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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  • Why aren't more of you guys taking fisetin at 60 mg/kg (5 mg/kg HED) per day, everyday? Chronic (daily, dietary) administration of fisetin has been demonstrated to extend the median and maximum lifespan of mice, whereas acute administration hasn't been proven to do the same, as far as I know.

    Like 1
      • Fairy8i8
      • Fairy8i8
      • 3 mths ago
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      Florin I am not familiar with those studies. Would you please provide links to them? Also, most people here are following a conservative approach aligned with the Phase 2 trials being conducted by the Mayo Clinic. Those results are not yet published, so data on the effect on humans is still lacking. Also, one study indicated a toxic accumulation in the liver of mice at a high dose, which may have been a result of the DMSO delivery, but it is still unknown, so people are being conservative until more clear long term toxicity studies are conducted. Toxicity is being studied as part of one of the newer Phase 2 human trials, but we are still probably 2 years away from those results, and it is following the Mayo Clinic protocol, not the much more aggressive one you suggest.

      As for myself, I have been very happy with the Mayo Clinic protocol. I have less arthritis symptoms and can see the moles and wrinkles in my skin lightening and diminishing. I have upped consumption to 2 days every 2 weeks because I was seeing a regression if I waited a full month. However, I am relatively young, so don't feel the need to be aggressive in my treatment. I also consider fisetin like weight lifting. A stimulus is good, but you need recovery time to allow the adaptation to occur. Off time is when the body regenerates and heals. Fisetin is causing a stress response and literally killing cells in the body, and that process takes its toll, so recovery is important. Senolytics cause a stress response. Your body needs to be able to adapt. Too much, and you get other negative side effects, like with the chemotherapy drugs. High doses kill the cancer, but they also begin to affect healthy cells and stress the body's ability to process and eliminate both the chemotherapeutic and the destroyed cells.

      Like 1
    • Fairy8i8 Very nice summary and thank you. Agree with what you said, and I have also gone to 2  Mayo  treatments/month ( 20mg/kg bodyweight for two consecutive days)

      My own personnel experience is that there was initially an immediate response  to the Mayo protocol in that my endurance, strength and color vision were almost instantaneously enhanced. This immediate response did not increase after my first treatment, but it has not diminished either. Others on this forum have reported similar experiences.  It seems to me that there has to be more than removal of senescent cells and/or mTOR inhibition to explain the initial response.  I have done a minor literature search and have not found an explanation my initial response. I wonder if there is some sort of impact on mitochondria. It may be that my age  (80 yr old) has something to do with the initial response. 

      Like 1
      • Michael
      • Michael.1
      • 3 mths ago
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      Fairy8i8 Do you have a link to the study? Thank you

      Like 1
      • Florin
      • Florin
      • 3 mths ago
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      Fairy8i8 It's the same study that this entire discussion is based on. Here's the relevant info:

      Ercc1−/∆;p16Ink4a-luciferase mice were fed a standard Teklad 2020 chow diet with or without supplementation with 500 ppm (500 mg/kg) of fisetin, ad libitum (approximately 60 mg/kg fisetin per day)

      To determine if fisetin-mediated clearance of senescent cells impacts the health or lifespan of mice, WT f1 C57BL/6:FVB mice were fed a diet containing 500 ppm fisetin beginning at 85 wks of age, roughly equivalent to age 75 years in humans. This resulted in an extension of median as well as maximal lifespan (Fig. 5A-B).

      So, 500 ppm = 60 mg/kg fisetin per day.

      The WT (wild-type) mice were the only ones demonstrated to have any lifespan extension. You might think that this effect was probably all due to the elimination of senescent cells, but it might also have been caused by other factors such as chronic admin of fisetin affecting the microbiome which the paper also speculated about.

      Regarding toxicity, I'm not sure what would be more toxic: acute, mega doses of (possibly contaminated) fisetin or lower chronic doses? Mega doses might be safer if heavy metal contamination would be the only concern, but what about stuff like hinokiflavon (where the dose might make the poison)? Although I'd like some human data (I did request blood test results for liver function in another thread), I'm not too concerned about fisetin accumulation in the liver; chronic administration in this study was beneficial, not harmful. The study which suggested liver toxicity used 223 mg/kg, whereas I'm referring to 60 mg/kg which apparently didn't have any toxicity. That same study also mentioned that there was no observed toxicity even at 112 mg/kg. And as for the Mayo Clinic's protocol, the reason it's going for acute admin rather than chronic is probably because it wants to avoid drug interactions (several drugs and substances were contraindicated) and perhaps hoping that acute admin would produce faster results than chronic.

      Whatever happens with stress and recovery, the data we have suggests that chronic admin might be better than acute for lifespan extension. Isn't maximum efficacy what everyone wants, given the same level of safety?

      Fisetin is a senotherapeutic that extends health and lifespan
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

      Anti-cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: In vitro and in vivo studies
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034928/

      Like 2
      • Fairy8i8
      • Fairy8i8
      • 3 mths ago
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      Florin Thanks for clarifying. I'm really glad you commented! I always got so caught up with the initial groups, that I failed to contemplate the significance of the final group. Refreshing to see a decrease in oxidative stress in the liver. However, we do not know how the different methods compare to longevity because the first 3 groups of mice on various diets were sacrificed rather than allowed to live. Also, there is a standard chart for adjusting dosing of animal subjects to human subjects. I don't have it off hand, but it's not 1 to 1, so 60mg/kg for humans would not be the indicated amount from this study.

