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Resveratrol, Bioavailability and Enzyme Inhibition

question resveratrol cyp1a2 p450

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#1 Nate-2004

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Posted 14 November 2017 - 08:05 PM


In light of this article I'm revisiting resveratrol. From what I understand the issue may be with its bioavailability, not its absorption. Which P450 enzymes are directly involved in its metabolism? From what I understand it's CYP1A2, but what if this enzyme were to be strongly inhibited with verapamil or some other substance like fluvoxamine prior to taking resveratrol?

 

Has anyone experimented with this?


Edited by Nate-2004, 14 November 2017 - 08:09 PM.

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#2 maxwatt

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Posted 15 November 2017 - 04:16 AM

I don't know of anyone experimenting with CYP inhibitors, but one contributor to this forum with access to an HPLC column tested blood serum levels in several subjects over time with a measured dose.  The levels achieved apparently varied depending on the subjects CYP1A2 efficiency, as indirectly determined based on ethnicity.  Most east Asians genetically have less efficient CYP1A2 than most Europeans,  and had correspondingly greater blood levels of resveratrol. 

 

However, I don't think that is the limiting factor.  One can take a bigger dose to overwhelm CYP1A2, though it might become somewhat upregulated with chronic usage.

 


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#3 Nate-2004

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Posted 15 November 2017 - 05:58 PM

According to 23 And Me data I *think* my CYP1A2, which apparently also metabolizes caffeine, is highly efficient and naturally upregulated. I'd have to take an awful lot of resveratrol to overwhelm it. I may try to find some way of getting my hands on some verapamil or fluvoxomine to try this.



#4 Oakman

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Posted 15 November 2017 - 10:10 PM

Concerning CYP1A2 levels > coffee, broccoli, and enzyme interactions.


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#5 Nate-2004

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Posted 16 November 2017 - 12:38 AM

Given that birth control pills apparently inhibit CYP1A2 by up to 40%, I'm sure at least some women drinking caffeine on birth control have taken resveratrol at some point. No sudden reversal of age reported but who knows? Apparently naringenin can inhibit it by up to 30% so maybe combined with caffeine and about 20 oz of grapefruit juice (way too much fructose?) Also the half life of naringenin is really short. 2.2 hrs max, about the same as resveratrol. I'd have to drink even more throughout the day, add caffeine and on top of that add a heavy dose of resveratrol. At that point I might get some spike in various other tissues beyond the liver.


Edited by Nate-2004, 16 November 2017 - 01:12 AM.


#6 Oakman

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Posted 16 November 2017 - 04:41 AM

Based on this list of CYP1A2 inhibitors, I say a better strategy (wo/prescription drugs) would be to binge on St John Wort and wash it down with dandelion and peppermint tea, all the while ingesting some Resveratrol, say the Micronised trans-Resveratrol for best absorption and duration of plasma levels. Possibly a 24 hr period rejuvenation would be enough, maybe a bit more, but if the inhibition of CYP1A2 worked, that may be time enough to do some telomere lengthening, etc. I think it's something to do only occasionally.

 

I have sublingual St John's Wort and normal Resveratrol and dandelion root. If I grabbed some teas, I could give it a try. Just not sure if the effect would be noticeable?



#7 Nate-2004

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Posted 16 November 2017 - 01:49 PM

Crap I didn't realize the difference between trans and cis resveratrol until now. I ordered the wrong one, hopefully they let me cancel.  Good ideas though, I'll try that.

 

I wonder why it has to be specifically German chamomile. I have tons of chamomile tea, not sure what the difference is.


Edited by Nate-2004, 16 November 2017 - 01:51 PM.


#8 maxwatt

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Posted 16 November 2017 - 07:31 PM

Generally only trans-resveratrol is available.  Cis-resveratrol will, in the dark at room temperature, convert into trans resveratrol. 

 

Looks like that is true except at neutral pH,

 

J. Agric. Food Chem. 1996, 44, 1253−1257 :

 

Resveratrol: Isomeric Molar Absorptivities and Stability

Brent C. Trela and Andrew L. Waterhouse* Department of Viticulture and Enology, University of California, Davis, California 95616

 

Resveratrol has attracted interest as a wine constituent that may reduce heart disease. Published data on the molar absorptivity and chemical stability of cis- and trans-resveratrol have varied greatly. Accurate values for UV absorbance for trans-resveratrol [UV λmax (EtOH) nm () 308 (30 000)] and cis-resveratrol [UV λmax (EtOH) nm () 288 (12 600)] were determined and are used to improve chromatographic quantitation methods. Trials conducted under a variety of commonly encountered laboratory conditions show that trans-resveratrol is stable for months, except in high-pH buffers, when protected from light. cis-Resveratrol was stable only near pH neutrality when completely protected from light.

