1079 replies to this topic

[OP2040]

All good questions John,

And the answer to most of them is that we just don't know for sure

 

1.There's tons of information out there on Fisetin at successive low doses, but that will not clear SCs.  Successive high doses will, but I think people are overestimating how soon a second dose would be needed under ideal circumstances.

2.600mg is probably the bare minimum for removing SC's based on the study we are trying to mimic.  I don't know where the 20-50% figure comes from but if that can be achieved it would be great.  I would say at that low a dose 6 months may be appropriate.  But then why not 1000-1500mg and only once a year, which will be my plan.

3.There is no need to fuss about residual SCs.  Young people have SCs too, it is only the excess SCs that start to cause problems.  There aren't going to be any hard and fast numbers, you just have to make educated guesses.  If we could develop some metrics for how many SCs we have, then how many have been removed, it would change everything.  But I don't see anything out there that's feasible at the moment.  Even a rough ability to measure SASP would be a game changer here. 

4.Don't quote me on this but I think that SCs are somewhat heterogeneous, although the differences don't seem to matter much for clearance purposes.  Most senolytics have done a pretty good job of getting a lot of them removed at least in some tissues.  There are cells characterized as quiescent, which I think are somewhere in between a viable and SC.  Who knows if these are targeted or not.  For humans, this is still more art than science.

[OP2040]

I found a staining kit for SA-B-Gal

https://www.cellsign...aining-kit/9860

 

But I have absolutely no idea how assays are supposed to work.  Does anyone know?  Is it as easy as a blood drop?  If so, then that would make it doable for senescence markers in blood, and therefore a metric? 

 

Here's a good breakdown of the process:

https://www.ncbi.nlm...les/PMC5565152/

Edited by OP2040, 12 October 2018 - 06:00 PM.

[QuestforLife]

Is there any information/study on successive dosing with fisetin? It was reported (someplace here) that it eliminates 20%-50% of senescent cells in various tissues. I have taken 600mgs per day for 5 days and hope that it will eliminate at least some of the SCs. If I then take a repeat dose of 600 x 5 in six months time will it remove the same proportion or is there something special about the SCs that it removes, making the remaining SCs difficult to get rid of? Do SCs go through stages with only some stages being susceptible to removal?

If you read the paper that started this thread there is a graph with senescent cell accumulation at different ages for treated and untreated (age accelarated) mice. Even the repeat treated mice continued to accumulate senescent cells, but at a much slower rate. This suggests to me that there are some senecent cells that fisetin will never remove, but that repeated (occasional) doses are still worthwhile, to destroy the proportion of faulty cells that are susceptible.

[OP2040]

QuestforLife,

 

You're right.  After looking at that graph, dosing every couple weeks for the mice seems to be beating back the senescent cells quite effectively.  However, they still accumulate at a slower rate. In light of that a more aggressive approach may be even more helpful.

 

However, there is the issue of comparing mice and human ages.  If you translate 1:1 mouse to human years, the situation looks much more drawn out.  Two week intervals in mice is equivalent to 1.5 year intervals in humans.  And the span of interventions is from 4.1-16 weeks, which would be 3 years to 12 years.  And therein lies the problem with that graph, it's the one for progeroid mice.  I don't see an age graph that calcs senescent cells for the other, more exciting, interventions, but the same rule of thumb holds.  Two week interventions would be 1.5 year in humans.  I really don't know if it's exactly 1:1 like that, but you probably can't say two weeks of a mouse like is two weeks of a humans life.

 

So back to the idea of mega-dosing once a year if you want to mimic this study.  However, it does look like more interventions and more dose could be even better if you extrapolate from the data, but the study doesn't actually show that.

[extendcel]

What I see is reviewing the literature is successful in vivo and in vitro formulations of fisetin with significant bioavailabilities over free fisetin, so the question, "Why are these not produced commercially?"

https://www.research...itumor_efficacy

"In vivo, liposomal fisetin allowed a 47-fold increase in relative bioavailability compared to free fisetin."

https://www.scienced...928493116306117

"when the fisetin nanoemulsion was administered intraperitoneally, a 24-fold increase in fisetin relative bioavailability was noted, compared to free fisetin. Additionally, the antitumour activity of the fisetin nanoemulsion in Lewis lung carcinoma bearing mice occurred at lower doses (36.6 mg/kg) compared to free fisetin (223 mg/kg)."

https://www.ncbi.nlm...pubmed/27524059

"Results showed NPs having a mean diameter of 140–200 nm, and a percent loading of FS ranging from 70 to 82%. In vitro release studies revealed that NPs are able to protect and preserve the release of FS in gastric simulated conditions, also controlling the release in the intestinal medium. Moreover, the DPPH and ABTS scavenging capacity of FS, as well as α-glucosidase inhibition activity, that resulted about 20-fold higher than commercial Acarbose, were retained during nanoencapsulation process. "

Like I said before, it just isn't commercially viable. These nanoparticles are out of the question because the ingredients aren't approved for human use. In addition, the liposomal study used pharmaceutical level synthetic phospholipid variants. I looked at the paper and the concentration for the fisetin is abysmal. It was also injected rather than consumed orally.

