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Fisetin: Senolytic!

fisetin senolytic

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#1 OP2040

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Posted 02 October 2018 - 05:54 PM


Surprised no one has posted this yet.

 

https://www.scienced...81002114024.htm

 

It's looking like Fisetin has moved way up the list of senolytics, and it is available and quite cheap.  I am just reading through the study now.  So far I see it is the most powerful senolytic of the many they tested, and improved healthspan and lifespan in progeric and naturally aged mice.  The one drawback of all these kind of studies is they tend to be tissue specific.  In this case they were using fibroblasts and fat.  I really like that they used fibroblasts, but someone needs to come up with a way to measure senescence in detail throughout the body.


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#2 Phoebus

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Posted 02 October 2018 - 06:00 PM

been trying to get folks on the fisetin band wagon and no one seems interested. This is a great flavonoid to supplement 

 

Fisetin: A Dietary Antioxidant for Health Promotion

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

 

Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo

https://www.scienced...347861317302116

 

Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice

https://www.ncbi.nlm...pubmed/26944285

 

Cognitive-enhancing effects of Rhus verniciflua bark extract and its active flavonoids with neuroprotective and anti-inflammatory activities.

https://www.ncbi.nlm...pubmed/23688860

 

Promotes neurite ourgrowth 

https://onlinelibrar...59.2004.02563.x

 

promotes neurogenesis 

http://www.pnas.org/.../16568.full.pdf


Edited by Phoebus, 02 October 2018 - 06:01 PM.

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#3 Daniel Cooper

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Posted 02 October 2018 - 06:09 PM

Isn't it true that fisetin like quercetin is metabolized quickly by the human liver but not the mouse liver?

 

 

 


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#4 APBT

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Posted 02 October 2018 - 06:27 PM

Full text of study referenced in OP:  https://www.ebiomedi...0373-6/fulltext


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#5 OP2040

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Posted 02 October 2018 - 06:29 PM

I hope not Daniel.  If this is in any way translatable, it's a game changer.  This is a fantastic study, and after a quick read, here are some of the other main points.  I am not including any progeroid stuff even though it is also interesting:

 

- mice  12 weeks old,

   - in water, 60 mg/kg, daily on two intermittent weeks

   - reduction of SASP in fat, spleen, liver, and kidney

- mice 22-24 mo old

   - oral gavage, 100 mg/kg for 5 days

   - reduced senescent cells in T lymphocytes, NK cells, mesenchymal stem cells and endothelial cells

- mice 85 weeks (equivalent to 75 years!)

   - lower ALT

   - reduced pathology in several tissues

   - reduced SASP in several tissues

   - reduced oxidative stress in liver

   - Increased median and maximum lifespan!!!  (though I can't find the %, just a graph)

 

https://imgur.com/qPetBZn

 

This study is a goldmine, there is much more than this synopsis

 

 


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#6 OP2040

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Posted 02 October 2018 - 06:32 PM

been trying to get folks on the fisetin band wagon and no one seems interested. This is a great flavonoid to supplement 

 

 

 

What can I say, you were ahead of your time.  That's a lonely place to be. :-D


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#7 APBT

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Posted 02 October 2018 - 06:37 PM

Isn't it true that fisetin like quercetin is metabolized quickly by the human liver but not the mouse liver?

 

 

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

 

Pharmacokinetics and Bioavailability of Fisetin

 

Shia et al. have investigated the metabolism and pharmacokinetics of fisetin in rats (60). The activities of fisetin and its serum metabolites against 2,2′-azobis (2-amidinopropane hydrochloride) (AAPH)-induced hemolysis were evaluated and compared on an equimolar basis. After intravenous administration of fisetin (10 mg/kg body weight), the mean serum concentration–time profiles of metabolites showed that fisetin declined rapidly. The sulfates/glucuronides and glucuronides were largely at higher concentrations than the parent compounds at all time points, suggesting that fisetin was rapidly and extensively biotransformed by conjugation metabolism in the liver, mainly sulfation. Following oral dose (50 mg/kg body weight), fisetin levels were maintained after the first pass through the intestine and liver as shown by presence of the parent compound in serum. The (AUC)0-2880 of fisetin sulfates/glucuronides was 2.2-fold that of fisetin glucuronides, demonstrating that fisetin was rapidly and extensively metabolized to sulfates and glucuronides. Interestingly, it was observed that less sulfation occurred in enterocytes than in hepatocytes when serum levels of metabolites were compared after intravenous dose (60). It was shown that after treatment of 50 mg/kg body weight of fisetin, Cmaxand AUC0-2880 values of fisetin sulfate/glucuronide were 27-fold and 59-fold greater than the Cmax and AUC0-4320 values of 5-OH-flavone sulfate/glucuronide, respectively, following 40 mg/kg body weight of 5-OH-flavone. After an equal dose, the AUC0-4320 of 7-OH-flavone sulfate/glucuronide was found to be even lower than that of 5-OH-flavone sulfate/glucuronide (60). There was significant inhibition of AAPH-induced hemolysis by both fisetin and its serum metabolites, signifying that fisetin sulfates/glucuronides retain free-radical scavenging activity due to the presence of residual phenolic groups after conjugation metabolism (60).

