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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Have you considered doing a purity analysis of the Fisetin supplements that have been mentioned in the Forum like Doctor's Best, Swanson, Rejuvenation Therapeutics. Maybe we could fund a comparative analysis to the Fisetin used in the Fisetin article :
- https://www.ncbi.nlm.nih.gov/pubmed/30279143
- The article says the experiment used Fisetin from a company in Houston:
- https://www.selleckchem.com/products/Fisetin(Fustel).html
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JPA
The purity issues are (a) does the product actually contain the molecule of interest and (b) does the product contain contaminants that might have negative effects. The Selleck Chemicals product you mention claims to have 99.1% purity, but it is rather expensive ($70 for 500 mg of Fisetin powder). The Swanson Fisetin costs $12.34 for 30 x 100 mg capsules (i.e., $2.06 for 500 mg in 5 caps). It does not specify purity but lists other ingredients as: microcrystalline cellulose (plant fiber), hypromellose (vegetable capsule), and may contain one or both of the following: magnesium stearate and silica. (I don't think any of those should be problems.)
I would say that the Swanson product is very likely to contain Fisetin as claimed and that the impurities are likely to be irrelevant. Therefore, I doubt that an independent purity analysis would be needed or would contribute much information.
If there is an important difference between the mouse Fisetin experiment and our own self-experimentation adventures with Fisetin, it is perhaps the difference in drug delivery. In the mouse work, the Fisetin (which is insoluble in water) was dissolved in 60% Phosal 50 PG: 30% PEG400: 10% ethanol for delivery to the mice. On the other hand, we self-experimenting humans simply swallow the capsules of Fisetin powder and hope for the best. It isn't clear to me whether swallowing a water-insoluble compound like Fisetin will actually deliver it to the bloodstream with any efficiency.
Since Fisetin is soluble in ethyl alcohol at 3 mg/ml, one might consider breaking open the Swanson capsules and dissolving the Fisetin powder in a good singe-malt Scotch before administration. 🙂
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JGC Ah, but would it change the flavor of a decent wine?
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JGC JGC
I’m definitely changing my delivery method!
I have now completed 3 “dosings”. Each dosing was 1200 mg/ Day for 3 days. First 2 doses were a week apart. The 3rd a month later. I’m going to do that dosing once/month from here out. My delivery will be with good whiskey, except morning portion which might have to be a good Bloody Mary 👍
Gotta Love us self experimenters...
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JPA On quality, both Swanson and Doctor's Best use Bioriginals' branded Novusetin raw material: this is a well-established company with a reliable quality reputation.
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JGC
What are the opinions about taking Fisetin with Grapefruit juice?
Its been known to increase availability of many things.
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BobM Alcohol is the opposite of an anti-aging supplement. I'd cut it back close to zero if you're actually trying to live longer. There's some data showing that alcohol may have a very mild hormetic effect, but only at very low doses -- on the order of a few drinks a week.
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That's an interesting point. I found an article HERE that discusses the effect of grapefruit juice. It says: "Compounds in grapefruit called furanocoumarin chemicals are the cause of the increased medication potency. These chemicals interact with the cytochrome P450 3A4 (CYP3A4) enzyme, found in the small intestine and liver, which partially inactivates many medications under normal circumstances." One can click at the bottom of the document to get a document entitled "Appendix 1: Grapefruit Interacting Drugs and Associated Oral Bioavailability, Adverse Event(s), Risk Ranking and Potential Alternative Medications". It lists the reaction risk of combining grapefruit juice with Dasatinib as "High". I don't see any flavenoids on the list.
On that basis, I would say that combining D+Q with grapefruit juice is risky.
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JGC But he was asking about combining grapefruit juice with fisetin, not dasatinib. To my understanding of the metabolic pathways involved, there is no known interaction on that front.
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Iðunn
The digestive enzyme CYP3A4 in the small intestine is what is normally limiting the bioactivity of Dasatinib and the other drugs. From the web searches I have done, I have not found any information on whether CYP3A4 interacts with flavenoids like Fisetin and Quercetin and limits their bioactivity. Do you have any information on that?
