would be happy to read it.
Fisetin seems a bit better. Still wouldn't take it daily but I can attest to there being benefits to the stuff certainly short term.
I will also hold my hands up and state that I've bought some of the Q based once a week senolytic pills from LE. Bit of an experiment, but currently on hold as my covid jab is next week and I want my body to be in a 'normal' state for that. But mainly I'm sold on fisetin. Even my 500mg single dose seems to have aided the color perception in one of my eyes, which another poster here had noticed with a higher dose.
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D+F+P Side Effects with BioFisetin
Yesterday my wife and I did a senolytic session for the first time since September-2020. We took 10 mg of BioPerine, followed in an hour by 200 mg of Dasatinib (4 x 50 mg) and 80 mg (10 x 8 mg) of LifeExtension's BioFisetin. The nanoparticles of BioFisetin are coated with a LE-proprietary concoction involving Fenugreek extract that is supposed to boost the bioavailabity of the Fisetin by about x25, so our dose should have been the equivalent of taking 2 g of uncoated Fisetin powder (as we have done before).
This is the first time we have combined Dasatinib with BioFisetin. In all of our previous senolytic session experiences, the side effects were relatively mild. We had done D+Q+P and D+Q+F+P with Fisetin powder, and we had done a triple session with BioFisetin alone. This time, I would say that the side effects have increased to moderate. I had belly cramps all night and didn't sleep well, had multiple soft bowel movements this morning, and experienced a general feeling of unwellness all day. (My dog Taliesin and I did one run at a dog agility competition this afternoon, but we failed to qualify, partly due to my lack of energy and quick response near the end of the run.) My wife, who has never reported any senolytic-session side effects before, had a headache, a general feeling of unwellness, and decided to stay in bed until mid-afternoon today.
I'm not complaining. I take this experience as an indication that our session of D+F+P using LE's BioFisetin had a stronger senolytic effect than we had previously experienced. Possibly this is because LE's claim of a x25 boost is an underestimate of the LE BioFisetin's actual increased bioavailability, or possibly because taking the BioPerine one hour before D+F increases the boost factor. In any case, I'm impressed.
We will compete in dog agility again tomorrow, and based on previous experience I expect to be fully recovered and more energetic. We plan to do two more senolytic sessions soon, the next on Monday (4/19) and the last on Thursday (4/22), spacing the sessions with two off-days. I expect less side effects from these subsequent sessions. I'll report it if I'm wrong.
In the interest of full disclosure, I should mention that my wife and I have just completed a 15-day session of taking a 3 mg sublingual tab of Super-Nutrition's Epitalon (AEDG) every morning from April 1-15. We will repeat this on the 1-15 of May and June. We experienced zero side effects from this Epitalon session, and I doubt if it contributed to the side effects I am reporting above.
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JGC I enjoy reading your senolytic experience reports. I think yours may have been one of the first I read a year ago when doing research. Is there a reason you space them out so far? I am not sure I agree with Dr Green suggesting monthly Dasatinib but maybe quarterly at the most since it is pretty harsh, but certainly fisetin is safer and monthly seems reasonable and is getting pretty popular.
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Fred Cloud
My 3-session spacing with two off-days in between is done because Dasatinib is involved. When we did BioPerine+BioFisetin last year, I did not space the senolytic sessions and we did 3 days in a row. This spacing, like most of the other details of our senolytic sessions, are educated guesses, since we do not (yet!) have a direct way of monitoring the clearance of senescent cells. As for how frequently to do them, I think 6 months is about right. Some of the advocates for more frequent sessions would like to sell more pills.
Incidentally, as predicted, I did make a good recovery from yesterday's side effects and felt renewed and energetic. This afternoon my Shetland Sheepdog Taliesin and I did two masters-level agility runs, and we did very well, with only one problem when his tail hit a bar after clearing the jump.
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JGC
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JGC I would be hesitant to use 200 mg of d. According to the research when one does 200mg of d the likelihood of detrimental side effects goes up tremendously. Especially when you're using it with pepper which actually enhances absorption it means it takes it to a different level. According to most of the feedback from Life Extension we're not supposed to do strenuous exercise at all when we take d. I have found that my body rebelles when I try to to do anything intensely as far as exercise goes. The best I can get just a moderate walk. So I've stopped using pepper and I try to do it at least once a month if not more the recombination of DQ & F. I'm in my sixties so it does make a huge difference though. I take up words a 20 of Life Extensions fisetin with fenugreek which enhances its bioavailability tremendously. One definitely feels the energetic Rush one takes high amounts of fisetin. I do this for three straight days with only a hundred mg of D each day. I definitely feel results from this although I am definitely weak when I do this especially as far as exercise goes. I feel a little congestion in my lungs. I try to walk anyway but do so as much more leisurely Pace then normal. I am not suggesting to anyone here that they use such a high dose of fisetin especially the first few times you use it. I work my way up to it caution is always the best policy. Having a doctor's input is even better.
