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 kuffner said:
al liStaffan Olsson said:
similInteresting. I've had my 77 year old mother on the LE Senolytic Activator once weekly and she always reports feelings of well being after taking it. She reported very similar effects when I had her on mega doses of straight fisetin, which makes me believe that LE Senolytic Activator works just as well.
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Looks like Metformin has senomorphic effects. Is that the reason for the anti-aging effects?
https://www.frontiersin.org/articles/10.3389/fbioe.2021.730813/full
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Juan Daw Thanks Juan Metformin inhibits glucose production in liver thus dropping glucose levels in the body. Lower glucose = less inflammation = less plaque buildup in arteries in brain, heart and kidneys = reduced risk for heart attack, stroke and kidney disease + glucose stores calories as fat = weight gain. There is a reason they are doing the TAME trial with Metformin.
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Van If it ever gets launched...7+ yrs and running.
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It seems Rapamycin is also considered a senomorphic by some researchers.
https://academic.oup.com/biomedgerontology/article/76/6/1144/6126488
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Additional info on fisetin:
https://www.frontiersin.org/articles/10.3389/fchem.2019.00697/full
- Recent in vitro studies have given a mechanistic insight into how fisetin inhibits the target of the rapamycin pathway in various cell models and therefore influences cellular pathways that are known to affect aging (Syed et al., 2013; Pallauf et al., 2016).
- It has also been found that fisetin in combination with other epigenetically active molecules which are able to cross the blood-aqueous and blood-retina barriers exhibit synergistic beneficial effects. This applies for a low dose red wine polyphenols, as well as for vitamin D3 and some other compounds of small molecular weight, synergistically improving visual acuity in patients with advanced atrophic age-related muscular degeneration, including the older ones with advanced stages of the disease for whom very few options remained (Ivanova et al., 2017).
- The anticancer activity of fisetin can be enhanced by some auxiliary substances. For example, fisetin significantly impairs carcinoma cell growth in the presence of ascorbic acid, which results in a 61% inhibition of cell growth, in 72 h; the treatment with ascorbic acid alone had no effect on cellular proliferation (Kandaswami et al., 1993).
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The well known ITP reports Fisetin does not extend healthspan or lifespan in mice. It also did not remove senescent cells. Video here: https://www.youtube.com/watch?v=42PzfNs9egA&t=3294s
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Jimmy2
I just watched Miller's presentation. His mention of Fisetin was very brief and dismissive, and he did not say specifically how it was given to his test mice. It is well known from Kirkland et al that for any senolytic effects there is a threshold that must be exceeded and that too small a dose does nothing. It is not clear whether they used large burst doses for a few days or if they just added modest amounts of Fisetin to their daily mouse chow. Also, he said that they had not tried Quercetin, and he did not even mention Dasatinib, so it's clear that did not try D+Q as a senolytic. Finally, I don't understand why he was so dismissive of lab results done by administering the molecules in question to senescent human cell cultures. I would think that such tests are at least as indicative as tests on a distant short-lived species.
ITF may be the "gold standard" for testing supplements, but I'm skeptical of how well their mouse longevity tests can be applied to humans. Miller said that 70% of their test mice die of cancer, whereas the human mortality rate due to cancer is about 0.2%. Therefore, the supplements that ITF is testing may be just suppressing mouse cancer rather that extending their general lifespan. He did allude to mouse fitness and cognition tests, but mouse death seemed to be the principal ITF criterion.
On the positive side, I liked what he said about the NIH bureaucrat's bogus "see-saw" between healthspan and lifespan, which had stunted the field of aging research for decades. Also, the "promising" supplements he identified, particularly those that are available over-the-counter, are well worth considering for addition to our daily list of supplements.
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JGC Remember the ITP has three test sites. From what I remember in previous experiments there are 100 control mice and 50 experiment mice at each location. So the ITP is actually reporting the results in culmination from all three sites. That’s why any conclusion they come up with has weight. They also tested the fisetin at two different doses. So let’s wait and see. However, they also reported fisetin doesn’t hurt. So while we wait we can still take it without harm.
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Jimmy2
OK, I went to the Interventions Testing Program (ITP) web site looking for more information on just how they tested Fisetin. They list a large number of ITP publications, but none I could find that mention Fisetin in the title or abstract. Their "Compounds in Testing" table indicates that they tested Fisetin as a part of their 2018 Cohort on mice from age 20 month to death (mice live about 36 months). They administered 600 parts per million of Fisetin in the mouse chow in the cycle of 3 days on and 11 days off. It is not clear what mg/kg dose level corresponds to 600 parts per million (it depends on how much chow the mouse eats and how much the mouse weighs), but it sounds small. I suspect that their dosage was not over the senolytic threshold.
