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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Do u have any preference on ,"oil" ? Thanks karl
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karl kuffner I used avocado oil. When I take senolytic doses of fisetin I will use the same mix as in the original research. " 100 mg/kg of fisetin in 60% Phosal 50 PG:30% PEG400:10% ethanol". Now I have recieved the substances. (From amazon). When it comes to creating a formula that increase the bioavailability of fisetin, the researchers doing the research must be more competent than myself.
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I like olive oil, but I have used other oil such as you would have in your kitchen for baking etc. Surprisingly, with the Fisiten and Quercetin it wasn't bad tasting and none of that unpleasantness you might get from just eating a tablespoon of oil...
Personally, I am somewhat leery of ingesting PG and PEG.
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Dan Nave
I am also a bit reluctant to use PG, PEG. But will go for it when I start my fisetin experiment.
By the way I want to inform you about a research I read the other day. If you take Quercetin It might be a good idea to not drinkgreen tea before, during and after a senolytic session.
When Quercetin is co-administrated with Green tea polyphenols it increase the tissue absorption of Green tea polyphenols in some tissues. Lung and kidney.
(But I have read somewhere else that Prostate tissues might have the same tendencies, that Q increase the absorption of Green tea polyphenols).
https://europepmc.org/articles/pmc3590855
"We observed a 2 to 3-fold increase of total and non-methylated EGCG in lung and kidney and a trend to increase in liver. In summary, combining quercetin with GT (Green Tea) provides a promising approach to enhance the chemo prevention of GT.
Responses of different cancers to the combination may vary by tissue depending on the intrinsic COMT and MRP activity."
"When mice were treated with quercetin alone, about 95 percent of quercetin was found in methylated form (isorhamnetin) in lung, kidney and liver tissues (Figure 5B). The combination of quercetin with GT decreased the tissue concentrations of total quercetin by 20-50% along with a decrease in isorhamnetin ratio to quercetin by 90%, 81% and 61% in lung, kidney and liver, respectively "
This indicate that when you are aiming for senolytic effects, it is reasonable to be careful with ingesting Green Tea. It looks like it takes large doses to achieve a Senolytic effects and Green tea might hold back the maximal tissue concentrations of Quercetin in some tissues.
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Dan Nave
I have to correct myself. The study that I had in mind before is not about tissue concentrations. It is about synergies, it's about how quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933702/
"Our data indicate that human prostate cancer cell lines contain a small population of CD44+CD133+ cancer stem cells and their self-renewal capacity is inhibited by EGCG. Furthermore, EGCG inhibits the self-renewal capacity of CD44+α2β1+CD133+ CSCs isolated from human primary prostate tumors, as measured by spheroid formation in suspension. EGCG induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2, survivin and XIAP in CSCs. Furthermore, EGCG inhibits epithelial-mesenchymal transition by inhibiting the expression of vimentin, slug, snail and nuclear β-catenin, and the activity of LEF-1/TCF responsive reporter, and also retards CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Interestingly, quercetin synergizes with EGCG in inhibiting the self-renewal properties of prostate CSCs, inducing apoptosis, and blocking CSC's migration and invasion. These data suggest that EGCG either alone or in combination with quercetin can eliminate cancer stem cell-characteristics."
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Staffan Olsson
This article (Linked) is very interesting. It was published in 2010. Darn it takes a long time for good data to get to the public!
It is a tough read for non-medical folks like me.
Has anyone figured out dosing suggested from this?
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BobM Yes this kind of articles are tough reads, Indeed very tough.
regarding human dosing of EGCG and cancerprevention/treatment I have found this article.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824026/
"When the amount of EGCG necessary for the complete elimination of tumors in mice is converted to that for humans, it would be 6 – 9 Japanese-size-cups of green tea, i.e., 1.37 – 2.05 g EGCG/day/person." (2 g EGCG is a lot and might not be tolerated well)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384709/
"The 10-year prospective cohort study by Drs. K. Nakachi and K. Imai revealed that drinking 10 Japanese-size cups (120 mL/cup) of green tea per day delayed cancer onset in humans by 7.3 years among females and by 3.2 years among males. "
At least 1.2 liters of green tea. But keep in mind that different green tea has different amount of EGCG. So it's difficult to give specific recommendations.
When it comes to EGCG and green tea extracts there is an issue with absorbtion.
To increase absorption of EGCG the recommendation is to drink green tea (or take supplements) on empty stomach and to have your tea with some vitamin C. Piperine, quercetin is also promoting absorption of EGCG. Most important is to avoid have green tea after a meal. At least if you want maximal absorption of EGCG.
yes its difficult to understand and to draw conclusions from the plentyful in vitro research that is done on green tea and EGCG.
