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Fisetin: Senolytic!

fisetin senolytic

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#31 QuestforLife

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Posted 03 October 2018 - 03:00 PM

Makes you wonder how many anti-aging compounds are out there, but perhaps humans have a much more restrictive bio-availability than mice.  That would make sense because mice seem to have a telomeric strategy which allows them to take many more hits of damage to their cells and mostly they die of cancer, whereas humans have other strategies where we are more susceptible to chemical or other types of damage, and a much more advanced filtering system is needed.

 

It's just differnt biochemistry. Both humans and mice get rid of resveratrol quickly, but only humans get rid of fisetin so quickly (apparently). Off topic but other exampes include Methylene Blue, which is bioavailable in humans, but not in dogs. TA-65 is reasonably bioavailable in mice and rats, but not in dogs or humans.



#32 VP.

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Posted 03 October 2018 - 04:00 PM

A new article by someone who talked to the researchers. They believe Fisetin is a more potent senolytic then D&Q?  Not completely clear from story. These are the same scientists that did the mouse D&Q study in July.

 

New research has revealed that fisetin – a natural flavonoid found in many fruits and vegetables – functions as an effective senolytic agent by clearing out damaged aging cells, improving health and extending lifespan.

When our cells lose the ability to effectively divide and replicate, they generally die and are cleared out by our immune system. But, as we age our immune system becomes less efficient at clearing out these stagnant damaged cells. Called senescent cells, many anti-aging researchers hypothesize the build-up of these cells as fundamental to the development of many chronic age-related diseases.

A great deal of work is currently underway to develop effective senolytic drugs, compounds designed to help clear the body of these senescent cells with the hope of reducing a variety of symptoms we generally associate with aging. Earlier this year a team of researchers revealed a combination of two existing drugs were found to effectively reduce the number of senescent cells in mouse experiments, and extend the animal's lifespan.

The same team has now published a new paper expanding on the previous work, and homing in on better, more potent, senolytic agents. The new research tested ten different flavonoid compounds and discovered fisetin displayed the most potent senotherapeutic effects in both mouse and human tissue experiments.

 

This isn't the first time fisetin has been implicated in beneficial anti-aging effects. A 2014 study in mice engineered to develop Alzheimer's disease suggested the compound prevented progression of memory loss and learning difficulties. At the time, researchers could only hypothesize exactly how fisetin could be preventing the degenerative characteristics of Alzheimer's since it unexpectedly seemed to have no effect on the build-up of amyloid plaques, thought to be the primary cause of the disease.

It is only recently that researchers have started to investigate associations between neurodegenerative disease and the build-up of senescent cells. Just last month a breakthrough study from a team at the Mayo Clinic suggested evidence of a causal link between cellular senescence in the brain and the symptoms of neurodegenerative disease. This new discovery adds to the growing hypothesis that targeting senescent cells in the brain may be an effective strategy in battling dementia.

One of the key innovations in this new research is the utilization of a technology called mass cytometry to directly observe how a given compound functions within an individual cell. This technology, used here for the first time in aging research, allowed the scientists to closely observe whether a tested treatment was effectively targeting specific senescent cells.

"In addition to showing that the drug works, this is the first demonstration that shows the effects of the drug on specific subsets of these damaged cells within a given tissue," says Paul Robbins, one of the researchers on the project.

As well as its ability to function as a potent senolytic agent, the study examined the effects of fisetin on both health and lifespan, particularly when administered at a late stage to elderly mice. The treatment did successfully reduce a variety of age-related pathological biomarkers as well as extend the median lifespan of the animals.

It is important to note that this research is still only in its nascent stages, and currently only verified in mice models. As many scientists can attest, the leap from animal tests to human verification can often be very large. However, the natural origins of fisetin and its significant track record of safety in humans suggest the research should be able to rapidly move into human clinical trials offering further clarity on whether this treatment will offer anti-aging effects in elderly subjects.