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JGC
I took 1/4 teaspoon of ground black pepper along with 1g fisetin and ~1g quercetin dissolved in oil, for 3 consecutive days (on an empty stomach). From the effects I felt on the days taking it, and several days afterwards, I feel that it was well absorbed and was effective. I actually feel better than usual now after a couple of weeks. -
Dan Nave good evening ; I took 2,800 mgs of fiestin and 1000 mg quercitin w black tea for 3 days ( on day 3 I added le senolytics activator) without any side affects ( I'm a heavyweight) and first positive effects was tonight "evening walking" felt younger and. Felt like running/ jogging for first time in a long time. Questions: do I go back to once weekly senolytics aactivator? Question: when can I optimally do 3 day first in treatment again? Thankyou
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karl kuffner
I'm not sure that anyone can advise you of that at this time. The large doses of substances to function as synolytics should be done intermittently because they kill off senile cells and then the body needs time to recuperate. Also, if the senile cells are killed off, what is the point to continue the senolytic until there are more senile cells to kill off? There are some potential drawbacks of using senolytics constantly.
I think that some of the confusion arises in that some of these substances act differently when given in high or low doses. (Although, I would presume that Dasatinib, for example, is always toxic...)
I am basing my strategy based on several of the lab tests and proposed trials.
My understanding is that the D+Q is given for 2 consecutive days, and then again in a week. I think they may repeat in 1 month, but it is not to be taken continuously.
The Mayo Clinic is giving the Fisetin for 2 consecutive days and repeating in 1 month.
I am doing F+Q, (dissolved in oil), +piperine (black pepper) for 3 consecutive days, and repeating in 1 month.
I would consider repeating at 6 month or yearly intervals.
Low doses of these substances (except dasatinib) with low bioavailability may be taken continuously as a supplement with good results, as far as I know.
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Dan Nave
excellent summary!
thank you!
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Dan Nave
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JGC "To my understanding of the metabolic pathways involved, there is no known interaction on that front."
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Dan Nave I'll note again that "I don't think there's any evidence that piperine/BioPerine enhances absorption of flavonoids generally — just curcumin."
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Iðunn
I based my use of piperine based on a reference I saw that stated that piperine from black pepper inhibited the liver's ability to break down certain drugs, thereby ensuring that the substance remained in the bloodstream for a longer time.
I am having a hard time finding articles that speak to this, but I found a patent application that discusses it with references that you can look up yourself. It states:
"There are two plausible explanations of the role that piperine may have in drug bioavailability: a) non-specific mechanisms promoting rapid absorption of drugs and nutrients, e.g., increased blood supply to the gastrointestinal tract, decreased hydrochloric acid secretion which prevents breakdown of some drugs, increased emulsifying content of the gut, increased enzymes like gamma-glutamyl transpeptidase which participate in active and passive transport of nutrients to the intestinal cells, and b) non-specific mechanisms inhibiting enzymes participating in biotransformation of drugs, preventing their inactivation and elimination."
"Most drugs co-administered with piperine are probably more bioavailable as a result of both of the mechanisms, i.e., increased absorption from the gut and the slow down of biotransformation, inactivation and elimination from the system. The latter mechanism is probably the most important in sustaining the elevated blood levels of the drug, and making it more bioavailable to the tissue. Although a rapid absorption to the blood stream may account for increased blood levels of the drug, it is the inhibition of drug biotransforming enzymes with piperine that makes a drug stay in the body longer, in higher quantities, which makes it more effective." -
Dan Nave Sure, but that's generic information on how compounds can affect drug metabolism. The question is whether the specific effects of piperine can increase the bioavailable levels of fisetin based on its specific metabolic pathways. I know of no evidence for this.
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JGC @Iðunn
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
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Dan Nave
Thanks for the references, particularly "Interactions between CYP3A4 and Dietary Polyphenols". Just to drop the other shoe, I note that Fisetin and Quercetin are both classifiable as polyphenols.
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JGC
Yes, the structure of Fisetin is said to be very close to that of Quercetin. That's one reason that I initially decided to add Quercetin to the Fisetin for the protocol. I figured that whatever process was working to denature and remove the Fisiten would also have to deal with the Quercetin and therefore possibly maintain a higher dose of the Fisetin for a longer time. Hard to say. Perhaps the Quercetin provides its own effects.
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Dan Nave This morning I took the combination of Dasatinib and Quercetin strictly as recommended in the 2018 Life Extension publication Age Reversal Update, which I have been told very recently by Maximus is still the L.E recommended protocol. I took the full dose recommended for my weight, but I had no side effects. I am 75, so I would expect that I do have senescent cells, I don't quite know what to make of others having side effects--headaches, nausea, etc. and I have none. Am I still likely to experience benefit from this protocol? Is there any information on why some people have side effects and others don't, and does whether you have them or not, have any bearing on the medicine's effectiveness in eliminating senescent cells?