Thats why I rather trust the research made on green tea that humans actually drink. Like the 10 year prospective study mentioned above. I am not a big fan of pure EGCG supplements. Green tea is more than EGCG, For instance there is an indication that the small amount of coffein in green tea increase the absorbtion of EGCG and that the other substances in Green tea make EGCG more effective in preventing disease.
A guess made by using the above reasoning could be to drink 1.2 liter of green tea on empty stomach and before meals + quercetin + c-vitamin and maybe with piperine or black pepper. (One way to reach therapeutic level in vivo in the human body could be to take a dose of green tea extracts together with the real tea )
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Staffan Olsson
very good!
thank you!
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BobM I like to give this link to you. it explains the issues surrounding green tea research. And it explains why I put more value on forwardlooking research done by tracking real people over time, drinking real tea. That reasearch indicates meaningful benefits from drinking real tea (and coffee)
https://www.nature.com/articles/d41586-019-00397-2
EGCG supplements taken on their own is more questionable. Green tea looks great for creating synergies with other substances. One example of this is the Pomi-T study. "A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020278/
A small amount of polyphenol rich whole food showed great benefit. Green tea was a part of the polyphenol-cocktail.
The subject in this thread is fisetin. I am sorry if I fell out of line.
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Staffan Olsson
excellent!
thank you Staffan!
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BobM
Hi!
Since I have written a bit about green tea extracts poor availability I would like to share this link to Life extensions new product.
Claiming to be 10 – 12 times mora bioavailable than regular green tea extract and has 125 mg of green tea extract.
https://www.lifeextension.com/vitamins-supplements/item02305/green-t-max
The substance is called Origene 8 Liposome and is produced by coyne healthcare.
https://coyne-healthcare.com/origine8-green-tea-extract/
https://origine8.com/quality-science/
They claim that 125 gr extract is equal to 10-12 cups of tea. (And 250 gr origene 8 extract equals 20-24 cups of green tea).
But then again it is unspecific to talk about “cups” of tea. Serious researchers should talk about specific volumes measured in liters. A cup is sometimes referred to as 125 ml and other refer a cup of tea to 250 ml.
When it comes to EGCG content in green tea I read in that it can vary from 50 mg/cup to 125 mg/100 ml. And sometimes I see other figures as well. One statement I have seen is that a cup of tea contains a total amount of 150 – 300 mg catechins. The discussion needs to be more specific.
The bottom line is that a highly bioavailable green tea extract is very welcome. What we have to find out is if one capsule of life extensions new product is equal to the catechins in approx 1 liter of Japanese green tea. Because that is the amount of green tea that seems to be required to receive the hoped for benefits.
And hopefully this extract is easier for the liver to handle than other extracts.
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Staffan Olsson Staffan Olsson
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Staffan Olsson
Hi Staffan
ive been taking the new Like Extensions green tea supplement for a couple months now. I like it. One (or two tabs) a day. They are very small tabs, which is very welcome. And green tea colored ( most of what I see in supplements are brown).
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Staffan Olsson
just FYI all: Life Extension has quietly withdrawn its Green T-Max product. It’s now showing “Mega Green Tea Extract”. Nothing special. 725mg of 98% polyphenols, 45% EGCG.
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Staffan, If your weight is 100 kilos, what do you feel is an optimum dosage of fistiven, (spelled wrong?) in milligrams, assuming we take 500 mg capsules? (from a Brittish source) thankyou karl
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karl kuffner Karl, The clinical trial that is directed by James Kirkland at the Mayo Clinic uses 20 mg/kg on two consecutive days. That brings us to 2000 mg for a 100 kg person. that is four 5 mg capsules per day.
https://clinicaltrials.gov/ct2/show/NCT03675724
(Alleviation by fisetin of frailty, inflammation and related messures in order Adults).
Since we are at the beginning of fisetin human trials nobody can be sure what the optimum human dose is. My own speculation is that an optimum dose is above 20 mg/kg. In my next experiment I will increase my dose to 30 - 35 mg/kg.
How much fisetin that is actually absorbed is a crucial question. And I am very curious about how they handle the issues with absorption in the above mentioned human study. If we, in this forum, could get that information it would be of great help.
Since we, in this forum, use different approachens when it comes to the issue of absorption it is a hard for us to be very specific when we discuss optimum doses. What we can do is to be transparent about what we do to handle the absorption issue.
May I ask where you got the 500 mg capsules from? I have used 100 mg capsules and 500 mg capsules would be easier to work with.
