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
      • 11 mths ago
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      • Reported - view

      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 2
    • 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
      • 11 mths ago
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      • Reported - view

      Fairy8i8 Do you have a link to the study? Thank you

      Like 1
      • Florin
      • Florin
      • 11 mths ago
      • 2
      • Reported - view

      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
      • 11 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
      • 11 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.

      Like
      • Dan Nave
      • Dan_Nave
      • 11 mths ago
      • Reported - view

      Florin Because that would cost me $6,745 a year...

      Like
      • Florin
      • Florin
      • 11 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
      • 11 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
      • 10 mths ago
      • Reported - view

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

      Like
      • Van
      • Van
      • 10 mths ago
      • Reported - view

      Moustachiarty No

      Like
      • aribadabar
      • aribadabar
      • 10 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
      • 10 mths ago
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      • Michael
      • Michael.1
      • 10 mths ago
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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
      • 11 mths ago
      • 1
      • Reported - view

      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
      • 9 mths ago
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      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
  • For the last 3 days I've added 1600mg Fisetin (20mg/kg) to my normal mid-morning routine which includes 1g Quercetin, 1g Curcumin and 200mg Ubiquinol (kaneka) taken with a smoothie. The smoothie is loaded with fats and whole food sources of sulforaphane, pterostilbene, apigenin, luteolin, curcuminoids etc. which may be boosting the effects. 

    My experience:

    (1) First day - odd jaw tightness, trouble focusing, extremely hard to resist urge to nap

    (2) Second day - more intense jaw tightness, trouble focusing, unable to resist extended napping

    (3) Third day - continued jaw tightness, trouble focusing, continued desire to nap

    The effect takes 30-45 minutes to kick in and lasts for 8-10 hours. I am going to continue for 1-2 more days (4-5 total).

    So far I seriously can't imagine taking Fisetin more than 2 days a month. Never expected it to have such a noticeable impact on how I feel since none of the other flavonoids with senolytic potential that I've taken have had similar effects. It feels a bit like my body is going into some kind of battery saver mode where full functionality isn't available. Like the onset of napping doesn't feel like an inability to resist a desire for sleep as much as it does like a bit is being flipped and my body starts much more aggressively shutting down unecessary processes.

    The Fisetin I'm using is 400mg / pill from Do Not Age.

    Like
      • Fairy8i8
      • Fairy8i8
      • 7 mths ago
      • 1
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      Aaron Interesting symptoms. I felt like I had a sunburn the first time I took it and some random pains. I do get tired when I take it. I no longer get any pains while taking it, but some fatigue. I think it gets easier as you take it regularly. My husband, who had severe sepsis, feels like his muscles are sore like when he strength trains when he takes it, but he says that the soreness is getting less and less. I take that as a good sign that he is reducing his senescent cell load. It also does wonders for my arthritis, so the fatigue is worth it to me. I take it once a month for 3 days now. I was taking it twice a month for 2 days because I felt like there was too much regression month to month with just 2 days. Let us know how the full 5 days goes. Thanks for sharing!

      Like 1
    • Aaron When I take large doses of Fisetin I feel a weakness in thighs and I easily get sore muscle after extercise. When I have large amounts of dried Parsley (rich in apigenin) it has a sedative effect on me. Spermidine and sulforaphane also makes me sleepy. So those supplements I take only at dinner or later in the evening, (sulforaphane, Apigenin, Spermidine).

       

      When I take Quercetin, EGCG and curcumin (BCM-95) in the morning I get a boost of energy. 

      Like 1
      • Aka Loo
      • Aka_Loo
      • 7 mths ago
      • Reported - view

      Aaron . I have yet to start taking Fisetin. 

       

      I have some questions: is it recommended to not do vitamin IV drip while taking Fisetin or does that actually help to clear senescent cells?

      Is there a combination of Fisetin with other compounds that are good for women and to maintain healthy and regular ovulation?

       

      Are there any particular brands of Fisetin that are to stay away from?

      Like
      • Aaron
      • Aaron
      • 7 mths ago
      • 1
      • Reported - view

      Aaron The 4th and 5th days taking Fisetin the effects were similar, but a bit more muted. No noticeable change after completing the five days vs prior to starting. Going forward I think I'll continue to do 20mg / kg on 2x consecutive days once a month. It definitely seemed to have a bit more 'kick' than other flavonoids I've taken that have senolytic buzz.

      Like 1
      • Moustachiarty
      • I want to age like RIngo Starr.
      • moustachiarty
      • 6 mths ago
      • Reported - view

      Why such a 1600 mg and why combined with all those other things? That amount of fisetin far exceeds the Mayo protocol and as for the rest I'd worry about liver toxicity from too much of any one of them. Stacking and mega dosing them ... Is that based on any science done to date?

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

      Whoops! Reviewing the threads here I see now why the 1600 mg. Still not certain why you'd want to stack the stuff.

      Like
  • Decided to do a tolerance test before going ahead with fisetin. 

    According to the info in this thread I might go for a dose north of 2000mg based on my weight for a hit and run treatment (92kg and age 50, good health).

    I've had 100-200mg fisetin a day via capsules in the past and noticed nothing.
    3 days ago I cut 5 of the Doctors Best capsules into a bowl (500mg) and mixed with fresh cream and some ground black pepper. Consumed with some fresh blueberries and rasperries.

    After around 90 minutes I started to feel like I was coming down with something. Then I started getting an ache in the finger joints on my left hand. Starting wondering how severe the feelings would get, and ended up lying down for 20 minutes. Then it all started to recede to the extent I went on my normal 3 mile lunchtime hike as I usually would.

    Comments in the thread above have me thinking. It seems like a quarter dose had a reaction, but why so easy? Maybe the lecithin in the dairy cream was beneficial? Also perhaps it was my beverage; an hour after taking the fisetin I had my usual late morning brew a pint of hot green & black tea with lemon. (Two teabags with half a lemon sliced in). The lemon is to increase the bioavailability of some compounds in the green tea. Then was it warm water, the black tea, or just a coincidence I started to feel results after drinking this? 

    So, I'm going to take it steady. Some folks experienced nothing at higher doses than mine and that was not my experience. Next week I might try 700mg etc, and work towards an eventual 2000mg weekend shot.

    I've also ordered some of the Senylitic Activator pills by Life Extension (they kind of fake the D+Q action). Once again I'll take that careful with an initial half dose, and certainly not weekly as they suggest. Also, won't be combining fisetin and other senylitics at the same time. There's that nagging concern of kicking off something unpleasant like an auto-immune reaction.

    I'm not put off, in fact it might have taught me I have things going on in my left hand that I didn't know about. I have a slight arthritic ache in 1 finger joint as I type this, but now I'm thinking maybe I did before? 