Second, I have read through much of this discussion by those of you experimenting with Synolytics. Some of you are not doing the LE recommended protocol, but instead are substituting Fisetin for Quercetin or piperine, or possibly other things, Why? What have you read that has caused you to use these other substances either in addition to or instead of Quercetin? I would really appreciate it if some of you would share why you think that these substitutions improve the standard protocol?
Also, just in terms of Quercetin, I am not clear what brand or form of Quercetin is the best for the purpose of this protocol. This morning I used Life Extension brand Optimized Quercetin. However, talking with a Life Extension advisor yesterday, I find that there is a new product call Bio Quercetin that is absorbed 50 times better. But what then of the amount needed according to one's weight for this protocol? What product was used to come up with the weight to quercetin ratio in the Age Reversal Update? Without knowing, how whether it was Optimized Quercetin or Bio-quercitin, or some non LE Quercetin do you know whether it would actually mess with the balance to take the new Bio- Quercetin?
Lastly, some of you are talking about tests that you believe are useful in judging whether the protocol is effective or not. Could those of you who are having tests before and after, please explain how they are supposed to work and where you get them. Are these tests done by L.E.?
I would appreciate if anyone who has any insights about these matters or answers to my questions to please chime in with a response. Many thanks!
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Mermaid What is the recommendation for Dasatinib and Quercetin as per the 2018 Life Extension publication Age Reversal Update that you refer to? I am not able to find what this is. How much did you take and what for what body weight?
Many drugs, including Dasatinib as well as Flavonoids and Curcumin are affected by CYP3A4. "Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97) is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body."
"Quercetin inhibited CYP3A4 enzyme activity in a concentration-dependent manner"
I am not sure if Quercetin is actually acting as a senolytic. I suspect that it is being recommended and used as a sacrificial substance to neutralize this enzyme system which increases the effect of Dasatinib. It would actually work the same way when taken with Fisetin.
Black pepper (piperine) is also a CYP3A4 inhibitor.
These inhibitors are taken to increase the bioavailability and action of these senolytic substances in the body.
Dasatinib and Fisetin are both thought to be senolytic substances when taken at correct dosages (correct dosage is not clear at this point) but while they may target some of the same cell types, each targets some cell types that the other does not.
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Dan Nave Thank you for your response. "Age Reversal Update is a booklet given out by LE at the 2018 Radfest. It outlines current experimental protocols and sets up a preferred order in which to do them. If you don't have one of these, you may be able to get one by calling a life extension advisor and asking if they still have any of these around. Some of your post is a little to technical for me to really understand. However, I gather that for some reason you think fiseten is better to take with Dasatinib than Quercetin. Can you state in simple terms why? Also, I wonder if you have talked to Bill Faloon about this, because he wrote Age Reversal Update and he is recommending Quercetin? It would be good if you had a discussion about this and hammered out which one is better, or are they equal, or what.
Here are the basics regarding Step 3: Eliminating Sencescent cells, plus the figures showing my correct dosage since I weigh 130lbs.
Dosage for Dasatinib and Quercetin
I am 130 lbs. That translates to 59kg.
It is advised that a person take 2.5 mg of Dasatinib per kg. of body weight 2.5 mg x 59 kg= 147.5 mg of Dasatinib per dose. The Dasatinib I have is in 20 mg. tablets, so this would translate to 7.375 20mg tablets of Dasatinib) (Since this will be the 1st time I’m talking this medication, I’ll round that down, and take seven 20 mg tablets.)
It is advised that a person take 25mg per kilogram of body weight. 25mg x 59kg =1,475mg. The Quercetin I have is in 250 mg tablets, so I believe this translates into six 250 mg tablets of Quercetin=1500mg
I expect to be taking the 2nd dose this coming Sunday, as two doses are recommended-the second one week after the first, and then nothing for 6 months, after which time this same protocol can be repeated.
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JGC Agreed....grapefruit juice and Dasatinib dosing would require an adjustment to avoid toxicity....50MG of D with GFJuice has shown to raise max blood levels by as much as 4-5x with no GFJuice.....other testing showed it raised max blood levels 60%....so instead of 50mgs you'd want to take 10-15mgs w/ GFJuice.
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