58 replies to this topic

[sensei]

I would caution making statements regarding the elimination half-life of fisetin in humans.

The available pharmacokinetics data of a biphasic half-life of .9 and roughly 3 hours was measured in MICE not HUMANS. It may or may not be similar.

Caution is also warranted in that it has an IC80 of 100umol for the CYP3A4 enzyme.

https://www.research..._fig6_312187277

[FlorianReicht]

I'll give this a try. Adding some DMSO to the mixture for better absorption.

[nhenderson]

How about cocoa powder as a source of PCC1? given this

 

http://phenol-explor.../polyphenol/157

 

Also, two more questions 

1. Any thoughts about Life Extension's "Synolytic Activator" compound, just upping the dose?
2. Would dissolving the original protocol in full fat yogurt overnight be useful?

[Fafner55]

 

How about cocoa powder as a source of PCC1? given this

 

http://phenol-explor.../polyphenol/157

 

Also, two more questions 

1. Any thoughts about Life Extension's "Synolytic Activator" compound, just upping the dose?
2. Would dissolving the original protocol in full fat yogurt overnight be useful?

 

 

Great finds!

In my protocol I assumed that the PCC1 content of grape seed extract was 3%, based on

“Polyphenolic Composition and Antioxidant Activities of Grape Seed Extract” (2008) https://www.tandfonl...42910701584260 

while the reference cited by the phenol-explorer website give a similar result (2.63%).

“Levels of flavan-3-ols in French wines” (1999) https://doi.org/10.1...021/jf9810564  

 

If the 2.63% figure is used, the GSE dose would need to be increased from 4000 mg to 4300 mg. 

 

Cocoa powder could be a good substitute for GSE, but I'm skeptical of the 23% to 26% PCC1 content that http://phenol-explor.../polyphenol/157 reports. The original paper states a 2.58% recovery in Table 1. “Analyses of polyphenols in cacao liquor, cocoa, and chocolate by normal-phase and reversed-phase HPLC” (2020) https://academic.oup...2?login=false  

 

As for Life Extension's "Synolytic Activator", it is advertised as a "Proprietary Blend". Life Extension's website does not offer any quantitative measures of the effectiveness of Synolytic Activator. It only gives testimonials. That's marketing, not science. In contrast, the detail and support I put in the protocol document gives readers what they need to make fact-based decisions.

[FrankEd]

Fafner55, if you don´t mind, which brand of Fisetin and GSE you used in your protocol?

[Blueflash]

I've tried the first 3 days half dose. The first day I felt some fatigue, mild flu feeling. The second day at half dose I felt nothing. Today I did the full dose and again I felt the fatigue. Thanks for putting this together. Had been wanting to try something similar from the mayo clinic. 

[Fafner55]

I've tried the first 3 days half dose. The first day I felt some fatigue, mild flu feeling. The second day at half dose I felt nothing. Today I did the full dose and again I felt the fatigue. Thanks for putting this together. Had been wanting to try something similar from the mayo clinic. 

 

I also experienced mild flu-like feelings when first-time removing senescent cells: minor aches and a low grade fever. Now I only experience slight fatigue.

[Woody42]

I just mixed 4G of GSE with 2G of Fisetin in 30 ml of olive oil with 10 ml of lecithin and 100 ml of water.

Man did it tast bad !   Anyone have any further thoughts about just using cocoa powder instead of the

GSE perhaps it would be easier to swallow.

 

[Fafner55]

GSE powder tastes terrible. Try buying capsules.

[NewEnergy]

Hello Fafner55,

In your well written paper on PCC1 I am looking at the calculation on page 11 where you compute the amount of GS extract (I think) to get the amount of PCC1 needed.

 

I don't get the same number as you do:

Mouse dose is 20mg/kg. Mouse to Human scaling factor is 3/37 = .081
So 20mg/kg PCC1 X scale factor .081 X.03 content in GSE = 0.0486 mg/kg human dose. (Your Paper shows 54mg per kg.)
  What is wrong here?

 

I am trying to replace GSE with dark chocolate from the Ivory Coast which has 44 mg PCC1 per 100 grams of chocolate (source: Phenol Explorer website)..

So that should be .044%.

 

Thanks for helping.

 

[Woody42]

To equal the procyanadine  C1 content of 4000mg of GSE  how much cocoa powder would we need ?

 

 

[NewEnergy]

Woody,

Using Fafner55's numbers we see the updated amount of GSE is 4300 mg. That is based on a 2.63 % of PCC1 in grape seed extract.

  This amounts to 4300 x .0263 = 113.09 mg  (.11309 grams)

Because this is an extract and not whole grape seed we will need a lot more of cocoa than GSE. The data I found in a table showed that cocoa from the Ivory Coast (of Africa?) had the highest

amounts of PCC1 and this number was 44 mg per 100 G of cocoa. This gives a percentage of only .044/100 = .00044 or .04%.

 

So Amount of PCC1 desired / Percentage = Total Grams of Cocoa

    ( rounding) .113 grams PCC1 / .00044  = 257 Grams of Cocoa

 

I found that Trader Joe's sells an Ivory Coast cocoa (made in Italy). It is not always available there but keep asking about it.