"These results suggest that we can extend the period of health, termed healthspan, even towards the end of life," says Robbins. "But there are still many questions to address, including the right dosage, for example."

https://newatlas.com...se-study/56610/

 


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#33 John250

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Posted 03 October 2018 - 06:59 PM

He mentioned divided by 12.3.
Multiplying by (3/37) is approximately dividing by 12.3 anyways.

If you are to take the example you just quoted, you’ll find that 5 divided by 12.3 leads to approximately the same outcome.

That makes sense. If the fisetin study on mice was 100mg/kg then human dose would be approximately 8mg/kg I believe? So if I’m 108kg I would need 865mg fisetin as the dosage for 5 days.

Edited by John250, 03 October 2018 - 07:03 PM.


#34 OP2040

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Posted 03 October 2018 - 08:01 PM

That makes sense. If the fisetin study on mice was 100mg/kg then human dose would be approximately 8mg/kg I believe? So if I’m 108kg I would need 865mg fisetin as the dosage for 5 days.

 

That's exactly what I would want to go with, except I am not sure how to handle the bioavailability problem.  Would it be enough to just take it for a longer period of time, or up the dose 20%... or do we need to get more technical and get our hands on a liposomal version. 

 

I do plan on taking it whether we can answer these questions or not, but they are gonna keep me wondering whether I'm getting that full benefit or not.



#35 smithx

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Posted 03 October 2018 - 09:03 PM

This excerpt from

 

https://www.ncbi.nlm...les/PMC3689181/

 

Sounds rather worrisome (bolding mine):

 

Fisetin was tested for genotoxicity in human lymphoblastoid cell lines, and the cells were analyzed for malsegregating chromosomes as well as for the induction of micronuclei. Olaharski et al. employed the CREST micronucleus assay to discriminate between micronuclei formed from chromosomal breakage (CREST-negative) and chromosomal loss (CREST-positive) in fisetin-treated cells. A statistically significant increase in CREST-positive micronuclei suggested that at low concentrations, fisetin exerted genotoxic effects primarily through chromosomal loss (52). Further studies showed that fisetin is an effective inhibitor of the nuclear enzyme human topoisomerase II-α, essential for DNA replication, and interfered with chromosome segregation during the anaphase and telophase periods of the cell cycle. It was thereby concluded that fisetin acted both as an aneugen (affecting cell division and mitotic spindle apparatus resulting in the loss or gain of whole chromosomes, thereby inducing aneuploidy) and a clastogen (causing breaks in chromosomes, leading to sections of the chromosome being deleted, added, or rearranged). At low doses, fisetin was capable of interfering with proper chromosomal segregation and acted as an aneugen, whereas at higher concentrations, fisetin through effective inhibition of topoisomerase II inhibitor exerted clastogenic effects causing double-stranded DNA breaks in the cells (52).


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#36 QuestforLife

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Posted 03 October 2018 - 09:42 PM

Ciprofloxacin is an antibiotic that works through topoisomerase inhibition and it can cause tendon ruptures.

I'm just speculating here, but maybe the senolytic mechanism of action of fisetin is through topoixomerase inhibition, which I believe generates DNA breaks. Perhaps senescent cells can't repair them (hence apoptosis) whereas normal cells can?

Edited by QuestforLife, 03 October 2018 - 09:43 PM.

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#37 OP2040

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Posted 03 October 2018 - 09:55 PM

Either way I don’t find the fact that it kills cancer cells at all worrisome. It is known for it’s anti-cancer effects, which is probably why they used cancer cells in the study.I assume you are worried that it would also target normal cells? That wouldn’t make much since given that it had such a strong safety profile, even in humans.

Edited by OP2040, 03 October 2018 - 09:56 PM.


#38 VP.

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Posted 03 October 2018 - 10:13 PM

Fight Aging's take on Fisetin dosing:

 

Given that, results from the recent animal study of fisetin noted here greatly exceed expectations, surprisingly so. Fisetin appears about as effective in mice as any of the current top senolytics, such as the chemotherapeutics dasatinib and navitoclax. Per the data in the open access paper below, dosing with fisetin destroys 25-50% of senescent cells depending on organ and method of measurement. The dose level is large in absolute terms, as one might expect for a flavonoid. For aged mice and a one-time treatment, the researchers used 100 mg/kg daily for five days. The usual approach to scale up estimated doses from mouse studies to initial human trials leads to 500 mg per day for five days for a 60kg human.