    My energy levels are certainly improved but were already perhaps due to AKG, NMN or the vitamins I've been deficient in for years. Will report back when I do my proper senolytic dose with any observations.

    The journey continues.

    Like 1
      • Fred Cloud
      • Fred_Cloud
      • 6 mths ago
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      Jack Black Yeah I would proceed with caution and work your way up to the 2,000mg per day dose. I have had reactions with 500mg also and so have others. I think people could really get into trouble with jumping into the deep end of the pool with 2,000mg without dipping their toe first at lower doses. I hope the mayo study results will share how some people reacted to the 2,000mg they used. Anyway, the old protocol of 500mg for 5 days should be the first stepping stone to everyone wanting to use fisetin. I was thinking one could do a hybrid protocol of using a dose escalation of say 500, 750, 1,000, 1,250, 1,500, 2,000mg once you clear the 500mg x 5 day round.

      Like 2
      • Jack Black
      • Jack_Black
      • 6 mths ago
      • Reported - view

      Fred Cloud I wonder if you or others might want to try the same approach. Reason being I had just 100mg of Fisetin yesterday with the big pot of black tea, green tea, cinnamon stick and sliced lemon. Even then I felt a reaction though less than the 500mg. 

      The tea ingredients are intended to be synergistic but I'd be interested to know if anyone feels anything combining this with fisetin like I did. Small chance I know but maybe stumbled on a way to pep up the effect?

      btw no fatty medium used this time I just took a capsule at the same time as drinking the tea.

      Like
  • I don't have high regard for anecdotal evidence, even my own, due to its great susceptibility to variations, confounding variables, placebo effect, etc.  Nonetheless, I figure that it can't hurt to offer my own experience for those who might be interested.  For the past three months I've been taking once weekly doses (as suggested on the package) of Life Extension's Senolytic Activator (theaflavins 275mg, bioavailable quercetin phytosome 74 mg, and apigenin 50 mg) along with a weekly dosing of 64 to 72 mg of their bioavailable fisetin, which they claim is the equivalent of up to 1600 to 1800 mg of regular fisetin.  My age is 70 and my weight is 82 kg (about 180 pounds).  I have felt no differences whatsoever on dosing compared to non-dosing days, but don't feel confident enough to offer any interpretation (or misinterpretation) of that fact.  I'll leave that to you, friends!   

    Like 2
    • Brian Valerie hi Brian; try your formula , on an empty stomach,  and take a 12 minute walk, also, ( maybe double the le feistin,  and you will definitely,  " feel" a difference.         Enjoy;  karl

      Like 1
      • Brian Valerie
      • Semi-Retired Health Education Teacher
      • Brian_Valerie
      • 6 mths ago
      • 1
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      karl kuffner Thank you very much for sharing your experience with me, Karl. I reread your post in which you related positive effects, even including euphoria! Since I'm dosing weekly, I'm able to try different protocols. There are so many different individual experiences or perceptions, here and on the fisetin thread at longecity.org., with, for example, some folks reporting better effects by taking fisetin with oil. What do you think of the notion that perhaps we shouldn't expect to "feel" anything from what could well be simply a reduction in the rate of aging?

      Like 1
    • Brian Valerie   yes, I understand.   I'm almost 71 yrs myself, however I strongly feel  ," first thing in the morning, on an empty stomach w possibly some straight black tea , quercetin a (quarter teaspoon of olive oil?), and 12 minutes brisk walk, and you should definitely have some noticeable feelings/ sensations.    On another note , my wife is much younger ," 40", and she took senolytics 3 days in a row, ( on my suggestion) and her results were STUNNING!        karl

      Like 1
  • Brian Valerie I have been doing the same thing for almost 6 months now. I just add the Fisetin dose to the Senolytic Activator. I have done it weekly and haven't seen any benefits or reactions. The 2 times I took D&Q, I had a general malaise for ~12 hours but also no noticeable benefit. I will probably continue the once a week protocol but I think it's time I moved on to Rapamycin. I am 69 yro and feeling like I was born a little too early and not quite rich enough to experience age reversal with the coming CRISPR technologies.

    Like 1
      • JOHN
      • JOHN.1
      • 6 mths ago
      • 1
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      Michael Avenoso I would definitely be taking Rapa at your age. Try adding diet and exercise to the equation if you haven't already done so as well.

      This is the guy I follow the most --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/

      This is a very good article on the subject of anti aging medications.  

      Like 1
      • Brian Valerie
      • Semi-Retired Health Education Teacher
      • Brian_Valerie
      • 6 mths ago
      • 2
      • Reported - view

      Michael Avenoso Yep!  Maybe we shouldn't expect to feel any improvements from what could simply be a diminishing of the rate of aging.  Before and after biomarker tests of some sort might be more telling.

      Like 2
      • Fairy8i8
      • Fairy8i8
      • 6 mths ago
      • 1
      • Reported - view

      Brian Valerie I don't experience any side effects, and I take the 20mg/kg for 3 days in a row every 2 weeks. I think it's better if you don't experience negative side effects. I also don't tell people about it because I am waiting for the clinical trial results on humans, but when my mom took it, she had a dime sized flat mole disappear on her face. I started tracking some moles I have developed with age (not ones I had when young), and they have lightened and decreased in size. This has been a good indicator to me, and maybe it would be more helpful to you rather than pushing and combining other things until you get a negative reaction. Also, I am not sure about the once a week protocol, as I do not know if the creators of your supplement have a scientific basis for it. If you aren't seeing an improvement, maybe try switching to a 2 consecutive days monthly treatment and see if that helps, since that is the protocol in the human research studies. Someone here said the studies were updated to 3 days, which is why I do 3 days. I do it about every 2 weeks because I start to see more wrinkles appear after 2 weeks, and when I take the fisetin, they diminish again. Oh, what a girl will do for the look of her skin!

      Like 1
      • Brian Valerie
      • Semi-Retired Health Education Teacher
      • Brian_Valerie
      • 6 mths ago
      • 1
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      Fairy8i8 Thanks so much for sharing your experience and wise reflections with me, Fairy.  I do agree with you that we shouldn't assume that experiencing negative side effects is an indication that the protocol is more effective.  I will certainly start looking at my moles more closely!  As far as the one day per week dosing goes, you're correct that the Mayo Clinic researchers had chosen a two days per month protocol, but of course, that is purely a fisetin study, fisetin thus far seeming to have a quite good safety profile.  The folks at the Life Extension Foundation, creators of the Senolytic Activator supplement discussed above, do have impressive academic credentials, but considering that we're barely on the frontiers of the relevant research, I'm guessing that both they and the Mayo Clinic scholars are likewise guessing!  A two days fisetin protocol was used in rodent studies, but one could argue for an even longer duration in a longer lived species like ours.   Before adding the Senolytic Activator to my fisetin dosing, I was following the two days per month protocol, again not noticing any changes at all.  THANKS to your reply, I'm going to give the two days per two weeks (then three days?) with both fisetin and the Senolytic Activator a try!