It has been reported that the maximum fisetin concentration reached 2.5 μg/ml at 15 min, and the plasma concentration declined biphasically with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h after administration of fisetin at a dose of 223 mg/kg intraperitoneally in mice (68). These studies clearly demonstrate that the metabolism of fisetin has a significant role in its biological responses and anticancer activities. Ragelle et al. conducted a study to incorporate fisetin into a nanoemulsion to improve its pharmacokinetics and therapeutic efficacy (53). It has been shown that the fisetin nanoemulsion injected intravenously showed no significant difference in systemic exposure compared to free fisetin in mice, but when given intraperitoneally as compared to free fisetin, a 24-fold increase in the relative bioavailability of fisetin was found. The antitumor activity of the fisetin nanoemulsion in Lewis lung carcinoma-bearing mice occurred at lower doses compared to free fisetin (53).


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#8 OP2040

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Posted 02 October 2018 - 06:39 PM

I'm afraid it looks like Daniel is correct, at least confirmed by a few studies I just glanced at:

 

 

However, in vivo experiments also revealed that fisetin had low solubility and low bioavailability.

 

In the present study, the results of ALT and AST assays suggested that the fisetin dosage of 223 mg/kg may aggravate liver burden due to poor bioavailability. Further studies regarding increasing the bioavailability and reducing dose are required.

 

The good news is that it is only needed intermittently, and bioavailability problems are very solvable.


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#9 Phoebus

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Posted 02 October 2018 - 07:24 PM

 It has been shown that the fisetin nanoemulsion injected intravenously showed no significant difference in systemic exposure compared to free fisetin in mice, but when given intraperitoneally as compared to free fisetin, a 24-fold increase in the relative bioavailability of fisetin was found.

 

very interesting 

 

if this ever gets developed into a senolytic drug it will likely be injected, thus solving the liver issue 



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#10 Oakman

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Posted 02 October 2018 - 08:09 PM

I don't think Fisetin has been overlooked, rather the issues noted by other here have limited its potential and so its popularity. It is also rather limited in distribution, and I wouldn't call it particularly cheap either. It does seem to have anti-cancer effects and more according to studies and this age-extension factor adds to its usefulness, if, in fact, it actually get into the cells not just cleansed by the liver after oral supplementation. I've been using it off and on for a few years, with no noticeable effect good or bad...but hopefully somewhere down the road I'll be saved from something or other lol.

 

Until we know for sure, I'll just keep on eating those fruits and veggies (and take that Fisetin pill too for good measure!)

 

Fisetin: A Dietary Antioxidant for Health Promotion


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#11 VP.

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Posted 02 October 2018 - 09:41 PM

We will find out soon if it works in humans.

 

The chemical structure of fisetin is almost the same as quercetin except for a hydroxyl group in position 5. Thus, it is highly likely that these two closely related compounds exert many similar effects. Interestingly, preliminary medicinal chemistry on fisetin has identified analogues with enhanced senotherapeutic activity, suggesting that even more effective flavonoids can be developed for extending healthspan with minor alterations in the structure of fisetin.