 

 


Edited by maxwatt, 18 November 2017 - 03:45 AM.

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#9 hav

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Posted 17 November 2017 - 06:51 PM

Just had a chance to read closely through the study itself. Looks like they're trying to discover new reservatrol analogs, probably so they can patent them. The part I find interesting is that they started off comparing SIRT1 activation of promising molecules with Resveratrol itself (1) and resveratrol’s primary metabolite, dihydroresveratrol (2) using the carrier enzyme as a control (0).  Looks like the most promising analog only did 75% as well as resveratrol while its metabolite got slightly over 100%.

 

12860_2017_147_Fig1_HTML.gif

 

The splicing factor activation tests they did also showed Resveratrol doing the best.

 

Just keep in mind this was all in vitro on cell cultures. Although the analogs look promising and they screened for toxicity, they did no evaluation of comparative bio-availability which could tip things significantly.

 

Howard


Edited by hav, 17 November 2017 - 06:55 PM.

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#10 Nate-2004

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Posted 17 November 2017 - 07:26 PM

I also think their main discovery was that most of the benefit was not SIRT1 but splicing factor.


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#11 Iporuru

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Posted 17 November 2017 - 10:04 PM

Based on this list of CYP1A2 inhibitors, I say a better strategy (wo/prescription drugs) would be to binge on St John Wort and wash it down with dandelion and peppermint tea, all the while ingesting some Resveratrol, say the Micronised trans-Resveratrol for best absorption and duration of plasma levels. Possibly a 24 hr period rejuvenation would be enough, maybe a bit more, but if the inhibition of CYP1A2 worked, that may be time enough to do some telomere lengthening, etc. I think it's something to do only occasionally.

 

I have sublingual St John's Wort and normal Resveratrol and dandelion root. If I grabbed some teas, I could give it a try. Just not sure if the effect would be noticeable?

 

There seems to be a contradiction in Wikipedia's information on St John's Wort. In the article you quoted it is listed as an inhibitor of CYP1A2, but when you read the entry about it (https://en.wikipedia...icum_perforatum) it says: "St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzymes CYP3A4 and CYP1A2. This drug-metabolizing enzyme induction results in the increased metabolism of certain drugs, leading to decreased plasma concentration and potential clinical effect." And the referred paper says "Conclusions: An induction of CYP3A4 by SJW was confirmed. CYP1A2 appears to be induced by SJW only in females. The activities of CYP2D6, NAT2, and XO were not affected by SJW"
 



#12 Nate-2004

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Posted 17 November 2017 - 10:31 PM

 

Based on this list of CYP1A2 inhibitors, I say a better strategy (wo/prescription drugs) would be to binge on St John Wort and wash it down with dandelion and peppermint tea, all the while ingesting some Resveratrol, say the Micronised trans-Resveratrol for best absorption and duration of plasma levels. Possibly a 24 hr period rejuvenation would be enough, maybe a bit more, but if the inhibition of CYP1A2 worked, that may be time enough to do some telomere lengthening, etc. I think it's something to do only occasionally.

 

I have sublingual St John's Wort and normal Resveratrol and dandelion root. If I grabbed some teas, I could give it a try. Just not sure if the effect would be noticeable?

 

There seems to be a contradiction in Wikipedia's information on St John's Wort. In the article you quoted it is listed as an inhibitor of CYP1A2, but when you read the entry about it (https://en.wikipedia...icum_perforatum) it says: "St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzymes CYP3A4 and CYP1A2. This drug-metabolizing enzyme induction results in the increased metabolism of certain drugs, leading to decreased plasma concentration and potential clinical effect." And the referred paper says "Conclusions: An induction of CYP3A4 by SJW was confirmed. CYP1A2 appears to be induced by SJW only in females. The activities of CYP2D6, NAT2, and XO were not affected by SJW"
 

 

 

Well shit. Who's right? These guys: https://www.ncbi.nlm...pubmed/10871299 or These guys? https://www.ncbi.nlm...les/PMC1884478/ or these guys? https://www.ncbi.nlm...pubmed/15100173 or these guys? https://www.ncbi.nlm...pubmed/17214607

 

The study cited on Wikipedia was a rat study, the study showing induction is a human study, go figure.  Also go figure there are no studies in humans on peppermint or dandelion but only chamomile tea's effects on enzymes.