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garland
Thanks for the heads-up. I am 2/3 of the way through our latest senolytic session, but for the next phase on Thursday, I'll do 100 mg of Dasatinib. The 2nd phase was yesterday morning, with 200 mg of D. I felt a bit lethargic all day, but otherwise there were not the side effects I had reported above from phase 1 on Friday afternoon.
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garland
Last Thursday (4/22/2021) I did the third of three D+F+P senolytic sessions at about 3 PM in the afternoon (about the same time that I had done the first D+F+P session on the previous Friday and experienced unpleasant side effects). After considering your warning, I decided to go ahead and take the usual 200 mg (4 tabs) of Dasatinib. Sure enough, after going to bed with no side effects, I was awakened at about 2 AM with stomach cramps, which persisted for the rest of the night. Tylenol helped me go back to sleep. The next day (Friday, i.e. yesterday) I felt unwell enough to cancel our participation for the day in a dog agility trial held north of Seattle.
I conclude that (a) perhaps 200 mg of Dasatinib is indeed too much, and (b) that one should do the senolytic doses in the early morning (not at 3 PM) to avoid the 2 AM cramps. In any case, today I felt fine and did pretty well at the ongoing dog agility trial. Perhaps a day of stomach cramps is an acceptable price to pay for getting rid of the senescent cells (e.g., pre-cancerous colon polyps) in the lower digestive system.
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JGC likely best to do this monthly or every 6 weeks!
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GEdwards
I am doubtful that senescent cells build up fast enough to make it worth doing a set of senolytic sessions every month or 6 weeks. However, this is at present a matter of opinion, since we don't have a good way of finding out just how many senescent cells are being cleared in a given senolytic session. Perhaps soon some lab will provide an inexpensive urine or blood test for the presence and quantity of the molecule dihomo-15d-PGJ2, and we can be more analytic about which senolytics work the best and how often they should be used.
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JGC Sheeky Science show did a piece on that marker this week, did you also see that?
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Jack Black
Thanks for the heads-up. Here's the LINK to her discussion. The problem is that she didn't give any help in actually finding a lab that will tell you the quantity of dihomo-15d-PGJ2 in a blood or urine sample.
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JGC yes the research on Dasatinib is quite clear that side effects increase dramatically when one does more than 100 mgs. And it can get serious especially since Fisetin or Quercetin might attenuate Dasatinib, My personal feeling is to try fasting some when you do this combination. Taking other nutrients including anti - oxidants might reduce the effectiveness of them. In fact at Mayo they make everyone stop taking all supplements while doing their protocol.... I try to exercise but do not strain as Life extension warned against exercising while doing the protocol. I walk but do not strain as i get some pressure on my heart if I do anything too intense. But I do feel great when i do the protocol.... but tiredness does seem to be the most pronounced side effect asside from some heart pressure if push things. But for the next few days after everything clears up I do feel great and i can do yoga like I was 30 years younger and lots of good energy.
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garland ,@Dan Nave @garland,@Dan Nave
Another D&Q&F protocol with Bioperine.I am very afraid of dasatinib side effects. While the effect of piperine on dasatinib isnt clear, I read that “The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations.”
So to enhance fisetin/quercetin but not dasatinib, here is my once every 2 weeks D&Q protocol:
AM: 100 mg dastanib + 500mg fisetin in the AM with breakfast.
1PM (in under 3 hours from ingestion, all dasatanib is assumed to have been absorbed): 5mg Bioperine+ 500mg fisetin (effective dose estimate 1500 mg) (This is in addition to my daily GHA, EPA, and 250 mg quercetin). With meal.
If my estimates are correct, the protocol is fairly consistent with that of Dr. Green. I would like to increase the flavonoid dosage, but I havent been convinced that would be beneficial.
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garland
On Monday and Tuesday (July 5 & 6, 2021) we did another session of D+F+P senolytics (now taking 10 mg of BioPerine 5 minutes before the Dasatinib and BioFisetin). This time we took 100 mg of Dasatinib (instead of 200 mg) each day. On the first day, the only noticeable side effects were a slight headache and a body temperature elevated about 1° F above my normal.
However, last night following day 2, I woke up about 4 AM with abdominal cramps, the same symptom I had experienced in April. That has now dissipated some, but I still feel a bit unwell this morning. I'm sure this will pass, and I take it as an indication that some senolytics has been accomplished.
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JGC Some have written on here that Fisetin and Quercetin may enhance Dasatinib so much that it may enhance its potency so as to make it more likely to have some bad side effects. . In other words it may act in a similar way as BioPerine ...So I no longer take BioPerine because it maybe too much. I have tried it both ways and I also still take it with quercetin (maybe 1000 mg of the highly absorbable kind from Life Extension.. .I take 2300 mg of the highly absorbable kind of Fisetin from Life Extension)... Something seems to be giving me energy when I take this combo but I do feel pressure in my lungs or maybe my heart when I walk too fast. But for the week following it after about 2 or 3 days I start to feel great and i am extremely limber. So I know something is working. I walk but not too fast during this period. I do get stomach upsets usually in the form of Diarrhea but they have been less and less.