Given that fisetin is a natural product found in common foods and available as an oral dietary supplement and has no reported adverse side effects [45], our pre-clinical data suggest that fisetin should be imminently translatable and could have a significant benefit to the health of elderly patients. Based on these mouse studies, clinical trials to evaluate the short-term benefits of intermittent fisetin treatment on certain aspects of aging such as frailty are currently underway.

https://www.ebiomedi...0373-6/fulltext


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#12 OP2040

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Posted 02 October 2018 - 09:43 PM

I don't think Fisetin has been overlooked, rather the issues noted by other here have limited its potential and so its popularity. It is also rather limited in distribution, and I wouldn't call it particularly cheap either. It does seem to have anti-cancer effects and more according to studies and this age-extension factor adds to its usefulness, if, in fact, it actually get into the cells not just cleansed by the liver after oral supplementation. I've been using it off and on for a few years, with no noticeable effect good or bad...but hopefully somewhere down the road I'll be saved from something or other lol.

 

Until we know for sure, I'll just keep on eating those fruits and veggies (and take that Fisetin pill too for good measure!)

 

Fisetin: A Dietary Antioxidant for Health Promotion

 

I think it's been overlooked only because there has never been a definitive study like this that puts it squarely in the category of d+q, which is very popular but has huge drawbacks.

 

It is by no means limited or expensive.  It's a supplement you can buy on Amazon.  Granted, ~$15/month would be expensive, if you had to take this every month, but you clearly don't.

 

I don't really take anecdotal evidence from this forum very seriously.  There are a huge amount of very young people, who have almost no health problems, or ones that are not age-related.  When someone says, "it did nothing for me", my first question is "compared to what"  Anti-aging medicine is not supposed to make you feel like superman, it's supposed to stop or reverse age-related disease.  I apologize if I've mis-characterized you, but unless you have some age-related parameters to report, then it doesn't mean much.  When I look back to when I was 20-30 years, I had plenty of aches and pains that I would have liked to get rid of, or maybe I was into creating more muscle or something like that.  But these things have absolutely nothing to do with how I feel pushing 50, it is a totally different feeling with totally different, measurable parameters. 

 

Back to FIsetin.  It is now comparable to the best senolytics out there.  Senescent cells are one major cause of aging, and they have now been proven to be a causal agent in aging.  Furthermore, it has been proven that removing them by whatever technique works, will increase healthspan and lifespan.  Fisetin is now in the top 3 best in this class of anti-aging therapies (for mice), and possible top 2, the other two options having much larger drawbacks.  Fisetin is relatively cheap and readily available. 

 

The only problem I'm seeing is a very solvable bioavailability problem for translating to humans, and maybe some dosage tweaking.  We must be getting spoiled my friends, because that is a big deal.


Edited by OP2040, 02 October 2018 - 09:45 PM.

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#13 VP.

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Posted 02 October 2018 - 10:21 PM

Dose-dependent Targeting Of p16-expressing Cells In Naturally Aged Mice.

https://static1.squa...(ICSA2018)3.pdf

 

This is getting in way over my head. Is the way Oisin Bio is targeting the p16 gene the same as how fisetin is working? I see p16 is referenced 41 times in fisetin study. Any scientists here? 



#14 OP2040

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Posted 02 October 2018 - 10:26 PM

We will find out soon if it works in humans.

The chemical structure of fisetin is almost the same as quercetin except for a hydroxyl group in position 5. Thus, it is highly likely that these two closely related compounds exert many similar effects. Interestingly, preliminary medicinal chemistry on fisetin has identified analogues with enhanced senotherapeutic activity, suggesting that even more effective flavonoids can be developed for extending healthspan with minor alterations in the structure of fisetin.

Given that fisetin is a natural product found in common foods and available as an oral dietary supplement and has no reported adverse side effects [45], our pre-clinical data suggest that fisetin should be imminently translatable and could have a significant benefit to the health of elderly patients. Based on these mouse studies, clinical trials to evaluate the short-term benefits of intermittent fisetin treatment on certain aspects of aging such as frailty are currently underway.

https://www.ebiomedi...0373-6/fulltext


Now that’s more like it. But I see no reason to wait. We had people clamoring to take fox04-dri, a much more risky proposition. Maybe it’s hard to work up enthusiasm because it’s not exotic or new enough.
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#15 VP.

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Posted 02 October 2018 - 10:36 PM

Now that’s more like it. But I see no reason to wait. We had people clamoring to take fox04-dri, a much more risky proposition. Maybe it’s hard to work up enthusiasm because it’s not exotic or new enough.

I agree. I think many have taken fisetin (including myself in the past) at low doses every day but that may not be a good idea since it also seems to be a mTOR pathway blocker. 1000 mg once a month? Any ideas? 