 

https://www.fightagi...tive-senolytic/


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#39 triguy

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Posted 04 October 2018 - 12:11 AM

This seems like an awfully high dose. That would be 24,250mg for me. I take (2) 100mg caps from doctors best per day. What is the beneficial dosing?

 

 

know a reputable co for fisetin????



#40 John250

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Posted 04 October 2018 - 12:21 AM

know a reputable co for fisetin????


I’ve been using doctors best at 200 mg a day for several months but I didn’t realize you’re supposed to megadose it for only five days out of the year.

#41 OP2040

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Posted 04 October 2018 - 02:24 PM

I’ve been using doctors best at 200 mg a day for several months but I didn’t realize you’re supposed to megadose it for only five days out of the year.

 

Unfortunately, there really isn't any "supposed to" when it comes to these cutting edge therapies.  We're all just trying to make our best judgement based on all the studies available, the vast majority of which are mouse studies.  You can also include how other senolytics seem to work as a guide. 

 

I do think intermittent high doses are probably the way to go for any senolytic.  My biggest question about dosing at this point would be, when do you stop?  There is always the concept of "too much of a good thing".  Most people here are not elderly by any means, so what happens if I do this for the next 30 years.  Is that really necessary?  It would be nice to know if there are any studies on the "rate of accumulation of senescent cells".  That would be an easy calculation to determine how much to take.  The doses in this study were killing ~ 25% of senescent cells.  Lets say we want to be conservative and only periodically kill 75% of them.  If we know that they accumulate at a rate of say 1% a year, we would know when our next round of intermittent dosing should be.  Does anyone know of any studies that assess rate of senescent cell accumulation?

 

We would also have to figure out how eliminating some of them affects the exponential function of the accumulation.  Also, we know there are more in certain tissues than others, but I'm not sure that the rate is different between tissues unless there is a specific tissue-based disease.

 

Some other studies are showing a similar doubling rate of 20 years starting from birth, in various tissues.    I'm not sure what that means for the math on a year to year basis.  But if you are in your 40s like me, it means you have roughly twice as many senescent cells as when you were 20.  Anyone want to attempt to figure out what that means for a Fisetin routine, assuming it works like it does in the study?  It seems to imply that you can do a couple 5 day mega-doses once every 10 or 20 years, which seems too good to be true.

 

Bottom line is that this is still more art than science, though I fully expect that anyone taking Fisetin should benefit, that much is very clear.


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#42 John250

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Posted 04 October 2018 - 03:14 PM

Unfortunately, there really isn't any "supposed to" when it comes to these cutting edge therapies. We're all just trying to make our best judgement based on all the studies available, the vast majority of which are mouse studies. You can also include how other senolytics seem to work as a guide.

I do think intermittent high doses are probably the way to go for any senolytic. My biggest question about dosing at this point would be, when do you stop? There is always the concept of "too much of a good thing". Most people here are not elderly by any means, so what happens if I do this for the next 30 years. Is that really necessary? It would be nice to know if there are any studies on the "rate of accumulation of senescent cells". That would be an easy calculation to determine how much to take. The doses in this study were killing ~ 25% of senescent cells. Lets say we want to be conservative and only periodically kill 75% of them. If we know that they accumulate at a rate of say 1% a year, we would know when our next round of intermittent dosing should be. Does anyone know of any studies that assess rate of senescent cell accumulation?

We would also have to figure out how eliminating some of them affects the exponential function of the accumulation. Also, we know there are more in certain tissues than others, but I'm not sure that the rate is different between tissues unless there is a specific tissue-based disease.

Some other studies are showing a similar doubling rate of 20 years starting from birth, in various tissues. I'm not sure what that means for the math on a year to year basis. But if you are in your 40s like me, it means you have roughly twice as many senescent cells as when you were 20. Anyone want to attempt to figure out what that means for a Fisetin routine, assuming it works like it does in the study? It seems to imply that you can do a couple 5 day mega-doses once every 10 or 20 years, which seems too good to be true.