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karl kuffner Sir, thankyou for clarification on fisetin usage. This mayo clinic study appears to be only for 2 days total, and there posted results seem to be " only" reduction in inflammation markers. How does that relate to "frailty syndrome"? With your knowledge and experience, would you do this treatment protocol, monthly? What would you sum up are the most definitive benefits of your self experimentation.? THANKYOU karl
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karl kuffner
The dosing regimen regarding fisetin is in its infancy. There have been research done using fisetin on two consecetuive days. And then the same treatment was repeated again after 4 weeks.
There has been senolytic research done with dasatinib och quercetin with doses taken three days consecutively then 4 days without treatment. and then another three days treatment followed by 4 day without treatment. And then they had another three days of treatment. The same substances have also been used on a biannual protocoll.
As far as I can read from the fisetin mouse study they showed a senolytic effect also from chronic feeding with a lower dose and not only from the intermittent treatment.
I am not a person to give recommendations based my fisetin experiments. I have recently started with fisetin. But I decided to start with a intermittent protocoll.
Senescent cells are a driver of pathologies. Senescent cells ellicit an inflammatory respons and if a senolytic experiment reduce inflammation then that can be sen as an indication of a sucessful experiment.
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New Fisetin Senolytic Session
It has been about 30 weeks since our last senolytic sessions, which were done last January. This morning my wife and I each took 10 mg of BioPerine, followed in 90 minutes by 2.00 grams of 98% pure Fisetin powder "dissolved" in olive oil. I put "dissolved" in quotes because I am not able to distinguish fully dissolved Fisetin from undissolved Fisetin in a colloidial suspension in the olive oil.
I put room-temperature olive oil in a 1 oz shot glass, then added 2 grams of yellow Fisetin powder, as measured on a digital scale with a precision of 0.01 grams. I stirred until I had a smooth liquid that looked a bit like French's mustard. It did not become clear, which may be an indication that lots of undissolved Fisetin granules were still suspended in the oil. The taste was acceptable, but not great. I noticed a slight burning sensation in my throat as I was swallowing the liquid. We used pieces of bread to soak up the mixture remaining in the glass, to make sure that we got it all.
That was three hours ago, and so far we have experienced no observable effects. We will repeat tomorrow, and then I plan to warm the olive oil in the microwave a bit before adding the Fisetin powder, to see if it dissolves better.
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JGC
Thank you for your report. How do you feel now?
It has now been two weeks since I had my fisetin experiment. In two weeks time I will have two more days of fisetin treatment.
So far I have a clear reduction in joint pain. I hurt my AC joint quite some time ago ( a trauma, 11 Months ago, to the joint ).
I have not been able to swim without pain since that accident. After the fisetin treatment two weeks ago I can swim short distances without pain. Placebo or natural healing or senolytic effect? My guess is that it is an effect related to the fisetin.
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Staffan Olsson
This morning we did our 3rd BioPerine (10 mg) + Fisetin-in-olive-oil (2 g) session. I feel quite alert and well and have been working to good effect on a book rewrite. Even though my wife and I have each had a total of 6,000 mg of Fisetin in three days, I haven't noticed much in the way of side effects. The first night I did have a very vivid dream involving a long-dead female friend, and I have experienced a small amount of vertigo when I turn over in bed at night, but nothing else of note. No joint pains, but then I haven't had many of those lately.
My plan is to wait a week, do one more session with BioPerine + Dasatinib + Quercetin + Fisetin, and then wait another 6 months before any more senolytics.
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JGC
For your information and also to adress the issue of bioavailability I want to mention that, in their human study on idiopatic lungfibrosis, the El Mayo group used a Quercetinproduct from Thorne.
”Q: 250 mg capsules × 5/day quercetin phytosome Thorne Research Sophora japonica concentrate [leaf]/”.
They wrote that under 2.2.2 in the published paper.
https://www.ebiomedicine.com/article/S2352-3964(18)30629-7/pdf
as far as I have been ableto find out it should be this product since this is the only quercetin phytosome Thorne sells.
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JGC
Four weeks ago I did my first experiment with a fisetin combination. For two days I did 20 mg/kg Fisetin.
Today I did a 30 mg/kg fisetin combination. (Using Dr’s best brand). And here I share what else I did today and my thoughts about my approach. The combination and its sequence is described below.
1. Piperine + piperlongumine 2. fisetin in avocado oil 3. senolytic activator + strong black tea,
At 5,30 AM today I made a piper longum extract with 2 gr crushed piper longum fruits. I crushed the pepper and then I soaked the crushed piper longum for 45 minutes in 2 cl 40% award winning super 17 premium organic vodka with the brand name ”Purity”. I drank the extract at 0615 AM, after a 45 minutes of soaking. (An unusual start of the day). I will buy stronger alcohol for future extractations.
https://purityvodka.com/pages/purity-super-17-premium-organic-vodka
At 0645 – around 30 minutes after that I had the Piperine + piper longum extract I mixed 2400 mg of fisetin with avocado oil. That’s slightly above 30mg/kg. My weight is 78 kg. Before I drank the fisetin I had the fisetin and the avocado oil rest in a glass for 30 minutes. I stirred it on a few occasions.