For a regular supplement grade liposomal formula, the concentration would be very low and would require a very high volume of liquid. The total quantity of fisetin would be lower than the pill form, but the price would have to be higher. Just the perspective of someone looking to produce liposomal formulas for commercial purposes.

[able]

Just wanted to report back that the 4 grams I took on day 2 were well tolerated.  No noticeable problems.  Slept very well and felt great the days afterwards.

 

I plan on mixing some in DMSO and applying topically to left arm and legs for a few days.

 

Will likely repeat my 3-4 gram dosage in olive oil every month or two unless we get more information.

[stefan_001]

Just wanted to report back that the 4 grams I took on day 2 were well tolerated. No noticeable problems. Slept very well and felt great the days afterwards.

I plan on mixing some in DMSO and applying topically to left arm and legs for a few days.

Will likely repeat my 3-4 gram dosage in olive oil every month or two unless we get more information.

Have you checked the fillers and whether those dissolve? I recall a discussion that some are highly unhealthy to be absorbed in skin.

Edited by stefan_001, 13 October 2018 - 07:18 PM.

[stefan_001]

Its gone silent here. No experiences?

 

Personally I managed to have a severe allergic reaction while cleaning the cellar. In particular lungs reacted somewhat asthmatic and I picked some medication to calm things down. So at least no "permament" improvements to report yet from possible senescent cell removal. Lets see when back at full health.

[OP2040]

I'm about ready to start my experiment.  Second bottle of Fisetin will be delivered today.  Do you think your asthmatic reaction somehow relates to the Fisetin? 

 

These threads usually do die out because people's expectations are through the roof, expecting superpowers or something I dunno.  I don't need to feel anything special when I do my experiment.  As long as there are no adverse reactions, I'm going to incorporate this is my senolytic once a year.  The thing is, humans live for 80 years, that's a looooooong time, so one-time interventions are probably not going to show anything big.  It's the long game that counts.

[Alpharius]

Its gone silent here. No experiences?
 
Personally I managed to have a severe allergic reaction while cleaning the cellar. In particular lungs reacted somewhat asthmatic and I picked some medication to calm things down. So at least no "permament" improvements to report yet from possible senescent cell removal. Lets see when back at full health.

Do you think this could be from Dasatinib?
I am preparing to take Dasatinib (50-75mg) and Fisetin (2000 mg) together in the next days.

[stefan_001]

@OP2040 there could be some link as lungs felt slightly painfull and sensitive after the Fisetin use and hence more prone to reaction. Could be a n=1 type of thing only.

@Alpharius I have not used Dasatinib, only Fisetin

[NoodleHead]

Hi no one seems to have said anything about bromelain.
Quercetin supplements often come combined with doses of bromelain, apparently to increase absorption. Could the same be true of fisetin?
I plan to take 600mg fisetin + 1600mg quercetin+. 500mg bromelain for 5 days and report back here.
I'm a 37 year old man with IBS pain issues, otherwise healthy.
* I'll probably mix this with a small quantity of olive oil for good measure.

Edited by NoodleHead, 21 October 2018 - 06:39 AM.

[NoodleHead]

I'm about ready to start my experiment. Second bottle of Fisetin will be delivered today. Do you think your asthmatic reaction somehow relates to the Fisetin?

These threads usually do die out because people's expectations are through the roof, expecting superpowers or something I dunno. I don't need to feel anything special when I do my experiment. As long as there are no adverse reactions, I'm going to incorporate this is my senolytic once a year. The thing is, humans live for 80 years, that's a looooooong time, so one-time interventions are probably not going to show anything big. It's the long game that counts.

Very true but when you see the images of the mice recieving late life intervention in the D+Q study, it does raise people's expectations somewhat! My 65 year old father and my 85 year old grandmother have expressed interest in trying fisetin. They probably have a better chance of seeing improvement than me. I will give an update if they go through with it.

Edited by NoodleHead, 21 October 2018 - 08:09 AM.

[extendcel]

Hi no one seems to have said anything about bromelain.
Quercetin supplements often come combined with doses of bromelain, apparently to increase absorption. Could the same be true of fisetin?
I plan to take 600mg fisetin + 1600mg quercetin+. 500mg bromelain for 5 days and report back here.
I'm a 37 year old man with IBS pain issues, otherwise healthy.
* I'll probably mix this with a small quantity of olive oil for good measure.