Each bag contains 180 grams of cocoa. This cocoa has no sugar and so tastes very strong and bitter. It might be more palatable to make it into Chocolate Mousse!

 

 

Attached Files

•  Trader Joe cocoa.jpg   54.05KB   1 downloads

[Woody42]

Thanks I am not shure I am up to eating that much cocoa.   it just might be simpler to take 

a handful of GSE pills.  

[Groundhog Day]

Has anyone further explored the question of whether or not it's a good idea to remove senescent cells in the first place? 

[NewEnergy]

The studies show it is very good in mice. I am not aware of much success in humans yet. But I don't read all the new literature, just summaries.

[StephCThomp]

Any thoughts on the antimicrobial effects of GSE?  Quite potent, no?  Enough to damage your gut biome?

 

Pure speculation, but I also wonder whether this has a relationship with the effects of GSE seen on endothelial cells. Microbes are often found to be resident stimulators of atherosclerosis. Potently knocking them out with a massive dose of GSE might trigger changes that could be interpreted as a senolytic effect, perhaps.

[stockcarman]

And also how much procyamidin C1 is actually in the GSA we are taking . Most say it's to little to do any good for senolyic purposes .

[stockcarman]

And also how much procyamidin C1 is actually in the GSA we are taking . Most say it's to little to do any good for senolyic purposes .

[NewEnergy]

When you state "MOST say it is too little..." please define who MOST is. I have not seen anything written here about PCC1 not being a good senolytic at the 4300 mg suggested.

Do you have a reference please?

[nhenderson]

Grape seed extract can inhibit iron absorption and induce anemia.  Here: http://web.archive.o...edu/story/47964

 

Anecdotally, this protocol made me slightly anemic, but I had zero fatigue, etc. (it did make my doctor and me go through a lot of hopes looking for the reason.)

 

That said there is emerging literature on reducing iron to aid health and longevity.

[NewEnergy]

Just as another data point: About 6 years ago I took 1800 mg a day of GSE for 2 months. I purchased 200 grams of powdered GSE from BulkSupplements.com. I read several papers on it and learned it was safe at this rather high amount. I never had any side effects or bad effects. I still don't know if it was helping my problem because I was taking other things as well. But the problem went away, so success. Yes, iron is a good thing to keep down to the minimum level, I agree. I have no idea if my iron level was affected but I was getting blood tests every 2 weeks and no one mentioned that.

[nhenderson]

That should have read, my doctor and I went through a lot of hoops (not hopes).  Also I believe this what made me anemic, I am not certain.

 

[CynthesisToday]

Add some tryptophan in with the GSE and get some extra NAD production (1) where the greatest NAD flux happens (2). Also, GSE taken at the start of active period (ZT12) has higher bioavailability. (3)

 

(1) https://www.nature.c...icles/srep24977 "Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats" (2016) "PAC consumption induced an over expression of the genes that encode the enzymes involved in the de novo NAD+ biosynthesis pathway" specifically QPRT and NadSyn1 (Note: Tryptophan metabolism is a bit different in rats compared to humans.)

 

(2) https://www.cell.com...(18)30196-7.pdf "Quantitative Analysis of NAD Synthesis-Breakdown Fluxes" (2018)

 

(3) https://pubmed.ncbi....h.gov/34851030/ "Administration Time Significantly Affects Plasma Bioavailability of Grape See Proanthocyanidins Extract in Health and Best Fischer 344 Rats" (2022)

 

 

 

[Olive_skin]

 

(I had also added curcumin and boswellia serrata as I hoped it may potentially have an additional effect on 5-Lox and ROCK inhibition). 

 

 

The following study suggests, that there might be an issue with the strong binding with albumin (I only have access to the abstract though):

Boswellicacids are pharmacologically active ingredients of frankincense with anti-inflammatory properties. It was shown that in vitro 11-keto-boswellic acids inhibit 5-lipoxygenase (5-LO, EC 1.13.11.34), the key enzyme in leukotriene biosynthesis, which may account for their anti-inflammatory effectiveness. However, whether 11-keto-boswellic acids interfere with 5-LO under physiologically relevant conditions (i.e., in whole blood assays) and whether they inhibit 5-LO in vivo is unknown. Inhibition of human 5-LO by the major naturally occurring boswellic acids was analyzed in cell-free and cell-based activity assays. Moreover, interference of boswellic acids with 5-LO in neutrophil incubations in the presence of albumin and in human whole blood was assessed, and plasma leukotriene B(4) of frankincense-treated healthy volunteers was determined. Factors influencing 5-LO activity (i.e., Ca(2+), phospholipids, substrate concentration) significantly modulate the potency of 11-keto-boswellic acids to inhibit 5-LO. Moreover, 11-keto-boswellic acids efficiently suppressed 5-LO product formation in isolated neutrophils (IC(50)=2.8 to 8.8 muM) but failed to inhibit 5-LO product formation in human whole blood. In the presence of albumin (10 mg/ml), 5-LO inhibition by 11-keto-boswellic acids (up to 30 muM) in neutrophils was abolished, apparently due to strong albumin-binding (>95%) of 11-keto-boswellic acids. Finally, single dose (800 mg) oral administration of frankincense extracts to human healthy volunteers failed to suppress leukotriene B(4) plasma levels. Our data show that boswellic acids are direct 5-LO inhibitors that efficiently suppress 5-LO product synthesis in common in vitro test models, however, the pharmacological relevance of such interference in vivo seems questionable.

