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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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/
The original study bring forward some ideas. The reserchers show that curcumin is one of the few substances (besides fisetin) that have a proven but smaller senolytic effect. I can only speculate if curcumin, in combination with fisetin, Bioperine and quercetin, could bring some extra benefit. Maybe curcumin can complement fisetin by penetrating tissues where fisetin is less effective? This is a very speculative question but I will test it.
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Peter H. Howe Thanks for the response Peter. I am at an increased risk of Alzheimer's myself. My father just died from it, and his sister and mother died from it. Dr Green has instructed me to get a genetic test for the APOE4 gene. 23 and me does it for around $200 but the Alzheimer's Association does it for $125. Here is the link
https://www.alzheimersorganization.org/alzheimers-test
I'm not sure if he will change my protocol if I test positive. I know my chances are 50/50 if I test positive.
My wife and I did 5 different blood tests each before seeing Dr. Green. These were not covered but very affordable. We each paid $165 for all 5 tests. The link is below if you are interested.
https://www.health-tests-direct.com/
If you have not already considered it I would suggest getting on Rapa. That is the number 1 drug for aging health. In order of importance Dr Green said it was absolutely a miracle drug and the next big drug after antibiotics for mankind. He placed Metformin second and Fisetin third.
the only thing I would guess Dr. Green does different for me is prescribe a higher dose of rapa if I test positive. I take 6mg now. He takes about 10mg himself. I even started my 14 year old cat on Rapa at .5 mg twice weekly!
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JOHN First, note that 23andMe's test will include several hundreds of thousands of other gene variants that could be useful to have info on.
Secondly, do you know whether Dr. Green ups the rapamycin dosage for APOE-ε4/ε3s, or only APOE-ε4/ε4s? Note that the mouse studies compared transgenic 3/3s to 4/4s.
Thanks,
Brian
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BrianMDelaney He didn't specify what his next steps would be. I will know more after the test.
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JOHN Thanks John for your suggestion. My mother and one of her sisters died due to alzheimers. I have at least one younger cousin who has it. I already had myself tested and am homozygous APOE3-- but I can still get it.
I am following a Dr, Bredesen protocol which supposedly eliminates the risk and has been established to reverse Alzheimers and other neurological diseases. See attached.
http://www.aging-us.com/article/NjJf3fWGKw4e99CyC/text
He has also authored d a book entitled " The End of Alzheimer's". His approach consists of three protocols. #1 is no sweets and a 12 hour period in which you do not eat - from at least 6 pm to 6 am- gives your microglia time to get rid of B amyloid and tau. His second approach, based on bloodwork, is to replace deficiencies, one of which are your steroid hormones. The third is to test for toxics- such as metals and pestcides. Of critical importance in #2 is fish oil.
I agree with your comment on rapamyacin and am considering it. I am constantly modifying my lifestyle, but do not want to over do it. I just finished 2.5 years of intermittent fasting based on positive results documented in a number of peer reviewed papers. I stopped in June due to what I consider to be adverse impacts. One of the benefits to fasting is a decrease in mTOR . Without going into detail, there are some reports that fasting at a late age may not be beneficial for some. I backed off and will do bloodwork in Sept. to see if things return to normal. I "think" fasting may have adversely affected my immune system in addition to my steroid levels which I mentioned earlier. The literature indicates that this is possible.
This brings me to fisetin. It also reduces mTOR along with a myriad of other benefits. Since our last communication, I finished my third treatment on Sunday, July 5 which consists of 1.5 grams/day for two consecutive days. I take the 15, 100 mg Swanson capsules first thing in the morning on empty stomach and do not eat for 4 hours . The results yesterday were amazing. I did 28 chinups yesterday. Prior to starting the fisetin, , I could only do 20-21. This increased to 26 after my first treatment but is now at 28.
Before proceeding to Rapamyasin, I will let what I am currently doing run its course, but thanks for the suggestion.
I am of the opinion that fisetin may be as beneficial as fish oil in preventing age related problems. I am a fervent believer in fish oil as it also has multiple benefits documented in over 7,000 papers. LEF is publishing an update on fish oil in its August, 2020 magazine.
Thanks again for your suggestions.