Edited by Nate-2004, 17 November 2017 - 10:44 PM.


#13 rarefried

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Posted 18 November 2017 - 02:50 AM

Possible addition to the list of herbal CYP inhibitors, sweet wormwood (for its artemisinin content).

http://www.pharmacyt...11/2007-11-8279


Edited by rarefried, 18 November 2017 - 03:01 AM.


#14 Oakman

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Posted 18 November 2017 - 03:35 AM

 

 

Based on this list of CYP1A2 inhibitors, I say a better strategy (wo/prescription drugs) would be to binge on St John Wort and wash it down with dandelion and peppermint tea, all the while ingesting some Resveratrol, say the Micronised trans-Resveratrol for best absorption and duration of plasma levels. Possibly a 24 hr period rejuvenation would be enough, maybe a bit more, but if the inhibition of CYP1A2 worked, that may be time enough to do some telomere lengthening, etc. I think it's something to do only occasionally.

 

I have sublingual St John's Wort and normal Resveratrol and dandelion root. If I grabbed some teas, I could give it a try. Just not sure if the effect would be noticeable?

 

There seems to be a contradiction in Wikipedia's information on St John's Wort. In the article you quoted it is listed as an inhibitor of CYP1A2, but when you read the entry about it (https://en.wikipedia...icum_perforatum) it says: "St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzymes CYP3A4 and CYP1A2. This drug-metabolizing enzyme induction results in the increased metabolism of certain drugs, leading to decreased plasma concentration and potential clinical effect." And the referred paper says "Conclusions: An induction of CYP3A4 by SJW was confirmed. CYP1A2 appears to be induced by SJW only in females. The activities of CYP2D6, NAT2, and XO were not affected by SJW"
 

 

 

Well shit. Who's right? These guys: https://www.ncbi.nlm...pubmed/10871299 or These guys? https://www.ncbi.nlm...les/PMC1884478/ or these guys? https://www.ncbi.nlm...pubmed/15100173 or these guys? https://www.ncbi.nlm...pubmed/17214607

 

The study cited on Wikipedia was a rat study, the study showing induction is a human study, go figure.  Also go figure there are no studies in humans on peppermint or dandelion but only chamomile tea's effects on enzymes.

 

 

Here is a study on the other teas, but it's paywalled. Nevertheless, fairly impressive summary results, esp. for dandelion.

 

"Activity of CYP1A2 in the livermicrosomes of rats receiving dandelion, peppermint or chamomile tea was significantlydecreased (P ! 0.05) to 15%, 24% and 39% of the control value, respectively."



#15 rarefried

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Posted 18 November 2017 - 03:44 AM

Study (paywalled) suggesting resveratrol itself might be an inhibitor (at 500mg daily dose) of CYP2E1:

http://onlinelibrary...2/ptr.5549/full

 

I see other studies indicating resv induces CYP2E1.  These two indicating resv a CYP inducer at 1000mg: 

http://onlinelibrary...2/ptr.5549/full

http://www.mdpi.com/...9/22/8/1329/pdf


Edited by rarefried, 18 November 2017 - 04:07 AM.

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#16 Nate-2004

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Posted 20 November 2017 - 05:01 PM

Study (paywalled) suggesting resveratrol itself might be an inhibitor (at 500mg daily dose) of CYP2E1:

http://onlinelibrary...2/ptr.5549/full

 

I see other studies indicating resv induces CYP2E1.  These two indicating resv a CYP inducer at 1000mg: 

http://onlinelibrary...2/ptr.5549/full

http://www.mdpi.com/...9/22/8/1329/pdf

 

Anything that competes for the enzyme is considered an inhibitor so yes Resveratrol is an inhibitor of CYP1A2 in that sense.

 

This is CYP1A2 we're talking about not 2E1.



#17 Nate-2004

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Posted 20 November 2017 - 05:07 PM

This site states that peppermint has no effect on CYP1A2. WTF? Can anybody deliver some consistency here?

 

This article states that it does have an effect in humans but not really all that significant.


Edited by Nate-2004, 20 November 2017 - 05:12 PM.