I also read several studies that questioned whether it is a good idea to get rid of all our senelytic cells? It seems the have some useful purpose. So I now only do my program once a month or so. Feels good this way. Not sure how much help the labs would be as measurements of success but they are least some way to measure. My labs are incredible... but I also have been doing plaquex which is Phosphatidyl Cholines and one of the ways you can get rid of plaque in the arteries. It takes a fat to get rid of fat. Also been doing chelation. They literally save me 5 years ago from having to do triple by pass surgery. SO these procedures are also supposed to be anti-aging. Also taking nutrients that studies have proven to remove plaque from arteries.
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garland
You wrote: "I also read several studies that questioned whether it is a good idea to get rid of all our senescent cells? It seems the have some useful purpose."
I recently watched Dr. James Kirkland of the Mayo Clinic do a Foresight Institute video interview:
He made a comment that is relevant to this question. He said that the small-molecule senolytic treatments like D+Q act by turning off the mechanism that allows senescent cells to be protected from and unaffected by their own toxic SASP secretions. Thus, it is only the senescent cells that are producing SASP that are being cleared, while those serving useful purposes like wound healing are unaffected.
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Elsewhere on the forum someone states "some senolytic substances works through ROS activated apoptosis....stay away from antioxidant supplements before a senolytic treatment"
This led me to thinking is there any use in temporarily boosting oxidative stress before or during a senolytic session? Vigorous exercise, junk foods, even smoking?!
Serious question.
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Jack Black Yes Jack I totally agree that we should not use any anti-oxidants when we are clearing out senolytic cells. Just in case it may also clear out the nutrients responsible for clearing out aged cells. I may take them in the evening but not during the day. There is too many unknown here. What we do know is that it seems to work for people and when they do the studies they make everyone stop taking all other nutrients so that the other nutrients do not interfere with the senolytics. So we should try to mimic as much as possible what they do in the studies. Cause we know that protocol works. So it is pretty obvious to me that we should avoid whenever possible avoid things which may disrupt the effectiveness of D and F and maybe Q...
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garland Jack Black
Yes some senolytic substances and substances that drive apoptosis works (at least partially) through ROS dependent mechanisms and powerful antioxidants like acetyl cysteine can reverse the ROS accumulation.
I also consider the fact that ROS can create an environment which can make cell death and Autophagy go wild and cause (for instance neurological) disorders.
Just as well as antioxidants can impair ROS driven senolytic processes, we need antioxidant mechanism to protect the brain.
This leaves us with the quest to balance the extraordinarily complex cell physiology that is distorted by processes that drive ageing. We might need ROS for some positive cellular adaptations as well as ROS can be detrimental in other cellular settings.
Btw, Kirkland speculated in one paper that senolytic treatment might be improved if its combined with fasting or exercise.
https://www.hindawi.com/journals/omcl/2014/906804/
“Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253430/
“Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer.Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells. It increased ROS accumulation in HNC cells, an effect that can be blocked by the antioxidant N-acetyl-L-cysteine. Piperlongumine induced selective cell death in HNC cells by targeting the stress response to ROS, leading to the induction of death pathways involving JNK and PARP.”
“BACKGROUND:Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis, and its modulation represents a logical target for prostate cancer (PC) prevention and treatment.
RESULTS:The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome-mediated ROS-dependent mechanism.
CONCLUSIONS: Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in PC cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy."
“High oxygen demand is always accompanied by more ROS. The brain is rich in various polyunsaturated fatty acids sensitive to ROS, but is relatively devoid of antioxidant enzymes and GSH, adding that neurons are considered terminally differentiated cells, which make brain tissue more inclined to suffer damage from ROS . Robust evidence suggests that ROS display a recognized role in neuronal death after brain ischemia.”
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Staffan Olsson Yes I do intermittent fasting when I do this. I do believe it helps enhance the process. I do feel a bit drained after about 3 days. But it should be noted that the owner of Life Extension recommended that one NOT do ANY EXERCISE DURING THIS PROCESS!!! Not sure why as it was never explained that I could find. I still walk but not too extreme....
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Hi there , I am quite new to the subject but managed to read all 543 posts….. With the result of being totally confused. Since I am quite young (42y) and D is a) to expensive for me in germany and b) to experimental fir my taste I will go ahead and do Q F and P . Among all the combinations you guys tried : Is there one that is specifically recommended? I am completely unsure about dosage/ repetition intervall/ Daytime / ect …. What would you recommend to start with?
Thx for this great forum
Sebastian
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Sebastian
Shure, start with a few grams of Fisetin preceded by 10 mg of BioPerine an hour earlier. Do that for three days and you should achieve some senolytics. However, as I understand the available information, the flavenoids (F & Q) do senolytics mainly on fibroblasts and blood vessel linings. Dasatinib does senolytics on fat cells, and in aging humans there is lots of senescent fat.
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