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#16 John250

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Posted 02 October 2018 - 10:59 PM

I'm afraid it looks like Daniel is correct, at least confirmed by a few studies I just glanced at:


The good news is that it is only needed intermittently, and bioavailability problems are very solvable.


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?
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#17 OP2040

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Posted 02 October 2018 - 11:39 PM

Using the 100 mg/kg dose for naturally aged mice in the study, the HED for me (@ 190lb) is ~700 mg for 5 days. That might be exactly what I try. A large dose for maybe a week or two, once a year. Seems reasonable to me. If our is clearing senescent cells it doesn’t need to be an everyday thing.

The dose from the study is indeed way more than we’d ever take but not as much as that.

Only thing left is finding a way to get it past liver metabolism and improve bioavailability.

#18 Oakman

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Posted 03 October 2018 - 12:45 AM

When someone says, "it did nothing for me", my first question is "compared to what"  Anti-aging medicine is not supposed to make you feel like superman, it's supposed to stop or reverse age-related disease.  I apologize if I've mis-characterized you, but unless you have some age-related parameters to report, then it doesn't mean much.  

 

Ok, so compared to what you want to know? I'd give you as an example of something that "did something for me" - NMN, because it's something relatively new that I'm taking and I do notice it's affects, or so I believe anyway. Theoretically, it's preserving a more youthful homeostasis, due to the NAD+ boosting ability. Is it anti-aging? Perhaps, but importantly, I've felt a difference.

 

Just note that I didn't say fisetin "did nothing for me", I said "no noticeable effect". How would I ever know if it "works", if I don't feel any different from taking it? Anti-aging supplements are meant to stop or reverse the aging process", meaning weakness, fragility, muscle wasting, etc. Hopefully fisetin is helping, just not to the extent I've felt from NMN. IOW I take it on faith it works.  

 

Many people age and do not get diseases, they just get old, then simply die.  I want a healthy lifespan, without disease, and maybe fisetin, plus other things, is helping me do that. Nearing 70, I don't have any noticeable disease. But when you don't have something, it's impossible to pin the cause (of nothing) happening, yes?


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#19 Phoebus

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Posted 03 October 2018 - 01:11 AM

Using the 100 mg/kg dose for naturally aged mice in the study, the HED for me (@ 190lb) is ~700 mg for 5 days. That might be exactly what I try. A large dose for maybe a week or two, once a year. Seems reasonable to me. If our is clearing senescent cells it doesn’t need to be an everyday thing.

The dose from the study is indeed way more than we’d ever take but not as much as that.

Only thing left is finding a way to get it past liver metabolism and improve bioavailability.

 

 

how do you translate a mouse dose to a human dose? 

 

I thought it wasn't a simple mg/kg from mouse weight  to human weight?  

 

Someone said its more complicated than that, but I dont know 



#20 John250

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Posted 03 October 2018 - 01:49 AM

how do you translate a mouse dose to a human dose?

I thought it wasn't a simple mg/kg from mouse weight to human weight?

Someone said its more complicated than that, but I dont know


I think it’s divided by 12.3

https://www.research...animal_dose/amp

Using the 100 mg/kg dose for naturally aged mice in the study, the HED for me (@ 190lb) is ~700 mg for 5 days. That might be exactly what I try. A large dose for maybe a week or two, once a year. Seems reasonable to me. If our is clearing senescent cells it doesn’t need to be an everyday thing.

The dose from the study is indeed way more than we’d ever take but not as much as that.

Only thing left is finding a way to get it past liver metabolism and improve bioavailability.


Do you plan to take the full dose all at once? With or without food? Thanks

#21 Phoebus

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Posted 03 October 2018 - 02:13 AM

i dont think you can just multiply by 12.3 

 

here is a better explanation 

 

 

 

The most common instance is RODENT STUDIES wherein the dosages mentioned are applicable to either RATS or MICE; and wherein there exists the need to calculate what is the HUMAN EQUIVALENT DOSAGE (HED).

Therefore, I thought I'd post here the details regarding precisely how the HED can be calculated.

In short, the relevant formula is as follows:

HED (mg/kg) = Animal Dose (mg/kg) x [Animal K/ Human Km]

Human K= 37

Mouse K= 3

Rat K= 6

EXAMPLE: 

Say a STUDY conducted on MICE reports that a dosage of 5mg/kg was used; what is the HED?