      Like 1
  • Yes, I will definitely be starting the Rapamycin soon as well as continuing the senolytic therapy. I have been tweaking my diet since my early 20s and exercise as I can. I have chronic Lyme Disease so all this is a challenge. My motto, "Live long and suffer!" I figure if I can live long enough, maybe there will be some answers to the Lyme conundrum. 

    Like
    • Michael Avenoso 

      my understanding is serval herbs treat Lyme effectively.  But, going away from the herbs, high dose vitamin C,D, and NAD+ therapy is suppose to be magic for CLD. 
       

      it’s NEVER too late to get better. Just don’t think it will always be this way. 

      Like
      • Fred Cloud
      • Fred_Cloud
      • 6 mths ago
      • Reported - view

      Michael Avenoso There have been alot of advancements in chronic lyme. From biofilm busters, persister cell treatments like disulfarim, pulsing antibiotics, abx combos for persister cells. I would try all of those if you havent already. Find a good lyme doc or just treat yourself.

      Like
    • Michael Avenoso in the event you need an internist with Lyme specialty, if you are in the Charlottesville area I can give you a contact.

      Like
    • Thanks everyone. I've been dealing with chronic Lyme since 1991. Tried all the above including Disulfiram and NAD infusions. Mild HBO therapy has gotten me somewhat functional again.

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

      Michael Avenoso You tried all those approaches and failed? Well if all else has failed then you should read this book.

      Lyme Disease Supercharge: The Revolutionary Approach to Getting Better When All Else Fails

      Like
    • Fred Cloud Thanks Fred. I explored mold illness with Ritchie Shoemaker. M.D. Unfortunately it didn't help. At this point I am simply trying to stay alive long enough for an effective therapy to be discovered.

      Like
  • Fisetin in high doses just makes me feel sick,  I don't get then when taking Quercitin .

    Like
      • Jack Black
      • Jack_Black
      • 6 mths ago
      • 1
      • Reported - view

      Kelly K Just be careful how regularly you take Q. When it was given to mice every day it reduced their lifespan by a lot. It has a toxicity and the benefit seems to derive from occasional harnessing of that toxicity. Personally I'm only considering Quercetin for D+Q type hit and run therapies. Fisetin daily on the other has some genuine advantages I've seen myself, some mentioned by folks in the thread above, but anything regular 100mg sounds fine. As detailed above even just 500mg Fisetin had some sort of accompanied immune reaction. 

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

      Jack Black 

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      • Van
      • Van
      • 6 mths ago
      • 1
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      Van Dr Green as dropped Q from the protocol.  It is now Fistein 2,000 mg + Dasatinib 100 mg. x 2 days once a month or once every 2 weeks.  Not for your reasons, but Fistein works so much better.  Young people 2 days every 3 months

      Like 1
      • Jack Black
      • Jack_Black
      • 6 mths ago
      • Reported - view

      Van So it's now F+D ? Wow hadn't heard that. Interesting.

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      • Jack Black
      • Jack_Black
      • 6 mths ago
      • Reported - view

      Van What's his definition of young? I'm 50 and certainly my doctors describe that as young. :)  

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      • Van
      • Van
      • 6 mths ago
      • 2
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  • I was thinking of using LEF Quercetin tablets and alternating days with their Fisetin tablets. thoughts ??

    Like
      • Jack Black
      • Jack_Black
      • 6 mths ago
      • 1
      • Reported - view

      Kelly K To explain my comments above the reason I suggest not using Q at all regularly is the reasoning that it is chronic non-fatal toxicities that promote cancer. This idea is explained very well here; https://www.youtube.com/watch?v=nrqXKf3tprE

      Then consider this review here; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ where Q was actually detrimental to mouse lifespan. If that is the case why would chronic administration benefit humans?

      Aside from hit and run senolytics (alongside other compounds, Q doesn't seem to work alone) I am not aware of anything beneficial around Q, especially chronic dosing. Other forums has people talking about kidney damage. If you can direct me to anything to the contrary I would be happy to read it.

      Fisetin seems a bit better. Still wouldn't take it daily but I can attest to there being benefits to the stuff certainly short term.

      I will also hold my hands up and state that I've bought some of the Q based once a week senolytic pills from LE. Bit of an experiment, but currently on hold as my covid jab is next week and I want my body to be in a 'normal' state for that. But mainly I'm sold on fisetin. Even my 500mg single dose seems to have aided the color perception in one of my eyes, which another poster here had noticed with a higher dose.

      Like 1
  • D+F+P Side Effects with BioFisetin

        Yesterday my wife and I did a senolytic session for the first time since September-2020.  We took 10 mg of BioPerine, followed in an hour by 200 mg of Dasatinib (4 x 50 mg) and 80 mg (10 x 8 mg) of LifeExtension's BioFisetin.  The nanoparticles of BioFisetin are coated with a LE-proprietary concoction involving Fenugreek extract that is supposed to boost the bioavailabity of the Fisetin by about x25, so our dose should have been the equivalent of taking 2 g of uncoated Fisetin powder (as we have done before).

        This is the first time we have combined Dasatinib with BioFisetin.   In all of our previous senolytic session experiences, the side effects were relatively mild.  We had done D+Q+P and D+Q+F+P with Fisetin powder, and we had done a triple session with BioFisetin alone.  This time, I would say that the side effects have increased to moderate.  I had belly cramps all night and didn't sleep well, had multiple soft bowel movements this morning, and experienced a general feeling of unwellness all day.  (My dog Taliesin and I did one run at a dog agility competition this afternoon, but we failed to qualify, partly due to my lack of energy and quick response near the end of the run.)  My wife, who has never reported any senolytic-session side effects before, had a headache, a general feeling of unwellness, and decided to stay in bed until mid-afternoon today.

        I'm not complaining.  I take this experience as an indication that our session of D+F+P using LE's BioFisetin had a stronger senolytic effect than we had previously experienced.  Possibly this is because LE's claim of a x25 boost is an underestimate of the LE BioFisetin's actual increased bioavailability, or possibly because taking the BioPerine one hour before D+F increases the boost factor.  In any case, I'm impressed.

            We will compete in dog agility again tomorrow, and based on previous experience I expect to be fully recovered and more energetic.  We plan to do two more senolytic sessions soon, the next on Monday (4/19) and the last on Thursday (4/22), spacing the sessions with two off-days.  I expect less side effects from these subsequent sessions.  I'll report it if I'm wrong.

        In the interest of full disclosure, I should mention that my wife and I have just completed a 15-day session of taking a 3 mg sublingual tab of Super-Nutrition's Epitalon (AEDG) every morning from April 1-15.  We will repeat this on the 1-15 of May and June.  We experienced zero side effects from this Epitalon session, and I doubt if it contributed to the side effects I am reporting above.