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#18 Oakman

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Posted 22 November 2017 - 04:51 AM

I've come up with a regimen taken at ~9pm on an empty stomach:

  • 250mg 100% trans-Resveratrol 
  • 100mg isoquercetin​ (increased absorption of Resveratrol)
  • taken with Dandelion root tea
  • followed by 75mg St John's Wort sublingual (= 500mg oral dose)

Will try this nightly for a time. Also found this  - Resveratrol Metabolism Explained

 


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#19 Nate-2004

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Posted 22 November 2017 - 04:50 PM

What's Isoquercetin? Isn't resveratrol and quercetin more bioavailable when you eat fatty foods?

 

It appears that Chamomile, Celery and Parsley are the only herbs that are a competitive inhibitor of CYP1A2 unfortunately, or at least these are the only herbs with human evidence. Everything else is rats and as I mentioned above, peppermint does not work on humans the same way and I'll have to assume, due to a lack of study, that dandelion is the same way. 

 

St. John's Wort has no effect in humans on CYP1A2. So I didn't take it either.

 

Caffeine definitely helps but I'm a fast metabolizer so probably not by all that much.

 

I'd really like to get my hands on fluvoxamine or verapamil, these are strong inhibitors guaranteed to occupy the enzyme.

 

What I did do was this for ONE day, I split up a larger dose because of its otherwise short half-life (naringenin half life is also short):

 

Morning:

  • 20 oz Grapefruit Juice in the morning with Coffee
  • 600mg Trans Resveratrol

Early Afternoon:

  • 20 oz Grapefruit Juice in the afternoon with Coffee
  • 600mg Trans Resveratrol

Late Afternoon:

  • 30 sprigs parsley and 2 stalks celery blended into a smoothie
  • 600 mg Trans Resveratrol + 1200mg Quercetin

Evening:

  • 2 cups of Chamomile Tea with 2 bags each.
  • 600mg Trans Resveratrol + 1200mg Quercetin

 

If I can find or gain access to fluvoxamine I'll try that.

 

I'll do this routine once a week for a few weeks, see what happens.

  

 

 


Edited by Nate-2004, 22 November 2017 - 04:52 PM.


#20 Benko

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Posted 22 November 2017 - 07:47 PM

There is an article in Natural medical journal (not sure it is a real journal, but it does have references) talking about different forms of quercetin including isoquercetin.  Isoquercetin is available from a reliable company integrated therapeutics (not a household name because I believe they only sell directly to docs).


Edited by Benko, 22 November 2017 - 07:49 PM.


#21 Nate-2004

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Posted 22 November 2017 - 08:02 PM

There's also this.

 

But then again there's this conversation here.



#22 Oakman

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Posted Yesterday, 04:32 PM

There is an article in Natural medical journal (not sure it is a real journal, but it does have references) talking about different forms of quercetin including isoquercetin.  Isoquercetin is available from a reliable company integrated therapeutics (not a household name because I believe they only sell directly to docs).

 

The article you mention is here

 

"Comparative pharmacokinetics in humans demonstrates that the absorption of quercetin, isoquercetin, and rutin in humans involves different mechanisms. Rutin has the lowest relative bioavailability and is not significantly absorbed before 2 hours, showing peak plasma concentrations at 6 hours after intake. Metabolites of isoquercetin appear within 30 minutes in the systemic circulation; a rapid rise to a peak at 30 minutes is seen with isoquercetin, suggesting active or enhanced transport; quercetin aglycone exhibits a slow rise to a plateau at 1–4 hours, indicating absorption by passive diffusion from the stomach and through the intestines.41,42"

 

The superior bio-a of EMIQ, giving improved bio-a of resveratrol, plus the fact that querectin delays the attachment to detox molecules that metabolize resveratrol is most beneficial. I source mine here as EnduraQ (EMIQ) due to the favorable price, dose, and bioavailability (17.5x quercetin).

 

Info also here. "Since quercetin is nearly insoluble in water (<0.1 g/100 mL at 21 °C), enzymatic glucosyl conjugation has been performed to enhance its water solubility [78]. Enzymatically modified isoquercitrin (EMIQ) (Fig. 1) is one of water soluble glucoside derivatives of quercetin. EMIQ is produced from rutin via enzymatic hydrolysis, which removes the rhamnosyl group, followed by treatment of the product with glycosyltransferase in the presence of dextrin to add glucose residues. The bioavailability of EMIQ, which is absorbed as quercetin and metabolized like rutin, is about 17-fold greater than that of quercetin [8]. It is therefore reasonable to expect considerably greater health benefits with EMIQ. In Japan, EMIQ is approved as a food additive [9], and the U.S. FDA concluded that EMIQ is generally regarded as safe (GRAS) for use as an antioxidant."