Bottom line is that this is still more art than science, though I fully expect that anyone taking Fisetin should benefit, that much is very clear.


If absorption is an issue wouldn’t be best to order it in rolled powder add some bacteriostatic water and inject it?

#43 Rocket

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Posted 04 October 2018 - 03:22 PM

That makes sense. If the fisetin study on mice was 100mg/kg then human dose would be approximately 8mg/kg I believe? So if I’m 108kg I would need 865mg fisetin as the dosage for 5 days.

 

I for one do not believe in the conversion ratio for mice & men. That's why when I run Dasatanib, I run it 100% to scale of what the mice were administered. That's probably why when I run it, I get the flu-like symptoms for a day... because its working.


Edited by Rocket, 04 October 2018 - 03:23 PM.

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#44 OP2040

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Posted 04 October 2018 - 03:56 PM

I for one do not believe in the conversion ratio for mice & men. That's why when I run Dasatanib, I run it 100% to scale of what the mice were administered. That's probably why when I run it, I get the flu-like symptoms for a day... because its working.

 

I agree that it is not really known how to convert, it is more of a guess IMO.  Do you really do a 1:1 conversion though?  Mice are quite different in terms of metabolism and other things.  What strikes me most is that a 1:1 conversion usually ends up being a ridiculously large dose in human terms, which is why I always thought they were right in not doing that.


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#45 VP.

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Posted 04 October 2018 - 05:49 PM

The Mayo Clinic is doing a study of Fisetin 

Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (AFFIRM-LITE)
Fisetin 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months.

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#46 OP2040

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Posted 04 October 2018 - 06:59 PM

 

The Mayo Clinic is doing a study of Fisetin 

Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (AFFIRM-LITE)
Fisetin 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months.

 

 

 

Good find.

This is a phase II study, which implies that they already did a phase I safety trial.  So it's official, no safety worries.


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#47 OP2040

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Posted 04 October 2018 - 07:10 PM

There's a few studies out there showing mTOR inhibition as well.....



#48 OP2040

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Posted 04 October 2018 - 07:56 PM

ok, I think I've settled on this routine.  The study VP posted would equate to 1700 mg for someone my size

 

I am going to go for 1000 mg for 5 days, throw the remainder in the last day.  I was thinking of taking a nac before each just in case my liver needs the extra protection, though I sincerely doubt it's necessary, I have it so I'm going to use it.  Then not sure if repeat at year 1/5/10?  Seems weird to not take a supplement daily, but it doesnt seem necessary to do so.


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#49 smithx

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Posted 04 October 2018 - 11:14 PM

Good find.

This is a phase II study, which implies that they already did a phase I safety trial.  So it's official, no safety worries.

 

So chromosome loss and double-strand DNA breaks are not an issue for you guys? :unsure:

 

The fact that there were not enough short-term adverse effects to make the treatment fail phase I doesn't mean that this is at all safe in the long term.


Edited by smithx, 04 October 2018 - 11:15 PM.

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#50 OP2040

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Posted 05 October 2018 - 01:18 AM

All one has to do to see the very many things that are wrong with that statement is just read this thread.
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#51 extendcel

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Posted 05 October 2018 - 03:14 AM

So chromosome loss and double-strand DNA breaks are not an issue for you guys? :unsure:

The fact that there were not enough short-term adverse effects to make the treatment fail phase I doesn't mean that this is at all safe in the long term.


That study was done on a cancer cell line

Edit: Actually I may have misread it. Let me double check. But there is one mice study where they megadosed for toxicity testing.