    Like 3
      • Fred Cloud
      • Fred_Cloud
      • 6 mths ago
      • Reported - view

      JGC I enjoy reading your senolytic experience reports. I think yours may have been one of the first I read a year ago when doing research. Is there a reason you space them out so far? I am not sure I agree with Dr Green suggesting monthly Dasatinib but maybe quarterly at the most since it is pretty harsh, but certainly fisetin is safer and monthly seems reasonable and is getting pretty popular.

      Like
      • JGC
      • JGC
      • 6 mths ago
      • 1
      • Reported - view

      Fred Cloud 

          My 3-session spacing with two off-days in between is done because Dasatinib is involved.  When we did BioPerine+BioFisetin last year, I did not space the senolytic sessions and we did 3 days in a row.  This spacing, like most of the other details of our senolytic sessions, are educated guesses, since we do not (yet!) have a direct way of monitoring the clearance of senescent cells.  As for how frequently to do them, I think 6 months is about right.  Some of the advocates for more frequent sessions would like to sell more pills.

          Incidentally, as predicted, I did make a good recovery from yesterday's side effects and felt renewed and energetic.  This afternoon my Shetland Sheepdog Taliesin and I did two masters-level agility runs, and we did very well, with only one problem when his tail hit a bar after clearing the jump.

      Like 1
      • garland
      • garland
      • 6 mths ago
      • Reported - view

      JGC 

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      • garland
      • garland
      • 6 mths ago
      • 1
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      JGC I would be hesitant to use 200 mg of d. According to the research when one does 200mg of d the likelihood of detrimental side effects goes up tremendously. Especially when you're using it with pepper which actually enhances absorption it means it takes it to a different level. According to most of the feedback from Life Extension we're not supposed to do strenuous exercise at all when we take d. I have found that my body rebelles when I try to to do anything intensely as far as exercise goes. The best I can get just a moderate walk. So I've stopped using pepper and I try to do it at least once a month if not more the recombination of DQ & F. I'm in my sixties so it does make a huge difference though. I take up  words a 20 of Life Extensions fisetin with fenugreek which enhances its bioavailability tremendously. One definitely feels the energetic Rush one takes high amounts of fisetin. I do this for three straight days with only a hundred mg of D each day. I definitely feel results from this although I am definitely weak when I do this especially as far as exercise goes. I feel a little congestion in my lungs. I try to walk anyway but do so as much more leisurely Pace then normal. I am not suggesting to anyone here that they use such a high dose of fisetin especially the first few times you use it. I work my way up to it caution is always the best policy. Having a doctor's input is even better.

      Like 1
      • JGC
      • JGC
      • 6 mths ago
      • 1
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      garland 

          Thanks for the heads-up.  I am 2/3 of the way through our latest senolytic session, but for the next phase on Thursday, I'll do 100 mg of Dasatinib.   The 2nd phase was yesterday morning, with 200 mg of D.  I felt a bit lethargic all day, but otherwise there were not the side effects I had reported above from phase 1 on Friday afternoon.

      Like 1
      • JGC
      • JGC
      • 6 mths ago
      • 2
      • Reported - view

      garland 

          Last Thursday (4/22/2021) I did the third of three D+F+P senolytic sessions at about 3 PM in the afternoon (about the same time that I had done the first D+F+P session on the previous Friday and experienced unpleasant side effects).  After considering your warning, I decided to go ahead and take the usual 200 mg (4 tabs) of Dasatinib.  Sure enough, after going to bed with no side effects, I was awakened at about 2 AM with stomach cramps, which persisted for the rest of the night.   Tylenol helped me go back to sleep.  The next day (Friday, i.e. yesterday) I felt unwell enough to cancel our participation for the day in a dog agility trial held north of Seattle.

          I conclude that (a) perhaps 200 mg of Dasatinib is indeed too much, and (b) that one should do the senolytic doses in the early morning (not at 3 PM) to avoid the 2 AM cramps.  In any case, today I felt fine and did pretty well at the ongoing dog agility trial.  Perhaps a day of stomach cramps is an acceptable price to pay for getting rid of the senescent cells (e.g., pre-cancerous colon polyps) in the lower digestive system.

      Like 2
      • GEdwards
      • GEdwards
      • 5 mths ago
      • Reported - view

      JGC likely best to do this monthly or every 6 weeks!

      Like
      • JGC
      • JGC
      • 5 mths ago
      • 1
      • Reported - view

      GEdwards 

          I am doubtful that senescent cells build up fast enough to make it worth doing a set of senolytic sessions every month or 6 weeks.  However, this is at present a matter of opinion, since we don't have a good way of finding out just how many senescent cells are being cleared in a given senolytic session.  Perhaps soon some lab will provide an inexpensive urine or blood test for the presence and quantity of the molecule  dihomo-15d-PGJ2, and we can be more analytic about which senolytics work the best and how often they should be used.

      Like 1
      • Jack Black
      • Jack_Black
      • 5 mths ago
      • Reported - view

      JGC Sheeky Science show did a piece on that marker this week, did you also see that?

      Like
      • JGC
      • JGC
      • 5 mths ago
      • Reported - view

      Jack Black 

      Thanks for the heads-up.  Here's the LINK to her discussion.  The problem is that she didn't give any help in actually finding a lab that will tell you the quantity of dihomo-15d-PGJ2 in a blood or urine sample.

       

      .

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      • garland
      • garland
      • 3 mths ago
      • Reported - view

      JGC yes the research on Dasatinib is quite clear that side effects increase dramatically when one does more than 100 mgs. And it can get serious especially since Fisetin or Quercetin might attenuate Dasatinib,  My personal feeling is to try fasting some when you do this combination. Taking other nutrients including anti - oxidants might reduce the effectiveness of them. In fact at Mayo they make everyone stop taking all supplements while doing their protocol.... I try to exercise but do not strain as Life extension warned against exercising while doing the protocol.  I walk but do not strain as i get some pressure on my heart if I do anything too intense. But I do feel great when i do the protocol.... but tiredness does seem to be the most pronounced side effect asside from some heart pressure if push things. But for the next few days after everything clears up I do feel great and i can do yoga like I was 30 years younger and lots of good energy. 

      Like
    • garland ,@Dan Nave @garland,@Dan Nave
      Another D&Q&F protocol with Bioperine.

      I am very afraid of dasatinib side effects. While the effect of piperine on dasatinib isnt clear, I  read that “The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations.” 

      So to enhance fisetin/quercetin but not dasatinib, here is my once every 2 weeks D&Q protocol:

      AM: 100 mg dastanib + 500mg fisetin in the AM with breakfast.