      Also, I will add a third day to our dose round (today) because I just took doses the last 2 days, based on the Mayo Clinic update and see how it goes. I have wondered about increasing a high dose to more days as the group of mice that was given the higher dosage for 5 days had more senescent clearance than the group given the 500ppm chow ad libidum pulsed on and off.  I never liked how that group had an initial decrease in senescent cells, but then a slow increase thereafter, even when given the chow again. It's too bad they didn't do the same imaging on the other groups to see senescent accumulation over time. If only I had money to fund research!

      I had discussed which way to take fisetin with my dad. The nice thing about intermittent doses is that it is cheaper as well. As I said, I am young (40) so I have time to wait and see what becomes of the research while having benefitted on the Mayo Clinic protocol. Also, I take Biotivia Pteromax and Jarrow Broccomax daily, so I do take things that stimulate the nrf2 pathway on a daily basis already. At this point, I am more concerned with healthspan rather than lifespan.

       Michael To which study are you referring?

      Like 1
      • Florin
      • Florin
      • 3 mths ago
      • Reported - view

      Fairy8i8 The only empirically-proven endpoints is that the chronic group had increased longevity and health. So, there's going to be a risk in assuming that intermittent or acute admin will provide the same or better results.

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      • Dan Nave
      • Dan_Nave
      • 3 mths ago
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      Florin Because that would cost me $6,745 a year...

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      • Florin
      • Florin
      • 3 mths ago
      • Reported - view

      Dan Nave It should cost a few hundred per year, not thousands. Remember that 60 mg/kg = 5 mg/kg HED (human equivalent dose) per day.

      Like
  • A clinical trial run by the Mayo Clinic and aimed at improving skeletal health in elderly women is upping the fisetin dosing schedule from two days to three and from one or two consecutive months to five months.

    https://clinicaltrials.gov/ct2/show/NCT04313634

    Like 1
      • Van
      • Van
      • 3 mths ago
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      • Reported - view

      Florin Dr. Green has always said 3 consecutive days of Dasatinib 100 mg and 3 consecutive days of Fistein 1500 mg "every month" for elderly people.  Every 3 months for younger.  He also preaches, Vitamin C with dosing to improve bioavailability.  He leaves it up to you on whether to take Quercetin.  Says Fistein is so superior it is not necessary.

      Like 2
      • Moustachiarty
      • I want to age like RIngo Starr.
      • moustachiarty
      • 2 mths ago
      • Reported - view

      Van Interesting. Do you know how much younger "younger" might happen to be?

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      • Van
      • Van
      • 2 mths ago
      • Reported - view

      Moustachiarty No

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      • aribadabar
      • aribadabar
      • 2 mths ago
      • Reported - view

      Moustachiarty  At least 45, and you won't be too much off.

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  • Now scientists at Tel Aviv University have shown that giving pure oxygen to older people while in a hyperbaric chamber increased the length of their telomeres by 20 per cent, a feat that has never been achieved before. 

    Scientists said the growth may mean that the telomeres of trial participants were now as long as they had been 25 years earlier. 

    The therapy also reduced senescent cells by up to 37 per cent, making way for new healthy cells to regrow. Animal studies have shown that removing senescent cells extends remaining life by more than one third.

     

    https://m.facebook.com/story.php?story_fbid=10157627604919135&id=702669134

    Like 1
    • Mel it appears FB removed  that  Study,  do  U  remember the name of  it?

      Like
      • aribadabar
      • aribadabar
      • 3 mths ago
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      • Michael
      • Michael.1
      • 3 mths ago
      • 1
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      aribadabar Curious enough about it to have just scheduled my first session on Thursday for the second week of December. If I decide to try three/four, will report back.

      Like 1
  • Hmmm...can you redo the link to the FB Israeli study...seems to be broken

    Like
      • Fred Cloud
      • Fred_Cloud
      • 3 mths ago
      • 1
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      GEdwards Unfortunately you cant edit posts here.

      But I assume everyone knows you could find the study yourself in about 10 seconds with google.

      Like 1
  • Anyone know what the cost of a typical two hour session might be?

    Like 1
  • Here’s an interesting discussion on senolytics. Seems it could be harmful if taken without something to replace cells that are removed

    also interesting that UBX0101 failed in part because of very high placebo effect

    Like 2
      • Fred Cloud
      • Fred_Cloud
      • 2 mths ago
      • 1
      • Reported - view

      Paul Beauchemin I think I see what they did wrong, these scientists killed off too many senescent cells. There is actually a therapeutic role of SASP, the normal function of the SASP is to restore tissue function by stimulating less-damaged neighboring cells to engage in tissue repair. So if they killed off all or too many senescent cells and your skin couldnt ever enter sasp mode you wouldnt be able to repair all the missing cells you just killed off and it would form skin ulcers. So there is a healthy range of senescent cells, if you have too many it accelerates aging, if you have too few you limit repair. Its a weird catch 22. Interestingly, if you put too much rapamycin on your skin, you get skin ulcers.

      These senescent cells also seem to have other effects in the body, I see the mice not only had ulcers from the skin not repairing they also had liver fibrosis. Check out this quote from a study finding.

      "acute myofibroblast senescence also has a role in repairing damaged organs such as the liver and thus is likely to represent a more common mechanism to limit fibrosis"

      So sasp mode may even limit fibrosis in the liver

      The role of senescent cells in ageing

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/

      Like 1
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