→ source (external link)

 

I am wondering, if one could conclude the same for the other potential, natural 5-LOX inhibitors by evaluating their binding ability with albumin (or just looking for an in vitro study, which uses albumin).

[osris]

I just saw this on YouTube:

 

"Quercetin & Fisetin – Why I’ve STOPPED Taking Them" by Dr Brad Stanfield

 

 

He says that testing by the Interventions Testing Programme, which he claims is an independent scientific body, came to the conclusion that fisetin wasn't a senolytic. Incidentally, he is looking for funding for a rapamycin trial he is organising, make of that what you will in the context of his video saying fisetin is useless.

 

Some people in the video's comments stream quite rightly criticised him for not mentioning that the Interventions Testing Programme had not used fisetin mixed with an oil substance to make it bioavailable. 

Edited by osris, 24 January 2023 - 06:11 PM.

[ortcloud]

Cocoa powder could be a good substitute for GSE, but I'm skeptical of the 23% to 26% PCC1 content that http://phenol-explor.../polyphenol/157 reports. The original paper states a 2.58% recovery in Table 1. “Analyses of polyphenols in cacao liquor, cocoa, and chocolate by normal-phase and reversed-phase HPLC” (2020) https://academic.oup...2?login=false  

 

 

looks like cocoa PCC1 can epimerize and be destroyed at roasting temps, so it would have to be raw

How about Cinnamon?

 

it looks like some cinnamon extracts contain PCC1 at 23.3%

 

Cinnamon cassia extract CC-E contains 23.3% procyanidin C1 PCC1

 

https://pubs.acs.org...cs.jafc.9b02932

 

https://sci-hub.ru/h...cs.jafc.9b02932

[Groundhog Day]

Stanfield just posted on Twitter:

 

A combination of 'senolytic' molecules (Dasatinib, Quercetin, and Fisetin) was associated with an increase in epigenetic age.

 

https://www.aging-us...cle/205581/text

 

I have not read the study yet. 

[Mind]

Stanfield just posted on Twitter:

 

A combination of 'senolytic' molecules (Dasatinib, Quercetin, and Fisetin) was associated with an increase in epigenetic age.

 

https://www.aging-us...cle/205581/text

 

I have not read the study yet. 

 

Thanks for posting this. A lot of potential angles.

 

- First of all, there is a summary of Fisetin research which indicates almost every study shows positive results, in fact very positive. There was only one negative point in the entire white paper. So if I was weighing the results, it would still be in heavy heavy favor of using Fisetin as a supplement.

 

- A lot of the spectacular health promoting effects of Fisetin were found in animal trials - which don't always translate into positive human results.

 

- This was a small trial, only 28 participants. Most medical research cannot be replicated - so it would be good to get a larger dataset.

 

- No other measures of aging were done. We there some other health benefits (detriments)?

 

- Maybe it says more about epigenetic markers as an accurate measure of biological age than whether Fisetin is helpful or not (based upon all of the extremely positive past animal research). Michael Lustgarten eats a ton of strawberries, which have high levels of Fisetin, and his epigenetic age is much lower than his biological age. Maybe there is a low dose response curve?

[WMinBerlin]

regarding note 3 - in the study ZT-12 is 20:00

 

"This study shows a strong influence of circadian rhythm on the plasma bioavailability of phase-II metabolites. Many biological processes involved in metabolism and absorption of functional food factors follow circadian rhythm. According to the time of the day, metabolization and absorption processes change, being most optimal during the active phase of the organism and reaching the highest levels of most intermediate metabolites. In the case of the rodents, the maximum level of these metabolites is observed at night."

 

So one's own circadian rhythms should be taken into consideration.  

 

 

 

Add some tryptophan in with the GSE and get some extra NAD production (1) where the greatest NAD flux happens (2). Also, GSE taken at the start of active period (ZT12) has higher bioavailability. (3)

 

(1) https://www.nature.c...icles/srep24977 "Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats" (2016) "PAC consumption induced an over expression of the genes that encode the enzymes involved in the de novo NAD+ biosynthesis pathway" specifically QPRT and NadSyn1 (Note: Tryptophan metabolism is a bit different in rats compared to humans.)

 

(2) https://www.cell.com...(18)30196-7.pdf "Quantitative Analysis of NAD Synthesis-Breakdown Fluxes" (2018)

 

(3) https://pubmed.ncbi....h.gov/34851030/ "Administration Time Significantly Affects Plasma Bioavailability of Grape See Proanthocyanidins Extract in Health and Best Fischer 344 Rats" (2022)