      1PM (in under 3 hours from ingestion, all dasatanib is assumed to have been absorbed): 5mg  Bioperine+ 500mg fisetin (effective dose estimate 1500 mg)  (This is in addition to my daily GHA, EPA, and 250 mg quercetin). With meal.

      If my estimates are correct, the protocol is fairly consistent with that of Dr. Green. I would like to increase the flavonoid dosage, but I havent been convinced that would be beneficial.
       

      Like
      • JGC
      • JGC
      • 3 mths ago
      • Reported - view

      garland 

          On Monday and Tuesday (July 5 & 6, 2021) we did another session of D+F+P senolytics (now taking 10 mg of BioPerine 5 minutes before the Dasatinib and BioFisetin).  This time we took 100 mg of Dasatinib (instead of 200 mg) each day.  On the first day, the only noticeable side effects were a slight headache and a body temperature elevated about 1° F above my normal.

          However, last night following day 2, I woke up about 4 AM with abdominal cramps, the same symptom I had experienced in April.  That has now dissipated some, but I still feel a bit unwell this morning.  I'm sure this will pass, and I take it as an indication that some senolytics has been accomplished. 

      Like
      • garland
      • garland
      • 3 mths ago
      • Reported - view

      JGC  Some have written on here that Fisetin and Quercetin may enhance Dasatinib so much that it may enhance its potency so as to make it more likely to have some bad side effects. . In other words it may act in a similar way as BioPerine ...So I no longer take BioPerine because it maybe too much.   I have tried it both ways and I also still take it with quercetin (maybe 1000 mg  of the highly absorbable kind from Life Extension.. .I take 2300 mg of the highly absorbable kind of Fisetin from Life Extension)...  Something seems to be giving me energy when I take this combo but I do feel pressure in my lungs or maybe my heart when I walk too fast.  But for the week following it after about 2 or 3 days I start to feel great and i am extremely limber. So I know something is working. I walk but not too fast during this period. I do get stomach upsets usually in the form of Diarrhea but they have been less and less.

      I also read several studies that questioned whether it is a good idea to get rid of all our senelytic cells? It seems the have some useful purpose. So I now only do my program once a month or so. Feels good this way. Not sure how much help the labs would be as measurements of success  but they are least some way to measure. My labs are incredible... but I also have been doing plaquex which is Phosphatidyl Cholines and one of the ways you can get rid of plaque in the arteries. It takes a fat to get rid of fat. Also been doing chelation. They literally save me 5 years ago from having to do triple by pass surgery. SO these procedures are also supposed to be anti-aging. Also taking nutrients that studies have proven to remove plaque from arteries. 

      Like
      • JGC
      • JGC
      • 3 mths ago
      • 3
      • Reported - view

      garland 

          You wrote: "I also read several studies that questioned whether it is a good idea to get rid of all our senescent cells? It seems the have some useful purpose."

          I recently watched Dr. James Kirkland of the Mayo Clinic do a Foresight Institute video interview:

       

          He made a comment that is relevant to this question.  He said that the small-molecule senolytic treatments like D+Q act by turning off the mechanism that allows senescent cells to be protected from and unaffected by their own toxic SASP secretions.  Thus, it is only the senescent cells that are producing SASP that are being cleared, while those serving useful purposes like wound healing are unaffected.

      Like 3
  • Elsewhere on the forum someone states "some senolytic substances works through ROS activated apoptosis....stay away from antioxidant supplements before a senolytic treatment"

    This led me to thinking is there any use in temporarily boosting oxidative stress before or during a senolytic session? Vigorous exercise, junk foods, even smoking?!

    Serious question.

    Like
      • garland
      • garland
      • 6 mths ago
      • 2
      • Reported - view

      Jack Black Yes Jack I totally agree that we should not use any anti-oxidants when we are clearing out senolytic cells. Just in case it may also clear out the nutrients responsible for clearing out aged cells. I may take them in the evening but not during the day. There is too many unknown here. What we do know is that it seems to work for people and when they do the studies they make everyone stop taking  all other  nutrients so that the other nutrients do not interfere with the senolytics. So we should try to mimic as much as possible what they do in the studies. Cause we know that protocol works. So it is pretty obvious to me that we should avoid whenever possible avoid  things which may disrupt the effectiveness of D and F and maybe Q...

      Like 2
    • garland Jack Black

      Yes some senolytic substances and substances that drive apoptosis works (at least partially) through ROS dependent mechanisms and powerful antioxidants like acetyl cysteine can reverse the ROS accumulation.

      I also consider the fact that ROS can create an environment which can make cell death and Autophagy go wild and cause (for instance neurological) disorders.

      Just as well as antioxidants can impair ROS driven senolytic processes, we need antioxidant mechanism to protect the brain.

      This leaves us with the quest to balance the extraordinarily complex cell physiology that is distorted by processes that drive ageing. We might need ROS for some positive cellular adaptations as well as ROS can be detrimental in other cellular settings.  

       

      Btw, Kirkland speculated in one paper that senolytic treatment might be improved if its combined with fasting or exercise. 

       

      https://www.hindawi.com/journals/omcl/2014/906804/

      “Piperlongumine (PL), a natural alkaloid from Piper longum L., possesses the highly selective and effective anticancer property. However, the effect of PL on ovarian cancer cells is still unknown. In this study, we firstly demonstrate that PL selectively inhibited cell growth of human ovarian cancer cells. Furthermore, PL notably induced cell apoptosis, G2/M phase arrest, and accumulation of the intracellular reactive oxidative species (ROS) in a dose- and time-dependent manner. Pretreatment with antioxidant N-acety-L-cysteine could totally reverse the PL-induced ROS accumulation and cell apoptosis. In addition, low dose of PL/cisplatin or paclitaxel combination therapies had a synergistic antigrowth effect on human ovarian cancer cells. Collectively, our study provides new therapeutic potential of PL on human ovarian cancer.”

       

      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.”

       

      https://www.urotoday.com/recent-abstracts/urologic-oncology/investigative-urology/52516-piperlongumine-induces-rapid-depletion-of-the-androgen-receptor-in-human-prostate-cancer-cells-abstract.html

      “BACKGROUND:Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis, and its modulation represents a logical target for prostate cancer (PC) prevention and treatment.

      RESULTS:The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome-mediated ROS-dependent mechanism.

      CONCLUSIONS: Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in PC cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy."

       

      The Interrelation between Reactive Oxygen Species and Autophagy in Neurological Disorders (hindawi.com)

      “High oxygen demand is always accompanied by more ROS. The brain is rich in various polyunsaturated fatty acids sensitive to ROS, but is relatively devoid of antioxidant enzymes and GSH, adding that neurons are considered terminally differentiated cells, which make brain tissue more inclined to suffer damage from ROS . Robust evidence suggests that ROS display a recognized role in neuronal death after brain ischemia.”