 

"Another possible mechanism is related to the effects of rutin on mitochondria. Recent studies have suggested that quercetin exerts its beneficial effects independently of its antioxidant activity. Thus, quercetinmodulates pathways related to mitochondria biogenesis, elevation of mitochondria membrane potential, oxidative respiration and ATP anabolism, and intra-mitochondrial redox status [26]."

 

And given this,"Eventually all resveratrol is conjugated with sulfate or glucuronate as it passes through the liver, but the simulataneous  injestion of querectin or peperine delays the liver conjugation and allows for more immediately available free-unbound resveratrol in the blood circulation."  I suggest it is likely more beneficial to delay and keep free Resveratrol in the blood straight away after assimilation, rather than to go to extremes to try to modify P450 enzyme activity (which will occur regardless at a point). Doing both may be ideal, but  just the thought of consuming grapefruit juice and coffee together sounds a form of acid indigestion torture! Beyond that, as has been described, there seems to be a very vague story regarding just which CPY enzymes we should be inhibiting to attempt to delay resveratrol metabolism. From what I've read, focusing solely on CPY2A1 as a way to do this seems quite an oversimplification, to say the least. It appears Resveratrol's P450 metabolism is considerably more complicated, involving many enzymes.

 

Bottom line, who knew resveratrol's assimilation and metabolism could be so complicated and multifaceted?



#23 recon

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Posted Yesterday, 11:59 PM

Great question, Nate. I’ve been wondering about these too.
But I have several questions of my own that are tied to the discussion.

1) Should you be taking that much of resveratrol? Studies find a dose-dependent effect that shows quite negative effects at higher dosages.

2) Have you looked into black pepper, pepperine or bioperine? They seem to improve resveratrol bioavailability as they do for vitamin c and curcuminoids.

3) Have you looked into taking resveratrol along with its analogues or stilbenoid family? I think I read that piceid is synergistic with resveratrol. Revgenetics sold them once.
Pterostilbene is another stilbenoid that seemed to be the stronger sister to resveratrol. Megaresveratrol.net suggested a 1:2 ratio with resveratrol as complementary, and even Elysium Basis uses pterostibene rather than resveratrol.

#24 Nate-2004

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Posted Today, 03:15 AM

Yeah I dunno, I've seen studies showing good and bad at both low and high dosages, I think they were linked to earlier. I linked to the recent study involving resveratrol bringing senescent cells back to life, etc, they didn't use pterostilbene which has less study than any other right now. I don't know what to believe really. I am spacing out the doses based on half life on one day treatments every few days and trying to give it time in my system. I am pretty sure the studies didn't dose it this way but I'm trying something new. Maybe it'll do something, maybe not. Maybe it's harmful at high doses chronically but not intermittently. Maybe at low doses it's metabolized too quickly to stick around and do anything. So they've gotten bad results in both cases.


Edited by Nate-2004, Today, 03:17 AM.


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#25 recon

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Posted Today, 03:52 AM

Yeah I dunno, I've seen studies showing good and bad at both low and high dosages, I think they were linked to earlier. I linked to the recent study involving resveratrol bringing senescent cells back to life, etc, they didn't use pterostilbene which has less study than any other right now. I don't know what to believe really. I am spacing out the doses based on half life on one day treatments every few days and trying to give it time in my system. I am pretty sure the studies didn't dose it this way but I'm trying something new. Maybe it'll do something, maybe not. Maybe it's harmful at high doses chronically but not intermittently. Maybe at low doses it's metabolized too quickly to stick around and do anything. So they've gotten bad results in both cases.

Yeah, until someone does a conclusive study looking at all aspects of health changes during different dosages, it’s tough to know.

I read some longecity posts that taking it with food just delays absorption and reduces the peak but still have the same AUC. I also read some that says that taking empty will have a slightly greater AUC.

So, I now take 500 mg micronised trans-resveratrol with 250 mg micronised pterostilbene, 500 mg quercetin, 100 mg ubiquinol and 10 mg BioPQQ on empty stomach 30 minutes before any meal.
I read that resverstrol takes 0.5 hours to reach peak so I timed that to the start of the meal. Am hoping that the sirtuin activation will balance its inhibition by caloric intake.
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