Bromelain doesn't seem to have any properties that may help with bioavailability. It supposedly has anti inflammatory effects so that is likely why it is paired with quercetin.

I'd also like to mention piperine, which is a potent inhibitor of hepatic enzymes. Piperine combined with quercetin seems like it would significantly boost the bioavailability of fisetin.

[William Sterog]

I have found three interesting effects with this new intermittent use of higher Fisetin doses. The first is the only one that I consider adverse, and it is, I insist, that it seems to act as an antiandrogen, something that is backed up by the research that I posted here before; the two others, that may well be the same, are that I found long lived anti-inflammatory and pro-cognitive effects after fisetin use, specifically the sense of well-being and the mental clarity last at least three or four days after stopping the intake.

[stefan_001]

I have found three interesting effects with this new intermittent use of higher Fisetin doses. The first is the only one that I consider adverse, and it is, I insist, that it seems to act as an antiandrogen, something that is backed up by the research that I posted here before; the two others, that may well be the same, are that I found long lived anti-inflammatory and pro-cognitive effects after fisetin use, specifically the sense of well-being and the mental clarity last at least three or four days after stopping the intake.

 

https://www.ncbi.nlm...les/PMC2954499/

A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice

 

Could well be this is not selective for tumor cells but generic.

[NoodleHead]

Bromelain doesn't seem to have any properties that may help with bioavailability. It supposedly has anti inflammatory effects so that is likely why it is paired with quercetin.

I'd also like to mention piperine, which is a potent inhibitor of hepatic enzymes. Piperine combined with quercetin seems like it would significantly boost the bioavailability of fisetin.

 

Well someone appears to have started a rumour that it does as there are numerous claims to this online. I tried to find a better reference.

 

https://vitanetonlin...hread/412#bmeqa

 

There is one at the end of this article.

 

"Studies have shown that bromelain enhances absorption of antibiotics, presumably by increasing permeability of the gut wall.23, 24 Given that quercetin is a low molecular-weight compound, it is plausible that simultaneously ingested bromelain likewise enhances quercetin absorption."

 

A bit tenuous I know but at least I didn't make it up

Edited by NoodleHead, 22 October 2018 - 08:38 AM.

[tunt01]

 

 

Fisetin activates SIRT3 longevity pathway in vitro.  I remember seeing it come up a few times when I was reading about SIRT3, urolithin A/NAD+.

 

SOD2 activity was naturally upregulated.  [fig 2]

 

GSH/GSSG ratio improved.  [fig 5]

 

 

Zhao, C., Sakaguchi, T., Fujita, K., Ito, H., Nishida, N., & Nagatomo, A. et al. (2016). Pomegranate-Derived Polyphenols Reduce Reactive Oxygen Species Production via SIRT3-Mediated SOD2 Activation. Oxidative Medicine And Cellular Longevity, 2016, 1-9. doi:10.1155/2016/2927131

 

[ryukenden]

I took 300 mg of Fisetin today and play to take it for 3 days.

[eigenber]

Not sure if this article belongs on this thread, but...

http://www.anti-agin...n-and-the-sasp/

 

Especially this section:

A caution about senolytic approaches to health and longevity

A key point in the last quote, also emphasized in many other articles, makes me question the wisdom of senolytic approaches advocated by some antiaging researchers, which is simply to extend health and life by getting rid of senescent cells. At best, these senolytic approaches by themselves may be too simplistic, and at worst they might be harmful by removing senescence triggers of cell rejuvenation. The garbage heap of dysfunctional therapies based on “getting rid of the bad stuff” already has many things heaped on it, including bloodletting to get rid of “bad humors” in the blood and colonic irrigation and enema therapies to get rid of “rotten matter in digestive track.” I wonder if senolytic therapies might be headed for the same garbage heap. On the other hand, if there is so much expression of the SASP so as to cause the above-mentioned cell-intrinsic senescence arrest, then conceivably a companion senolytic approach might be useful.

 

 

[brundall]

Here's a potentially stupid question and an observation from the study.....

 

From the original text of the study it appears that Fisetin has a rapid half life of 0.09 hours (or 5.4 mins) and a terminal half life of 3.1 hours (or 186 minutes). Could someone with more knowledge than me explain what these two half life terms mean in laymans language? and....

 

does this mean if you took a 500mg dose of Fisetin (and you absorbed 50% of it....250mg) then it would remain in your system, albeit at a tiny amount, for more than 24 hours? Would this not 'build up' over time to a significant amount if you took it everyday?