      Like 3
      • garland
      • garland
      • 3 mths ago
      • Reported - view

      Staffan Olsson Yes I do intermittent  fasting when I do this. I do believe it helps enhance the process. I do feel a bit drained after about 3 days. But it should be noted that the owner of Life Extension recommended that one NOT do ANY EXERCISE DURING THIS PROCESS!!! Not sure why as it was never explained that I could find.  I still walk but not too extreme.... 

      Like
  • Hi there , I am quite new to the subject but managed to read all 543 posts….. With the result of being totally confused. Since I am quite young (42y) and D is a) to expensive for me in germany and b) to experimental fir my taste I will go ahead and do Q F and P . Among all the combinations you guys tried : Is there one that is specifically recommended?  I am completely unsure about dosage/ repetition intervall/ Daytime / ect ….   What would you recommend to start with?

    Thx for this great forum

    Sebastian

    Like
      • JGC
      • JGC
      • 4 mths ago
      • 1
      • Reported - view

      Sebastian 

          Shure, start with a few grams of Fisetin preceded by 10 mg of BioPerine an hour earlier.  Do that for three days and you should achieve some senolytics.  However, as I understand the available information, the flavenoids (F & Q) do senolytics mainly on fibroblasts and blood vessel linings.  Dasatinib does senolytics on fat cells, and in aging humans there is lots of senescent fat.

      Like 1
      • Fairy8i8
      • Fairy8i8
      • 4 mths ago
      • 1
      • Reported - view

      Sebastian Fisetin was found to reduce senescent cells in fat tissue as well. There is really only 1 study on Fisetin as a senolytic. They looked at several possible polyphenols, and fisetin was so much more efeective than even quercetin (alone) that they focused the study on it. You can google the study - Fisetin is a senotherapeutic that extends health and lifespan by Matthew J. Yousefzadeh, Yi Zhu, [...], and Laura J. Niedernhofer.  

      They went into Phase 2 clinical trials after this study, and are currently researching it on humans. You can find those studies by going to clinicaltrials.org and searching fisetin. The first, and a couple since, have set dosage to 20mg/kg body weight for 2-3 days in a row per a month. The fisetin is in a capsule with peg400 and a couple other things to increase absorption, as it is not water soluble. That specific capsule is not commercially available, so some here take Bioperine to increase absorption. I have taken a CoQ10 supplement with bioperine, and it upset my stomach, so I just take my fisetin with a meal with fat or with some omega 3 fish oil liquid that I often take. I just take the capsules as they are where some here will directly mix the fisetin powder with olive oil or some other oil. I would just try it, and remember that the best therapeutics have few side effects, so hopefully you won't feel much. I get a little extra tired. My husband says he feels sore muscles like after lifting weights, but he also had severe sepsis, so he has a lot of cellular inflammation from which to recover. He feels less sore now than when first taking it after the sepsis. My uncle said that just the fisetin according to the 20mg/kg for 2 days a month helped his arthritis significantly so his fingers hurt much less. Good luck! I am 41, I have taken fisetin for about 3 years or so. I mostly notice some reduction of fine lines in my skin and the cover of a fee moles. However, as my friends are aging, they are beginning to notice that I am aging slower than they are, so I think it may be doing something. The next 10 years from 40 to 50 is really the time to notice as aging speeds up. My runner friends all look young as well, so don't forget some good exercise to keep you healthy and promote autophagy.

      Like 1
      • Sebastian
      • Sebastian
      • 4 mths ago
      • Reported - view

      JGC Thank you for your fast reply and all the effort you are making

      Like
      • Sebastian
      • Sebastian
      • 4 mths ago
      • Reported - view

      Fairy8i8 I really appreciate this detailed description!! Thank you very much.Only 1 question left : Does it make sense to take F and Q ? Together or alterning or maybe just concentrate solely on F ? Sebastian 

      Like
      • JGC
      • JGC
      • 4 mths ago
      • Reported - view

      Sebastian 

          The answer to your question about F+Q is not completely clear.  However, it's likely that F and Q, both of which are similar flavenoids, play essentially the same role in senolytics, and F does it better.  That being said, we are operating in an information vacuum, and doing F+Q would probably not cause any problems.

      Like
      • Fairy8i8
      • Fairy8i8
      • 4 mths ago
      • Reported - view

      JGC I agree. Because clinical studies haven't been done with the 2 together, it would just be self experimentation. The nice thing about these plant compounds is that they are well studied in other applications and don't seem to have serious negative effects, even at high doses.

      Like
      • Dan Nave
      • Dan_Nave
      • 4 mths ago
      • Reported - view

      JGC and Sebastian, If you would want to take 1gm of Fisetin and 1 gm of Quercetin, I suspect you could leave off the Quercetin if you increase the Fisetin to 2gm.  The reason I say this is that I feel that, at the least, Quercetin might be considered to be sacrificial and extend the effect of Fisetin.  Both F and Q inhibit CYP3A4 activity in a dose dependent manner.  If you have plenty of Fisetin and are not concerned with the cost perhaps you could just bump up the quantity of Fisetin that you are using.  I would also recommend mixing with olive oil and either adding a goodly amount of ground black pepper or some piperene.  I have not seen any information that indicates whether you should take the piperene an hour before, or if you should just take it with the rest of the dose at the same time.  I do it at the same time.   The tests with Dasatinib that I have seen have all been done with Quercetin.

       

      I just did another protocol this week as follows.  I wanted to do both the Dasatinib + Q and the Fisetin + Q instead of doing two separate protocols.  What I ended up doing was taking 100mg of Dasatinib with 500mg of Quercetin in the morning, either before or after I had eaten.  In the evening, on an empty stomach, I took 1500mg of Fisetin and 1000mg of Quercetin all mixed in olive oil with a couple of 10mg pills of bioperine (piperene).  I did this for 3 days in a row.  (I am 69 and about 175kg)

      The reason I separated them like this is that I did not want to potentiate the effect of the Dasatinib as I am somewhat leery of getting too high a dose of that, but I wanted to potentiate the Fisetin/Quercetin so that it was absorbed better. 

      With this protocol the only real side effects were some headache from the Dasatinib, and some slightly loose stools on the fourth day rather than the all day diarrhea that I had experienced earlier after 2 doses of Dasatinib at 200mg with bioperine...

      Like
    • Dan Nave According to the rep at Sabinsa, Bioperine should be taken at the same time as the Quercetin, the reason being that the piperine will only be active for about 15 minutes after ingested.

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

      chuck stanley In my mind this is the best site for senence treatment https://senolyticstreatment.com/

      Like 1
    • Van Yes, absolutely the best site, with the most relevant studies! And if its been a while, its well worth the re-read!

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

      chuck stanley 

          I looked up the Piperine half life on the web and found this:
      "Serial blood samples were collected and plasma piperine concentrations were determined using HPLC. After intravenous administration the apparent terminal half-life (7.999 hr), apparent steady state volume of distribution (7.046 L/kg) and total body clearance (0.642 L/kg/hr) were calculated." 