"However, in the case of fisetin, there is no evidence for either short- or long-term toxicity. In a short-term study done by an outside laboratory, mice were orally administered 2000 mg/kg bw of fisetin, examined for 48 hr and sacrificed. No indications of toxicity were observed. The effects of long-term feeding of fisetin on health were also evaluated (18). No significant differences in body weights were seen between control and fisetin-fed animals given fisetin at 0.05% in their diets for 9 months (~25 mg/kg bw). Following sacrifice, multiple tissues (lungs, spleen, liver, kidneys, heart, stomach, intestine, testes and ovary) were examined using standard toxicological pathology criteria and no toxicity was associated with fisetin treatment. Furthermore, fisetin was negative in the Ames test. In addition, fisetin showed no inhibition of hERG activity at concentrations up to 10 μM, the highest concentration tested (unpublished results). It also showed no inhibitory effects on the activities of cytochrome P450s 3A4, 2C9 and 2D6 at concentrations up to 10 μM (unpublished results). Thus, at the present time, there is no indication of fisetin toxicity from either in vitro or in vivo tests."
https://www.ncbi.nlm...27824/#S16title

This combined with passing stage 1 trials demonstrate a good degree of safety. One other thing to consider is the use acute dosing rather than chronic dosing for senolytic use.

Edited by extendcel, 05 October 2018 - 03:23 AM.

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#52 smithx

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Posted 05 October 2018 - 05:32 AM

Does standard toxicology pathology examine chromosome loss or DNA strand breakage?

 

I don't think so but if anyone knows please weigh in.


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#53 recon

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Posted 05 October 2018 - 06:21 AM

It is possible that the DNA damage occurs only on cancer cell line.

Take, for example, a study on quercetin that was known to have low senolytic effects and is also a flavanol. I quoted a couple of interesting and relevant excerpts from the study below.

Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis
Scientific Reports volume 6, Article number: 24049 (2016)
Shikha Srivastava, Ranganatha R. Somasagara[…]Sathees C. Raghavan
https://www.nature.c...icles/srep24049

Under Results,
“Hence, our results show that quercetin induced significant toxicity in both leukemic and breast cancer cell lines, however, its effect on normal cells was minimal.”

“DNA fragmentation is one of the hallmarks of apoptosis differentiating between the necrotic and apoptotic modes of cell death.”

Under Discussion,
“In our ex vivo assays, we find that quercetin induces cytotoxicity in leukemic cells effectively; pre-B cell line, Nalm6 being most sensitive with an IC50 value of 20 μM”

but,

“However, normal cells derived from human embryonic kidney as well as mouse embryonic fibroblasts were insensitive to quercetin. The ability of quercetin to spare normal cells has also been reported previously.”

“Besides, an increase in cells in Sub G1 phase was observed in a dose dependent manner, when Nalm6 cells were treated for 48 h. This suggests that quercetin might induce DNA damage, which need to be corrected before cell division takes place. Considering the ability of quercetin to interact with DNA, the observation can be easily explained (see below). A similar S phase arrest has been observed previously as well5,11. However, as reported by others, we did not observe either G0/G1 or G2/M arrest9,10,12,13,14. Difference in the cancer type used may account for such a disparity in the observation.”

“Thus we conclude that quercetin is more effective than ellagic acid in inducing cytotoxicity in different cancer cells.”

“A 5-fold increase in life span was observed in tumor bearing animals following treatment with quercetin compared to that of untreated tumor bearing mice. This indicates that quercetin induced cytotoxicity in tumor cells without significantly affecting the normal cells.”

“DNA intercalation is one of the mechanisms by which anticancerous drugs cause DNA damage, accumulation of which could culminate in apoptosis.”

Therefore, isn’t it possible that the same thing is going on with fisetin, considering that both have senolytic effects and both are flavanols?

Edited by recon, 05 October 2018 - 06:22 AM.

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#54 OP2040

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Posted 05 October 2018 - 11:50 AM

It's sad that we have to go off into this side track.  The entire purpose of that study was to show how Fisetin works its anti-cancer magic, as it was already known that it does so.  Cherry picking a couple lines from the study, hoping people will not read it in context, is intellectually dishonest.  The study is clearly showing that Fisetin affects various mechanisms against cancer, one of which causes DNA breaks. How exactly does one think cancer cells are killed anyway!?!? By hugging them to death???

 

It took me exactly 10 seconds to find a half-a-dozen studies on Fisetin's anti-cancer effect.  Here's just three with a relevant quote, also which took me less than a minute to gather. 

