Fisetin Failed In The ITP Trial. Was It The Dosage?
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- Опубліковано 8 лип 2024
- Here we review the result for fisetin in the recent ITP paper. Fisetin, a senolytic, did not extend median or total lifespan in the mice and also did not clear the senescent cells. We look at the data and doses used.
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Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used
link.springer.com/article/10....
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#fisetin #senolytics #itp - Наука та технологія
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Richard, I think ITP paper says "Also, we were not able to reproducibly detect Fis in the plasma of the treated mice". I do not know if this point is explained. The problem may not only be dosage but delivery method, e.g. In fat. I think they should have clarified the bioavailability of fisetin before reaching the conclusion that it is ineffective.
Good point ✅. Was this study designed to fail❓
Hi thanks for sharing. Yes, I saw this and should have commented on it. As you point out, it may be the delivery mechanism though according to Dr Richard Miller the ITP consults with the sponsor of the intervention to understand how it is delivered so it should be similar to that used in the earlier trials.
I have a couple of questions.
1) In older people, what percentage of senescent cells reappear after 4-6 weeks? Also, how long until the percentage of senescent cells are back up to what they would be if Senolytics hadn’t been used?
2) Fisetin isn’t very absorbable. Has anyone measured absorption comparing fisetin soaked in oil vs not?
Hi Julia, thanks for your questions. Unfortunately, at least in humans I don't think we know. We discussed this with Dr Campisi and Dr Kirkland. Dr Campisi thought that it took longer and suggested a senolytic once a year might be enough. However, I think the main thing is we do not have a good way of measuring senescent cells in vivo in humans. The Mayo Clinic is at the forefront of this research and they use a timing of once a month.
I could not find studies on this. In the ITP the fisetin was included in the chow, which should contain some fat. However they did say that they could not detect fisetin in the blood. So, either it was being cleared quickly or not absorbed.
Agreed - the dose they used was about 1/4 of whats in the Mayo clinical trial, once the correction for mouse metabolism is made. The Mayo protocol was amended though. Now Dr Kirkland is giving the dose for three days in a row instead of two. I would assume it's because he wasn't seeing an effect. That's a shame if Fisetin won't work - it's so cheap and non toxic. I also have some grape seed extract but don't know if that does anything either.
Hi Paul, thanks for sharing and mentioning the 1/4. I should have explicitly covered that in the video as well. Interesting that the Mayo is going up to three days in a row. Though most of the studies are meant to be placebo controlled so Dr Kirkland should not know whether it is working or not until the trial is over!
Very interesting, Richard!
This is vital information. Thank you, Richard.
Hi thank you!
Why would you assume senolytics would extend lifespan? If they are successful in removing senescent cells (not proven in this trial to my knowledge, although happy to be corrected), then those destroyed cells would then require replacement. Therefore I'd expect senolyitcs to improve aspects of healthspan, but not lifespan necessarily.
Senescent cells produce SASP chemical which induces senescence in other cells. So there is a theoretical rationale.
Replacing destroyed cells has to happen anyway.
How well it happens depends on the transit amplifying and stem cell pools available.
Replacement does not therefore imply no improvement in lifespan is possible with senolytics.
@@coffeebreakchat2450 There is no need to use higher dosages as this will harm the body. Moreover, the tendency to clear senescent cells is also observed with low dosages of fisetin. Why didn’t the animals live longer? They were probably given the drug too often. A small number of senescent cells must remain to promote cell proliferation with their secretions.
@coffeebreakchat2450 no those cells would not necessarily have been replaced, atleast not on that (short) timescale. Hence you'd expect a short term improvement from forced replacement, but long term, all bets are off,.as it depends on the balance between removing SASP, depleting stem cell pools, and other factors. My point is that a negative lifespan result does not necessarily imply improper dosage but could be expected as per my explanation, and no one is discussing this.
@@WillowUfgood
I agree that there are indeed many variables to consider here.
There is clearly a route in principle, however, for senescent cell removal to have a beneficial long term effect on the organism. After all, that's what happens in youth with an effective immune system.
Done right, senolytics can just clear the accumulated senescent cells that should have been removed anyway under optimal biology.
Hi Willow, thanks for your comment. I do think that the question of whether reducing senescent cells would extend lifespan was not addressed in this result. The fisetin did not appear to reduce the senescent cell burden so we don't know whether it would have helped or not. Why fisetin did not do this is a matter of speculation. I think it would be great to try a higher dose in the intermittent group but all we know is that the current dose did not work and cannot say that a higher dose would work.
In terms of reducing senescent cells, I think it makes sense that removing them would help extend healthspan, which would probably extend at least median lifespan.
Thanks Richard.
Hey Ron, thanks!