          I take this to mean that the half life of Piperine in the bloodstream is about 8 hours, not 15 minutes.  Therefore, I still think it's a good idea to take the BioPerine an hour before taking flavenoids, to give it a chance to do its job.

      Like
      • Dan Nave
      • Dan_Nave
      • 3 mths ago
      • Reported - view

      @JGC did you see chuck stanley's comment about the timing of Bioperine ingestion?

      Like
    • JGC Very interesting. I will ask the manufacturer to explain the contradiction. I think that a significant portion of Bioperine sales are for use in compounding with bioflavonoids, so the efficacy of simultaneous ingestion is crucial.  

      Like
      • Dan Nave
      • Dan_Nave
      • 3 mths ago
      • Reported - view

      JGC Correct me if I am wrong, but isn't the enzyme in question, and the action we are looking for, in the intestine?  How are we testing this if it is given intravenously?

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

      Dan Nave 

      I don't know enough anatomy, but it is my understanding that the Perine has to get into the bloodstream to interfere with the production of the digestive enzymes.

      Like 1
    • JGC and Dan Nave This clarifies the mechanism: "The mechanism of action  responsible for the bioavailability enhancing effect of Bioperine® is because a small amount of piperine stimulates the release of catecholamines, thermogenic hormones whose activity is made possible by the presence of cyclic adenosine monophosphate (cAMP) . The thermogenic effect has been localized in the epithelial cells of the intestine that increase the absorption of nutrients. However, the catecholamine-mediated thermogenic response is relatively short. Therefore, the window of absorption has a narrow temporal scope. These thermogenic properties may explain how a minimal amount of BioPerine® can produce such a powerful effect on the uptake of serum nutrients"

      Like 1
    • JGC Piperine acts as a bioenhancer both in the Gastrointestinal tract and in the liver and in othter metabolic processes responsible for the elimination of substances:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634921/

      From: Bioavailability enhancers of herbal origin: An overview:

       

      " 6.1. Mechanism of action of piperine
      Different mechanisms for the bioenhancer activity of piperine have been proposed including DNA receptor binding, modulation of cell signal transduction and inhibition of drug efflux pump[29].

      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.

      Some other suggested mechanisms include making target receptors more responsive to drugs, acting as receptors for drug molecules, increasing GIT vasculature by vasodilation to increase absorption of drugs, modulation of the cell membrane dynamics to increase transport of drugs across cell membranes[33].

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

      Staffan Olsson  @chuck_stanley

          OK, to summarize, it would appear that the short-duration (~15 minute) bio-enhancement effect of taking Bioperine is that it stimulates gut cells to release catecholamine hormones that stimulate the nutrient-absorbing epithelial cells of the gut to briefly go into overdrive, increasing the absorption of flavenoids.  The long-duration (~8 hour) bio-enhancement effect is that piperine gets into the bloodstream and travels to the liver, where it turns down the first-pass elimination there of flavenoids that have made it to the bloodstream.

          The conclusion seems to be that taking Bioperine with (or perhaps 5 minutes before) flavenoids like Fisetin, Quercetin, Curcumin, and others has the best effect on enhancing bioavailability, but taking Bioperine an hour before the flavenoids (as had been our practice) would do some good.  We will accordingly modify our senolytic protocol.

      Like 1
    • JGC  What you write should be about optimal, at least according to what the research  can tell us now. 

       

      There is an obvious advantage of using piperine, this since it makes it possible to use exact doses every time. But when it comes to apoptosis and cell cycle arrest, black pepper has other advantages. In theory the other effects could be beneficial in a senolytic treatment.  

       

      https://www.mdpi.com/2072-6651/12/12/747/htm

      "Overview of the Anticancer Potential of the “King of Spices” Piper nigrum and Its Main Constituent Piperine"

       

      Like
      • Dan Nave
      • Dan_Nave
      • 3 mths ago
      • Reported - view

      I just wanted to post this again separately as I think it is a good compromise for incorporating a protocol of dasatinib, quercetin, fisetin and bioperine.

      I just did another protocol this week as follows.  I wanted to do both the Dasatinib + Q and the Fisetin + Q instead of doing two separate protocols.  What I ended up doing was taking 100mg of Dasatinib with 500mg of Quercetin in the morning, either before or after I had eaten.  In the evening, on an empty stomach, I took 1500mg of Fisetin and 1000mg of Quercetin all mixed in olive oil with a couple of 10mg pills of bioperine (piperene).  I did this for 3 days in a row.  (I am 69 and about 175kg)

      The reason I separated them like this is that I did not want to potentiate the effect of the Dasatinib as I am somewhat leery of getting too high a dose of that, but I wanted to potentiate the Fisetin/Quercetin so that it was absorbed better. 

      With this protocol the only real side effects were some headache from the Dasatinib, and some slightly loose stools on the fourth day rather than the all day diarrhea that I had experienced earlier after 2 doses of Dasatinib at 200mg and Quercetin at 1gm with bioperine...

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      • GEdwards
      • GEdwards
      • 3 mths ago
      • Reported - view

      Dan Nave hello, after some research I've found that bioperine potentiates flavanols.... Like fisetin and Q. The primary way to potentiate Dasatinibis taking it with grape fruit juice (white works best, not pink). But separately the dosing is not generally needed unless you continue to take the large dose of Dasatinib instead of half in the am and the other in the pm.  You might try just splitting it all am and pm.  The GF juice does not potentiate Q or Fisetin but it certainly does for the D!  Be careful with other meds you take as the GF juice effect lasts about 12 hours but only affects certain meds.  If you have other meds search their names with ' and Grapefruit juice' .

      Like
  • For anyone concerned about BPH or prostate cancer here is an interesting artlcle related to possible benefits of fisetin as a treatment. There is a lot of medical detail, but the essence of it is that fisetin seems to help increase high molecular weight HA and lower low molecular weight HA. The human dose noted near the bottom of the article looks like (1.5–2g/day) as dietary supplement. https://academic.oup.com/carcin/article/37/9/918/2450013

    Like
      • Jay Orman
      • Jay_Orman
      • 3 mths ago
      • Reported - view

      Jay Orman Addition to my note about BPH: The article mentioned did not have any reference to senolytic activity which I found interesting.  

      Like
    • Jay Orman There are many ways to improve prostate health with natural substances.

       

      To name a few: Grape seed extracts, quercetin in combination with green tea and gamma tocotrienol. Broccoli extracts+curcumin+green tea+pomegranate. And yes Fisetin is one. 

       

      After all a long life come with an increased risk of prostate related issues that might need to be managed. So the forum might use a special section for sharing information about this area.