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Dan Nave I have decided to not add curcumin to the Quercetin/Fisetin senolytic protocol. I no longer recommend adding curcumin to the mix.
My feeling is to take Curcumin separately, if you wish, but not to add to the Q+F protocol. Perhaps make a separate protocol with Curcumin.
I have seen several reference to Curcumin and Fisetin having counteracting effects to each other, but am not able to find any literature that clears that up in my mind.
Also, I felt really good after the Q+F, lasting for a long time, while the Q+F+C was much harsher and I didn't notice as much change for the better after taking it.
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Dan Nave If you caught a cold I would encourage you to take 10,000 IU's of vitamin D3 daily and then get your blood levels checked. You need to be above 50. You will stop getting colds and or the flue. This is why people tend to get them in the winter. There's a direct link and I should know having grown up with reoccurring soar throats. After suffering from these for over 40 years I discovered high dose vitamin D3 and they disappeared. It's a crime the government won't mention this. Fauci finally admitted that he takes high doses of D. Like I say - it's a crime.
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Peter H. Howe 26 chinups???? How old are you? I was proud of doing 16 in my mid 20's after a gym workout. Now at 71 ............................
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Robert Olin I will be 81 in early Oct. At the time I did the 26 I had just completed my first Mayo fisetin protocol and the number of chinups increased from 20 to 26. I had also just terminated a 3 year stint of a strict 5:2 diet. I have gained ~10 lbs since than and my chinups have decreased to ~24.
My son says I cheat in that my chinup consists of dropping to a 45 degree angle with my arms and than lifting myself so that my chin is above the bar.
My epigenetic age based on the Epiaging test was 58 in last fall. If it is an actual representation of my biological age, I attribute this in large part to 25 + years of high dose fish oil ( ~5.5 gms EPA/DHA per day) started after an emergency bypass in 1994. This reduced my inflammation so that my Il- 6 is below detection. There are also studies that indicate fish oil will enhance strength by preventing sarcopenia.
I also maintained optimum levels of testosterone, estrogen ( that is correct), DHEA etc. for the past 25 years.
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Peter H. Howe Wow! You are an inspiration to us youngsters in our 70's. I still work a physical job installing and maintaining septic system. Although at 65 my aching back forced me to get a young fellow to lift those heavy concrete lids.
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Peter H. Howe Did you use exogenous testosterone to maintain? Or, supplements?
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Dorian Gray It is complicated for me as I am and have been hypogondal for a long time, and it probably contributed to my need for a bypass almost 30 years ago (1994) Specifically in terms of total testosterone, I use a 4 mg androderm patch. Even with this, my total testosterone is only ~ 300 ng/dl. I keep my free T around 15-20 pg/ml or about 5 % of the total which is high percentage as it is typically in the 1-2 % range. The high percentage can be attributed to my supplementation with DHEA-S ( 25 mg/day ) and use of high dose of fish oil ( about 5.5 grams DHA/EPA/ day. You can check with Google and you will find that both will increase free testosterone. I also supplement with 50 mg pregnenolone daily.
Apologize for the long response.
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The F + Q + C (at approx. 1 gm each, in oil) + black pepper (approx. 1/2 tsp) seemed to be a little extreme for me, possibly because of the 50% increase of the quantity of senolytics taken with the addition of the 1 gm of curcumin. Lots of aches and pains for up to 2 weeks and taking longer to return to normal than the first time last month with just F + Q + black pepper. I also noticed lack of healing for a couple of small issues during the protocol. I wouldn't want to do this again for perhaps 6 months. I feel I got very good absorption and duration doing it this way. Joints seem good and there is a definite reduction of spider veins. Who knows if the benefits are deeper than that, time will tell...
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Dan Nave Hi Dave!
I am doing this step by step.
First, I took senility activator double dose on two consecutive days. I felt good during those two days and I also felt good a few days after.
After two weeks I tried a double dose of senolytic activator again and then I also added more quercetin. That made me feel even better during the two days as well as during a few days after.
Then after a few weeks I tried double dose senolytic activator with extra quercetin and I also added tocotrienols and curcumin and mixed it all in avocado oil, Then I added crushed piper longum fruits which was soaked in alcohol (piper longum has piperine as well as piperlongumines). That coktail made feel unwell.