Shouldn't the phenyl-butyrate have been given to fiber-deficient mice, since bacteria make butyrate? Or are these molecules unrelated?
ITP made mistakes in their assessment of resveratrol.
They asserted resveratrol could not extend lifespan in mammals.
MIce overwhelmingly die of cancer.
Humans die of many problems, and significantly less of cancer than mice. Resveratrol has minimal effect on cancer risk but profound ones on cardiovascular risks.
Hence, it does not follow that lask of life extension in mice implies lack of life extension in other mammals or Humans.
Several researchers question dosing in the resveratrol ITP study (too high!) and timing in life (too late?) .
Here we have ITP results in conflict wih other studies. ITP may not be the gold standard it aspires to be.
How was Fisetin assimilarion guaranteed? Same as in Mayo clinic?
Isnt Fisetin senolytic in combination with Quercetin?
Maybe single variable testing is flawed here; only synergies with other supplements produces powerful senolytic effect.
Can you comment on the Resveratrol study that improved cardiovascular results? Based on several doctors review of published studies. Resveratrol had no impact. Hence my interest in your claim.
Hi thanks for sharing. These are good points. The ITP has some specific good points, (multiple locations, genetic diversity) but is still "just" another trial. Certainly the point that because something does or does not work in mice does not mean it will or will not work in humans (which is something that Dr Richard Miller of the ITP also says). So I see it as another data point to be viewed along with the results of other studies.
@@keng7758
I will have to consult my notes.
As I recall the latest understanding is that low dose resveratrol is a senomorphic, restoring some of the functions of previously senescent cells.
@@ModernHealthspan
I have massive respect for ITP and the heavyweight academics behind it.
Its a fantastic undertaking that will provide a great deal of longevity data. However that doesnt mean we should uncritically accept everything it asserts. The devil is often in the detail!
Thanks, Richard - excellent analysis. I'm currently taking the Novos Core product which has 100mg Fisetin daily - obviously too low according to this work. I'm going to consider a larger cyclic dose now.
Disappointing, it’s an expensive product
Hi Ken, thanks for sharing. I would agree with your assessment.
or maybe do not take unproven supplements, which are 99% of them
@@juicebox853 NOVOS Core actually has many studies completed on it, some showing positive benefit
Fisetin dosing seems to be a bit of a guessing game. I think David Sinclair and Bryan Johnson take 500mg as a maintenance dose, which seems reasonable, even though some manufacturers state double this for a daily dose. It makes sense to do a flush and a rest every now and again too.
David Sinclair is a known fraud
PS One more thing on dosing. The astaxanthin trial was done with a very high dose and again no explanation as to why they chose that level and no human equivalent. It would be helpful to know what the least effective dose was. They should have at least run another arm which was closer to normal intake and what typical supplements contain.
Hi Peter, thanks for your comment. The fisetin dose coming out at a reasonable number gives me more confidence that the astaxanthin calculation was correct, which would indeed imply a large dose. It would be interesting to see if a lower dose had the same effect.
@@ModernHealthspan Would 12 mg of astaxanthin be considered high dosage?
Important video.
Thanks!
I thought the results of the large mayo clinic fisetin study were to be published by Dec 31 2023?
The ITP should have used it liposomally. Ordinary fisetin has terrible bio-availability into tissues and organs.
At approximately what age would one start on Fisetin? Would under age 60 be too early to start?
Hi John, thanks for the question. I think that the senescent cells build it before 60, though it also depends on health and metabolic status.
Just to clarify, for intermittent usage, it’s two days in a row every two weeks?
Hi John, thanks for the question. In the ITP trial, it was 3 days in a row every 2 weeks. The Mayo Clinic trial (clinicaltrials.gov/study/NCT03430037#study-plan) is using 20mg/kg for 2 consecutive days for two consecutive months.
@@ModernHealthspanCan you share your fisetin regiment? Thanks.
the failure of butyrate is sign of overhype in microbiome therapy ?
Hi thanks for the question. I think that they tested butanediol, a precursor to butyrate and it did not extend lifespan. I asked Dr John Newman, as one of the people studying ketones about this (ua-cam.com/video/xhQap-QSG3k/v-deo.html). Though I see it more as a test of ketones than of the microbiome, but you could be right.
The itp used relatively young mice. Younger mice carry a low senolytic load and are unlikely to have no benifit. Why not use older mice? Hmm
There seems to be an epidemic of poorly designed studies going on out there by people intelligent enough to know better. I have finally hit on monthly doses of 1,600 mg (4x 400mg) per day for three days in a row. In for a penny, in for a pound 😊.
You need to keep in mind that it’s just possible that Fisetin, like Resveretrol, don’t do anything for human health.
We know that we do not know anything...