After two hours (at 0845 AM) I had a double dose of senolytic activator (4 capsules) + strong black tea.
During the day I had a few short episodes of stinging headache on the left side of the top of my head. Headache gone after a few seconds. I did not eat any food until 2 PM. Before 2 PM I had only the strong black tea made of black tea powder. And also after that I had some homemade bulletproof coffee made of coconut oil and some C8 oil. At 2 PM I had my first meal of the day and my daily dose of curcumin 400 mg BSM 95.
Reflections:
Yes, black tea contains very little theaflavins but I thought I should give the senolytic activator some extra assistance in the senolytic cocktail. I drank the black tea shortly after I had taken the senolytic activator. Senolytic activator has a fair amount theaflavins in its formula. But my reasoning behind adding strong black tea to the senolytic activator is that extracts (like the one in SA) sometimes lack some of vital components that can be found in the real food or drink. For instance, it seems to be difficult to get clear and positive results on health from ingesting EGCG extract alone. But studies of people that drink large amounts of real green tea show that green tea seems rather beneficial for human health. I also see something similar when it comes to lycopene. The experiments with lycopene does not seem to be as successful as the results from studying the health of humans that eat “cooked real tomatos” like results from people eating large amount of tomato sauce etc. This is the thinking behind my attempt to eat or to drink the real thing together with extracts. And that’s also why I made myself some really strong black tea today which I drank when I had taken the senolytic activator.
Below is a link about theaflavin as a BCL-2 inhibitor and BCL-XL inhibitor. A PDf file.
http://www.dermaceutical.com.mx/oncoxin_estudios/ONCOXIN_8118.pdf
I add a link to inform how to extract piperine and piperlongumine from piper longum fruits. Kindly look below at Fig 1 and table 2.
And I also quote from the link below ”Piperlongumines, PL, appears to be very safe, and its maximum tolerated oral dose in mice is >1 g/kg, while the effective therapeutic doses for cancer can be as low as 2.4 mg/kg by oral dosing." that indicates that 2,4/12,3=0,195 mg/kg is the humna dose to reach to acheive a possibly therapeutic dose in humans.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087492/
its also looks like it is possible to reach therapeutic levels of piperlongumine with a made home extract that is easy to make. Made from crushed piper longums fruits soaked in ethanol.
Since the piper longum extract contains a large amount of piperine as well as piperlongumine and PL works in more than one way, whereof one way is ROS dependent, it made me think that it is possible to get more than the piperine effect from the piper longum extract. But then it might be crucial to take the piperlongumine before the fisetin. This since fisetin can act as an antioxidant and I don’t want this effect to disturb the effect of the piperlongumine. One effect to avoid is that piperlongumine can be neutralized by antioxidants like (NAC) N acetyl cysteine.
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.”
“Co-exposure to PL and the antioxidant NAC or the PARP inhibitor 4-ANI protected cancer cells from apoptosis.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191878/#!po=53.0303
It will be interesting to see what role (if any) piperlongumine may have in future senolytic therapy. Especially it maybe it can act in synergy with ABT-263(=navitoclax) so the serious side effects from navitclax is reduced to an acceptable level (by reducing the dose of navitoclax that is needed). I quote:
"Another potential use of PL and its derivatives is in combination with ABT-263, or other inhibitors of Bcl-2 family proteins, for a synergistic senolytic effect. Although ABT-263 is a highly specific senolytic agent, it causes transient thrombocytopenia and neutropenia in patients this results from its inhibitory effect on Bcl-xL, which is important for platelet survival. We showed that PL had a strong synergistic effect on the senolytic activity of ABT-263 in vitro, potentially reducing the dose of ABT-263 needed to effectively deplete SCs. We expect this therapeutic approach would significantly reduce ABT-263-induced thrombocytopenia, making senolytic treatment with ABT-263 safer.”
This is my thinking about todays approach. Yes, there are crude assumptions in my approach. But they are assumptions that, hopefully, are based on the results from qualified researchers. I am especially happy for feedback about piperlongumine and the possible role it might have in senolytic therapy.
Tomorrow I do my next round of Fisetin.
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Staffan Olsson
very creative indeed Staffan!
And well thought out!
Did you notice any changes in basic things like blood pressure, heart rate or blood sugars?
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Staffan Olsson
Question: When you "dissolved" the Dr's Best Fisetin in avocado oil, did it actually dissolve (so that the liquid became clear) or did you just have a colloidal suspension of the fine powder? My experience using olive oil was that I probably got the latter.
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