I don’t know if feeling unwell was good or bad. Proof of strong reaction? Or maybe I did somehting to which my body answered ”this is to much”?
Now I am aiming for fisetin experiments.
As I have read in the now famous paper, They used both chronic feeding with Fisetin as well as intermeittent and acute short term use of larger doses of Fisetin. All experiments produced positive antiaging results.
Later on I will add Fisetin to my daily supplements. But now I go for the larger senolytic doses.
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Staffan Olsson
Hi Staffan, can you kindly share your previous dosing of each item (F, C, SA) , and your body weight?
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BobM
sorry F+ Q + C and the piperine
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BobM
Hi Bob! My body weight is 77-78 kg.
I have gradually incresed the dosing and along the way I have added more substances. (curcumin, tocotrienols and piperlongum)
During my most recent senolytic experiment I used:
- Double dose of senolytic activator. That is 4 capsules. That should equal up to 2500 mg regular Quercetin.
- 3 capsules of Quercetin. The Quercetin I use is Life extension. Bio quercetin. (the same quercetin that's in the senolytic activator). That should equal up to 1500 mg regular quercetin.
https://www.lifeextension.com/Vitamins-Supplements/item02302/Bio-Quercetin
- 1 capsule of Life extensions Super Bio-Curcumin® Turmeric Extract. (BCM-95®)
- https://www.lifeextension.com/Vitamins-Supplements/item00407/Super-Bio-Curcumin-Turmeric-Extract
- Piperine. I have no exact dosing for the piperine. This since I used three crushed piper longum fruits which was soaked in alcohol after they were crushed.
The best experiement so far was double dose senolytic activator + 3 capsules of Bio-quercetin.
For my next experiment I will not use piperlongum and I will not use tocotrienols.
I have not yet started with Fisetin. I want to go through the selfexperimentation with the other substances first.
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Staffan Olsson
Hi Staffan
Thank you so much for sharing all the details!
Excellent data!
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When doing Fisetin and Quercetin senolytic doses consider dissolving the powders in oil before taking. You could try with or without black pepper or piperine, etc. to see if that makes a difference. F + Q are not water soluble and I think dissolving them in oil increases their uptake massively. I don't think one absorbs much of the F + Q without dissolving it in oil.
For daily supplementation, you might be fine just taking a pill without the oil.
Piperine is supposed to increase absorption massively (2,000% for Curcumin) and keep the liver from quickly metabolizing them. F + Q + Curcumin are all substances that are affected by piperine according to my reading.
My advice is not to massively increase the dosages of these substances if you are going to use these mechanisms to increase their absorption and action. I used only 1 gram of each for 3 days, seeing definite effects. (Weight of approx. 77kg) I saw more effect when adding the Curcumin to the F + Q.
Mechanism of piperine action:
"In general, it inhibits drug metabolizing enzymes, stimulates absorption by stimulating gut amino acid transporters, inhibits the cell pump responsible for drug elimination from cells and inhibits intestinal production of glucuronic acid.
It may increase the absorption of drug in the GIT, or inhibit enzymes responsible for drug metabolism, especially in the liver when the drug passes through the liver after absorption from GIT. Oral administration of piperine in rats strongly inhibited the hepatic arylhydrocarbon hydroxylase and UDP-glucuronyltransferase activities[30].
Another study demonstrates that piperine modifies the rate of glucuronidation by lowering the endogenous UDP-glucuronic acid content and also by inhibiting the transferase activity[31].
Piperine inhibits human P-glycoprotein and cytochrome P450 3A4 (CYP3A4)[32]. Both the proteins contribute to a major extent to first-pass elimination of many drugs.
Some of the metabolizing enzymes inhibited or induced by piperine include CYP1A1, CYP1B1, CYP1B2, CYP2E1, CYP3A4 etc. Most of the drugs metabolized by these enzymes will therefore be influenced by bioenhancers."
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Dan Nave
So far I have learned that I get a rather strong feel good effect from senolytic activator. Especially when I take it with extra quercetin. An effect that lasts 2-3 days.