By calculation, the HUMAN EQUIVALENT DOSE (HED) = 5 x [3 / 37] = 0.405 mg/kg 

https://www.longecit...nimal-to-human/


Edited by Phoebus, 03 October 2018 - 02:16 AM.

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#22 recon

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Posted 03 October 2018 - 06:28 AM

i dont think you can just multiply by 12.3

here is a better explanation

https://www.longecit...nimal-to-human/

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.
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#23 Harkijn

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Posted 03 October 2018 - 06:47 AM

Quercetin in part improves the bioavailability of Resveratrol by protecting it from glucuronidation.  Makes me wonder if it can do the same for Fisetin.


Edited by Harkijn, 03 October 2018 - 06:47 AM.

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#24 Harkijn

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Posted 03 October 2018 - 06:54 AM

Fisetin has received more attention in the past than some think:

 

https://www.longecit...on-sensitivity/



#25 William Sterog

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Posted 03 October 2018 - 08:29 AM

I have never felt a thing from the use of Fisetin. I was really hyped about this compound, but my expectations were not satisfied.

I'm "just" 25, but I have several health problems: impaired cognition and low energy, Fisetin didn't help at this regards.

Creatine, ALCAR, Noopept, Phosphatidylserine, PQQ, Shilajit, Cordyceps, etc. are a little effective, for example.

Edited by William Sterog, 03 October 2018 - 08:42 AM.


#26 Ducky-001

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Posted 03 October 2018 - 09:54 AM

There is a new review article on alternative delivery methods for Fisetin out just now also. 

 

Review

Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine

 

https://www.scienced...753332218336965

 


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#27 OP2040

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Posted 03 October 2018 - 11:15 AM

....

 

It seems I did mis-characterize you, at least in terms of your age.  You must be doing something right if all you have are aches and pains.  I had the same experience with NMN, but the initial very obvious positive results have sort of plateaued as I continue to use it.  Hopefully, that just means that it is working and keeping me at a new normal. 

 

Aside from delivery, this probably is one of our biggest issues.  We don't actually know if something is working.  It would be nice to have a cheap and easy test for senescent cells, and take a before and after.  Then, even if removing them didn't really help much, we can move on.

 

I would look into what the other guys brought up.  Maybe the FIsetin just isn't getting into your system in the amounts needed because of  the bioavailability problem.
 


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#28 OP2040

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Posted 03 October 2018 - 11:24 AM

I think it’s divided by 12.3

https://www.research...animal_dose/amp

Do you plan to take the full dose all at once? With or without food? Thanks

 

As you know, a lot of what we do is based on reading the evidence and then extrapolating based on your current pet theory.  Well, for me it seems logical that you would want to do it during a calorie restricted time of day or week since your cleaning processes will then be primed and ready to take on the task.  On the other hand, it may need to be taken with food for availability, haven't looked into that yet. 

 

I generally try to get fairly close to what they did in the study.  And all they did was 100mg for 5 days, nothing more, nothing less. Since one round was ad libitum and one was via oral gavage, and they both worked, I'm not sure it matters if you take it all at once or through the course of a day. 

 

Phoebus, the other folks are correct, that is the formula I use and it isn't a straight 1:1 relationship.  Not being all that bright, I have to look it up every single time I do it lol.  But I'm starting to get an eye for what is a reasonable dose or not just based on the original mouse mg/kg.



#29 QuestforLife

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Posted 03 October 2018 - 12:30 PM

Some possible solutions to the lack of bioavailability problem:

 

1. Take a large dose of quercetin beforehand as its structure is EXTREMELY similar to fisetin and may help to overwhelm the liver's ability to degrade Fisetin.

 

2. Fisetin is oil soluble, so take it like you would curcumin - dissolved in oil, or perhaps in alcohol.

 

3. It shouldn't be too hard to make a liposomal mix.

Attached Files


Edited by QuestforLife, 03 October 2018 - 12:32 PM.

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#30 OP2040

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Posted 03 October 2018 - 02:54 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 really a crime that there have been hundreds of mouse studies, all positive, going back decades, and not one human study.  I would wager that even with low bioavailability it would still prove  to be beneficial, and at least get the ball rolling.  Same old story, why do a study on something that is cheap and unpatentable.

 

Trehalose as the same exact problem with bioavailability in humans.  However, they did let a couple human studies slip through showing that it did have positive effects anyway.  I'm thinking the same will be true for Fisetin.


Edited by OP2040, 03 October 2018 - 03:17 PM.






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