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Jimmy2
Addressing the issue of whether Miller is using a large enough senolytic dose, I did the following calculation:
When I do a 3-day senolytic session (like yesterday through tomorrow), I take 2,000 mg of Fisetin per day for three days. I weight about 72 kg, so my senolytic dose level is about 28 mg/kg.
My agility champion Shetland Sheepdog Taliesin is fed about 100 g of kibble per day (I weigh it), and he weight is about 12 kg. If his kibble were to contain 600 parts per million of Fisetin, then he would get about 60 mg of Fisetin, which means that his senolytic dose would be about 5.0 mg/kg. If my dog is a good analog to Miller's mice, then Miller's mice are getting about 18% of the dose level that I and others take for senolytics. That's likely to be well below the senolytic threshold.
I'm not surprised that Miller's group sees no senolytic effect.
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Yes, very disappointing news from ITP. I will discontinue the use of Fisetin until the Mayo Clinic releases their results on human subjects in June. If they show no senescent cell removal, I will stop Fistein completely.
In other news, the ITP did show an increase in mouse longevity for Glycine\NAC supplementation of 24% which is huge. Studies using Glycine and NAC in humans over the age of 70 also showed very impressive results!
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Chris M You apear to be confusing the nugatory life extension the ITP reported with massive levels of glycine alone, with the recent report on GlyNAC, which was not from the ITP and was a BS study. All the animals were short-lived; it's just that the GlyNAC animals were less short-lived than the controls.
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Iðunn Yes, sorry I confused those two. So, do you think that GlyNAC will improve lifespan?
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Chris M No.
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Ahhhh this is sad news indeed...
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Moonlitnight
Waiting for the paper to be published.
https://www.youtube.com/watch?v=42PzfNs9egA&t=0s
Dr. Miller talks about two substances (minute 1:12:13) he is excited about, but the study is incomplete - astaxanthin and meclizine (dramamine - anti-motion sickness drug); also given to pregnant women for morning sickness).
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Juan Daw The best results come from Rapamycin and Acarbose (alpha gluosidase inhibitor). I am not ready to try drugs yet, so I will try a combination of Ashwaghandha with some natural alpha glucosidase inhibitor (maybe grape seed extract).
There is a whole bunch of alpha glucosidase inhibitors from food, to experiment with, but grape seed extract has the added benefit of its own study.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020213/
- Morus alba (White mulberry) is another plant species for which AG inhibitory activity has been well-studied [44], and its leaf extracts exhibited AG inhibition activity with an IC50 value of 91.63 µg/mL compared to that of acarbose (IC50: 402.33 µg/mL) [45]. A range of bioactive compounds isolated from the leaves of Mango (Mangifera indica L.) were screened for their inhibitory effect against AG and among them arjunolic acid and actinidic acid exhibited inhibitory activity with IC50 values of 239.60 ± 25.00 and 297.37 ± 8.12 μM, respectively [46]. Similarly, extracts from the peel of fruits of Jackfruit (Artocarpus heterophyllus) displayed the strongest inhibitory activity (IC50: 0.05 mg/mL) followed by its seed (IC50: 1.79 ± 0.15 mg/mL), pulp (IC50: 6.81 ± 0.52 mg/mL), and flake (IC50: 10.52 ± 0.73 mg/mL) extracts [47]. Grape seed and green tea extracts were also found to have strong inhibitory activity against AG with an IC50 values of 1.2 ± 0.2 and 0.5 ± 0.1 µg/mL, respectively. These inhibition potencies were much stronger than the inhibitory effect obtained from acarbose (IC50: 91.0 ± 10.8 µg/mL) [48].
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Juan Daw Juan, isn't dramamine dimenhydrinate? That's a powerful anticholinergic. I used to take Gravol (Canadian brand name) to help me sleep. I stopped when I heard the study suggesting a link between anticholinergics and Alzheimer's. I take astaxanthin daily.
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Moonlitnight Yes. I stand corrected. My fault, not the keyboard's.
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Juan Daw Dr. Miller has yet to publish his study about fisetin. Yet, people are already concluding fisetin's benefits have been discredited. I would want to read the study and compare with the study below.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30373-6/fulltext
- Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism.
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Juan Daw Thanks for posting that!
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Juan Daw The Dramamine used in the experiment is the non drowsy formula using meclizine. It is not the original formula!
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Chris M Agreed. I stood corrected by Moonlitnight.
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Juan Daw I think it is relevant to mention that Maqui Berry - Delphinidine has shown some distinct effects on fasting and Postprandial Glycemia and Insulinemia.
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