I also tend to get a minor feel good effect of a senolytic dose of fisetin. But that effect (if it’s not placebo) is definitely smaller that the effect I get from quercetin.
- Last weekend I took my first senolytic dose of Fisetin disolved in a 60% Phosalmix 50 PG, 30% PEG400. I took the same dose of fisetin on two consecutive days. I stayed at the dose used by the El Mayo researchers in their ongoing human trial, 20 mg Fisetin per kg. I was very inclined to use 35 mg/kg the second day but I decided to stay at 20mg/kg.
Any acute feel good effect is, of course, not a sign of a working senolytic therapy. But it is a pleasant surprise. There are plenty of harmful substances that produce acute feel good effects (Refined sugar is one out of many).
So it’s wrong of me to assume a strong correlation between acute feel good effects and improved long term health. Feel good effcts are very wellcome, at least when they arise from improved health or reduced disease or inhibited ageing.
I tend to experience some negative effects when I combine fisetin, curcumin, quercetin, and tocotrienols. Even if the dose for each substance is lower than what should be used in a serious senolytic approach. And even if they are taken without piperine containing compounds.
At this stage I can only guess which substance that cause the unpleasant experience My first wild guess is that it might be some interaction between the tocotrienols some of the other substances. This since curcumin and quercetin, when taken alone or when they are taken together give me a feel good effect.
I also have in mind that the unpleasant feeling and the reduced wellbeing that I experience from to above mentioned combination might be a pure coincidence and is not an effect of any of the substances.
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Staffan Olsson
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BobM
Great post. Thanks!
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Staffan Olsson
It seems to me that if a senolytic session is actually working, is should produce a transitory feeling of unwellness that might last up to a day or so. The expectation of senolytics is that an accumulation of senescent cells is being driven to aptosis, damaged cells are disassembled, and aptosis-derived component proteins and compounds are being released into the bloodstream. That seems likely to produce a mild fever and a feeling of unwellness.
However, after the senescent cells are cleared, toxins in the bloodstream associated with SASP should be significantly reduced, and one might then expect a feeling of improved health and wellness. That matches my own experience with fisetin and D+Q.
Of course, this is all theoretical, because we don't have a way of actually measuring and verifying the predicted clearance of senescent cells. But if quercetin does produce an immediate feeling of wellness, I doubt that it comes from senolytics.
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JGC that is a reasonable theory. For now my reasoning is that high doses of quercetin reduces whole body inflammation or reduce organspecific inflammation. And might have minor senolytic effects on some tissues. My brother has morbus bechterew and since 2 years he has a very bad case of sarcoidosis in his lungs. He responds in a favourable way to high doses of quercetin. Especially when I give him senolytic activator + quercetin. A few years ago quercetin got some attention when they did some sarcoidosis research (in England I think). Only 500 mg per day.
When my brother take large doses of quercetin he reports an immidiate and dramatic reduction in symtoms from his sarcoidosis. Now he has done three sessions and during every session he reports the same immidate and dramatic effect. I know that they have tried D+Q on idiopatisk fibrosis of the lungs. And for the first time the results showed that it was possible to increase of the functional capacity among the researched subjects (humans). Since qualified researchers in the field of senolytic therapy chose to specifically target a lungdisease as their first human deasease it might indicate that Q theoretically has a favourable organspecific effects on lungtissue.
Bottomline is that I think these observations is in line with what we know about Quercetin. That Q has minor senolytic effects but that Q Also has know antiinflammatory effects. And if my brother continue to report dramatic effects then I create a sarcoidosis thread here. this since he reports dramatic effects exceeding any medication.
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Staffan Olsson
Your thoughts about quercetin and inflammation are interesting.
I think it's important to measure as much as possible the effects of self-administered senolytic treatments. The only available measure of inflammation that I have available is the c-reactive protein (CRP) test. My CRP has almost always been rather low (<1.0 mg/L) in all the tests I've done before and after senolytic sessions. The exception was a test when I had a large bruise on my leg and the CRP gave 3.7 mg/L. It was back to the low value the next time I was tested when the bruise was gone.
Have you had any CRP tests while you were taking the large doses of quercetin?
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JGC No, I have not taken CRP test before the senolytic experiments.
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