      Like
  •     There is a paper to be presented at the upcoming meeting of the American Aging Association (July 20-23) in which the researchers do one single dose of D+Q senolytics (D: 5 mg/kg + Q: 50 mg/kg) on aging nonhuman primates (species not specified, but I suspect they are chimps).  They report that the senescent cell burden in the fat cells in their subjects showed a "24% reduction ... which rebounded at 1 month."

        This is relevant to the question of how often one should do senolytic sessions.

    Like 3
    • JGC 

      Here is the link to the paper you mentioned that was presented at the American Aging Association yesterday. (Titled: Senolytics reversibly improve metabolic health in nonhuman primates). Dramatic improvements were found after a single D&Q dose (5mg/kg dasatinib and 50mg/kg quercetin) as shown on a number of metabolic measures, including A1c and lipid profile as well as adipose tissue senescent cell accumulation.

      https://whova.com/embedded/subsession/aaaa_202108/1784597/1796606/?view=

      Like
  • After reading most of the comments I ordered Fisetin and Bioperine and will start some sessions. I think D is too expensive for me right now and I am not so sure about the quality of a similar product made in India .  I plan to do 2 days per month of 2g Fisetin with Bioperine and black tea. So my questions are: Is it ok to start right away with 2g a day or should I start with lower dosage? Do I have to be careful what else I am supplementing that day ? Is there any advantage/disadvantage between the daily or monthly protocol? Is it better to take Fisetin on an emoty stomache ? I know there is no real study about the things I am asking but maybe you can just share your experience . Thanks in advance 

    Sebastian 

    Like
      • Dan Nave
      • Dan_Nave
      • 3 mths ago
      • Reported - view

      Sebastian I like to take it on an empty stomach, but I add 1 Tablespoon of oil and mix the fisetin into it.  I don't have data to say taking it on an empty stomach is better, but I suspect it gets absorbed faster and more completely that it would mixed with a stomach full of food.  Fisetin is oil soluble but not very water soluble so that is why I add the oil.  I also add some bioperine or 1/2 tsp of ground black pepper.  (Yeah, it tastes terrible...)  It seems to have worked well for me.  I would suggest not taking any other supplements those days so they don't interfere with the action of the fisetin.  Maybe even stop supplements the day before and the day after.

      You might want to take 1 capsule only at first to make sure you don't have any sensitivities to fisetin or bioperine.

      Like
  • So, just asking... If bioperine made a substantial difference in fisetin absorption, why don't we see formulations for sale? Bioperine is cheap so it's doubtful a cost issue. Life Extension doesn't use it. Mayo didn't use it in their studies. ??  

    Like
      • Dan Nave
      • Dan_Nave
      • 3 mths ago
      • Reported - view

      Allen I'm glad they don't add it.  If they added 10mg of Bioperine to each 100mg capsule of fisetin you would be getting way to much since you would use 10 or more capsules at a time.  Better to add the amount you want separately.

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

      Allen 

          Papers in the literature indicate that BioPerine greatly enhances the bioavailability of the flavonoid Curcumin (which is contained in turmeric).  Curcumin, like the other flavenoids, has a small solubility in water leading to its low bioavailability, and digestive enzymes break it down fairly fast.  The BioPerine speeds its absorption and suppresses breakdown enzymes made in the liver, boosting the effectiveness of Curcumin.  It's an extrapolation to assume that other flavonoids like Fisetin and Curcumin are boosted by BioPerine in the same way, but I think it's a reasonable assumption.

          I note that Life Extension offers another way of boosting the bioavailability of Fisetin, Quercetin, and Curcumin, by coating the granules with fenugreek fiber to protect against digestive breakdown.  This is claimed to boost the bioavailability by a large factor.  The technique was invented by pharmacists in India to make Curcumin more bioavailable.

      Like 1
      • Dan Nave
      • Dan_Nave
      • 3 mths ago
      • 1
      • Reported - view

      JGC I am considering the possibility that using 1/2 tsp of freshly ground black pepper may be superior to using Bioperine.  Previous discussion indicated that the effect bioperine may last for 15 minutes.  Perhaps, like most refined products the bioperine is assimilated quickly and used up quickly.  The ground black pepper I would expect to take more time to be absorbed and may therefore act over a longer period of time allowing more fisetin, etc, to be absorbed.  I did notice a much stronger reaction when I took doses of F, Q, and C, when I took the 1/2 teaspoon of black pepper than when I took it with several pills of bioperine.  Of course, this is just preliminary conjecture on my part, but I think the next time I will try the black pepper with my F + Q...

      Like 1
    • Dan Nave I haven't been able to find any study that shows the amount of increased absorption of fisetin that is provided by piperine or Bioperine. I spoke to a scientist at Sabinsa and he guessed that based on fisetin's structure,  the effect of Bioperine would be similar to to the effect on pterostilbene, about a 2.27 fold increase. But the effect is dose-dependent. So I scaled up from the mouse study that used piperine  with resveratrol to get an enhancement of 229%. I calculated that for me at about 66 kg, I will expect an effective dose of 2000 mg fisetin if I coingest 1000 mg fisetin with 5mg Bioperine. Actually, I take 500mg each of F&Q on day 1. I do take the dasatinib separately, early in the day and the flavonoids about 5 hours later. On day 2 of my D&Q&F cocktail I take an additional effective dose of 1000mg of just fisetin. that seemed reasonable and I havent had any side effects. 

      Like 2
  • Bioperine is to (flavonoids) Tumeric or Fisetin etc what white grapefruit juice is to Rapamycin or Dasatinib......about a 3x increase in bioavailability.....  Grapefruit juice interacts with many other meds and the effect lasts upwards from 11 to 18 hours....so use caution when taking other meds with GF Juice.  Cut back on the recommended Dasatinib when taking with GF Juice.

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

      GEdwards GEdwards ARE YOU saying that pink grapefruit juice does not work vs white.

      Like
  • "Colored (pink and red) grapefruit pulp contains lower amounts of the furanocoumarin derivatives that cause pharmacokinetic interactions than white grapefruit pulp " ( https://pubmed.ncbi.nlm.nih.gov/18771009/ )

    Both work.....but white version works better.

    https://www.scientificamerican.com/article/grapefruit-juice-improves/#

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

      GEdwards The last line of the article reads, "Thus, colored grapefruit juice may produce drug interactions at the same rate as white grapefruit juice." May or may not is the operative word here.

      Like
  • Hi All,

    I’m looking for the link, recently posted, to a paper covering Fisetin and it’s excellent cancer fighting capabilities. It was on some .gov site as I recall. 
    Thanks !

    Like
  • I just heard that quercetin with a bio-available zinc does the same as HCQ in that it escorts the zinc into the cell to kill viruses.    Maybe off topic but thought you might like to know.   It's to be taken as a preventative.   Amazon is now selling them together in one supplement.

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