 

https://www.ncbi.nlm...pubmed/27059089

 

 

Dietary flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) found in many fruits and vegetables has been shown in preclinical studies to inhibit cancer growth through alteration of cell cycle, inducing apoptosis, angiogenesis, invasion, and metastasis without causing any toxicity to normal cells.

 

https://www.ncbi.nlm...les/PMC2944651/

 

 

In this study we demonstrate that fisetin, a natural flavonoid, induces apoptosis and inhibits invasion of chemoresistant PaC AsPC-1 cells through suppression of DR3 mediated NF-κB activation. Fisetin treatment resulted in dose-dependent inhibition of PaC cell growth and cell proliferation with concomitant induction of apoptosis.

 

https://academic.oup...36/6/696/276664

 

 

Intraperitoneal treatment of nude mice with fisetin at 30mg/kg resulted in a 35.7% (P < 0.001) inhibition of tumor growth.

 

 

So ya.....


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#55 Alpharius

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Posted 05 October 2018 - 05:46 PM

Does standard toxicology pathology examine chromosome loss or DNA strand breakage?
 
I don't think so but if anyone knows please weigh in.


The already quoted study says Fisetin was negative for the Ames Test (mutagen test).
https://www.ncbi.nlm...27824/#S16title
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#56 OP2040

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Posted 05 October 2018 - 06:19 PM

ok, now that nonsense is over, we can move on.  After reading many studies closely and perusing even more, I do see only one concern.  Fisetin is a COX inhibitor.  I am not really worried about that for a few reasons.  First, it only needs to be taken very sparingly.  Second, almost every protective compound we take is also a COX inhibitor.  Look up all your supplements and a I guarantee at least one is a COX inhibitor.  Third, the COX controversy is still very messy, even after ~20 years.  I don't entirely buy into it.  So, still a go for Fisetin IMO.


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#57 able

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Posted 05 October 2018 - 06:39 PM

I don't personally need a 100% guarantee on safety.  It sounds like it is more likely to have benefit rather than damage, so I am going to give it a try, using the 20 mg/kg dosage they use in the phase 2 human study.

 

My question is, what might help the effectiveness?

 

NAD+ helps distressed cells survive, which is not what we want for clearing senescent cells.  So I was thinking it might be good to try the Fisetin during the 2-3 days a week I am cycling off NMN - make sense?

 

Also wondering about fasting.  I practice periodic fasting, eating just one meal (dinner) a day, and periodically will skip dinner to make a 48 hour fast.  Does it make sense to try the fisetin during a fast?


Edited by able, 05 October 2018 - 06:41 PM.


#58 OP2040

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Posted 05 October 2018 - 06:46 PM

I agree completely able.

As for effectiveness, it seems it will be effective at a high dose.  My plan was to forego other supplements and fast also.  I am just going to fast for daylight hours, nothing extreme.  It makes sense to me that fasting would enhance senolytic potential.  My question then would be whether absorption is affected by food or not?



#59 micro2000

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Posted 05 October 2018 - 08:09 PM

Either way I don’t find the fact that it kills cancer cells at all worrisome. It is known for it’s anti-cancer effects, which is probably why they used cancer cells in the study.I assume you are worried that it would also target normal cells? That wouldn’t make much since given that it had such a strong safety profile, even in humans.


The strong safety profile is also related to its poor bioavailability in humans. Once you start pushing pharmacological dosages into the system, then we will see how safe or deleterious it is.
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#60 able

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Posted 05 October 2018 - 08:13 PM

I agree completely able.

As for effectiveness, it seems it will be effective at a high dose.  My plan was to forego other supplements and fast also.  I am just going to fast for daylight hours, nothing extreme.  It makes sense to me that fasting would enhance senolytic potential.  My question then would be whether absorption is affected by food or not?

 

 

I'm not too knowledgable about food/drug interactions, but I have read fat soluble supplements may have improved bioavailability when fats are present.  

 

So I  plan on taking with some fats, but otherwise fasted.  

 

Will also use a bit higher dosage than the 20 mg/kg they use in study, as those need to be a bit more conservative than I chose myself.







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