 

186 mins 125 mg (3.1 hours)

372 mins 75 mg

558 mins 37.5 mg

744 mins 18.75 mg

930 mins  9.375mg

1116 mins 4.6875 mg

1302 mins 2.34375 mg

1488 mins 1.171875mg (after almost 25 hours)

 

 

and now an observation....from the text it appears that 'Fisetin reduced the fraction of senescent T and NK cells (which) could help amplify the beneficial effects of Fisetin, since healthy immune cells are important for clearing senescent cells'...that's pretty cool isn't it? Fisetin increases the percentage of healthy killer cells thereby removing more senescent cells by the bodys own immune system rather than the direct action of Fisetin itself.

 

 

[ryukenden]

Just wanted to report back that the 4 grams I took on day 2 were well tolerated.  No noticeable problems.  Slept very well and felt great the days afterwards.

 

I plan on mixing some in DMSO and applying topically to left arm and legs for a few days.

 

Will likely repeat my 3-4 gram dosage in olive oil every month or two unless we get more information.

 

How much Fisetin are you dissolving in DMSO?

[Harkijn]

Always interesting to read Josh Mitteldorf's opinions:

https://joshmitteldo...cienceblog.com/

[Nate-2004]

I only find one brand claiming to be relatively pure fisetin and that's Doctor's Best brand. 100mg per cap. Josh's suggested human equivalent dosage is on the upwards of 1.5g which would mean taking 15 of the 30 in the bottle. I mean, do we even know how the bioavailability compares to quercetin's? Quercetin has horrible bioavailability bordering on utterly useless.

[Linx]

The second most effective senolytic in the paper was curcumin, and there are already bio-available formulations of curcumin available. Perhaps we should give curcumin a try.

[Kevnzworld]

Re :

A caution about senolytic approaches to health and longevity
A key point in the last quote, also emphasized in many other articles, makes me question the wisdom of senolytic approaches advocated by some antiaging researchers, which is simply to extend health and life by getting rid of senescent cells. At best, these senolytic approaches by themselves may be too simplistic, and at worst they might be harmful by removing senescence triggers of cell rejuvenation. The garbage heap of dysfunctional therapies based on “getting rid of the bad stuff” already has many things heaped on it, including bloodletting to get rid of “bad humors” in the blood and colonic irrigation and enema therapies to get rid of “rotten matter in digestive track.” I wonder if senolytic therapies might be headed for the same garbage heap. On the other hand, if there is so much expression of the SASP so as to cause the above-mentioned cell-intrinsic senescence arrest, then conceivably a companion senolytic approach might be useful.

That’s why we follow the published peer reviewed scientific studies....to avoid useless therapies and ideas.
The study that began this thread and the ones before it validate the concept of senolytics being a useful anti-aging tool.
Obviously more study needs to be done, but what we now know is at least encouraging.

[Nate-2004]

To compare attempts to eliminate death resistant senescent cells, or even to compare our current, evidence based understanding of cellular senescence and its effects on surrounding tissue, to the medieval, ignorant era of made up nonsense like humors and rotten matter or "toxins", is obnoxiously absurd and on the extreme end of pessimism, ignoring all the differences. For the record, humans have tried to cure many things in the 18th century that they can easily prevent, treat or cure here in the 21st.

 

I'm not referring to fisetin here, but I am referring to legit attempts to study and experiment with synolitics in clinical trials.  It's fine to be skeptical but this is completely dismissive of the facts.

 

Sure, nobody knows what fisetin can do in vivo or how easily it gets to where it needs to be in terms of targets when taken orally or otherwise. It warrants investigation though, hopefully Unity looks into this as well. This doesn't mean synolitics are doomed, jeez. 

Edited by Nate-2004, 24 October 2018 - 02:24 PM.

[mikeinnaples]

I only find one brand claiming to be relatively pure fisetin and that's Doctor's Best brand. 100mg per cap. Josh's suggested human equivalent dosage is on the upwards of 1.5g which would mean taking 15 of the 30 in the bottle. I mean, do we even know how the bioavailability compares to quercetin's? Quercetin has horrible bioavailability bordering on utterly useless.

 

Swanson and Doctors best both appear to be using Novusetin as the source? I trust those brands as much as you can trust a brand. I am curious about the powdered Fisetin I see available on Amazon and what I suspect some people here are using, regarding purity/COAs etc.

[OP2040]

I think we all know that senolytics are not the answer to aging.  Things like senolytics are a really important stepping stone.

 

I started my trial yesterday:

Started @ 1gram Fisetin, along side curcumin (with bioperin) and a  swig of olive oil.  I will go a bit higher now for the final three days, maybe 1.5grams.

I plan to do this routine every 6 months.

 

Nothing good or bad to report so far without delving into complete speculation.  Actually I do have one thing to report but it's a bit personal.  Ahh what the hell, this is for science.  You know the thing that dudes in their 20s wake up with every morning.  Well, that happens to me very rarely these days, but all the sudden.....

 

 

[JR7]

Do you folks feel there would be some auophagy synergy with combining fisetin and extended (5 day) fasts?