18 replies to this topic

[asexymind]

As reported in Kurzweill today - the study at http://www.cell.com/...4131(12)00143-X suggests that "

They show that resveratrol targets SIRT1 directly at moderate doses and hits other targets at higher ones. Importantly, SIRT1 is required for resveratrol’s benefits irrespective of dose. Based on the findings, Sinclair emphasizes the value of finding the lowest effective dose of resveratrol, and perhaps any drug, to avoid off-target effects."

In the study, they suggest that "

Following treatment with 25 μM resveratrol, C2C12 cells showed a significant increase in mitochondrial membrane potential." AND "but high doses of resveratrol (≥50 μM) resulted not only in SIRT1-independent activation of AMPK but also in toxic effects that included a dramatic reduction in mitochondrial membrane potential and cellular ATP levels."

I don't know the molar weight of resveratrol, nor how to convert mg of reseveratrol into μM. Does anyone know how to translate the amount of reseveratrol in wine/supplements into 25 μM?

Thanks! Mark

[poolboy]

One of the studies I have seen said that 25mg taken orally turned into 2 μM in humans. I don't know if it is linear in absorption, but if it is you would probably reach 25 μM by taking about 312 mg. Of course it would also depend on how much you weigh, too. So 250-500 mg depending on if you are a small or large person.

[CaptainFuture]

Does anyone have additional information? How can we find out if we take the right dosage?

[maxwatt]

The absorption of oral resveratrol is linear up to 1 gram dose, and falls off. Blood levels are in nano grams. I think we have nothing to worry about.

"Peak plasma levels of resveratrol at the highest dose were 539
F 384 ng/mL (2.4 Mmol/L, mean F SD; n = 10), which occurred
1.5 h post-dose."*

The highest dose was 5 grams. I doubt if one can reach a blood serum level sufficient to show the in vitro effects in the OP's cited study.

Most of those reporting here take under a gram, and average perhaps half that much on a consistent basis. A few outliers at two grams report good results re exercise.


*

Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52.

Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent.

Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE.

Source

Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester University, Leicester LE2 7LX, United Kingdom.

Abstract

The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption ofresveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels ofresveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 micromol/L, mean +/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 micromol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.

PMID: 17548692 [PubMed - indexed for MEDLINE] Free full text

Edited by maxwatt, 03 May 2012 - 04:40 PM.

[bixbyte]

What if I supplemented with a 50-100 milligram capsule of 99% Res every hour could I sustain a plasma somehow to continue my Sirtuin gene but not invoke the AMP pathway?

Edited by Michael, 10 June 2012 - 12:25 AM.

[CaptainFuture]

We want to target SIRT1. This was achieved with moderate doses in mice, while higher doses hit other targets. Poolboy said that 25 µM may be achieved by taking 312 mg in a normal human. In the end, we don't know what the optimal dose for humans is. Is there any way today, to test for the optimal dose? I bet there are differences in absorption etc., so the whole approach seems more like gambling as long as we cannot test for the right values in humans..

[niner]

One of the studies I have seen said that 25mg taken orally turned into 2 μM in humans. I don't know if it is linear in absorption, but if it is you would probably reach 25 μM by taking about 312 mg. Of course it would also depend on how much you weigh, too. So 250-500 mg depending on if you are a small or large person.

That sounds like buccal dosing from an ethanol solution. You would never get that blood level from swallowing that amount of resveratrol. This dosing method was discussed here.

The absorption of oral resveratrol is linear up to 1 gram dose, and falls off. Blood levels are in nano grams. I think we have nothing to worry about.

"Peak plasma levels of resveratrol at the highest dose were 539
F 384 ng/mL (2.4 Mmol/L, mean F SD; n = 10), which occurred
1.5 h post-dose."*

The highest dose was 5 grams. I doubt if one can reach a blood serum level sufficient to show the in vitro effects in the OP's cited study.

I agree. This is the problem with in vitro experiments. More often than not, they are using doses that are impossible to obtain in vivo. The reason for these experiments is to figure out what's going on at a molecular level; they would normally be followed up with animal experiments that look at the bioavailability of the substance.

The non-linearity of resveratrol absorption is interesting. It actually becomes more bioavailable as the dose is increased, probably due to the swamping of one or more of the systems that normally prevent it from getting through.

What if I supplemented with a 50-100 milligram capsule of 99% Res every hour could I sustain a plasma somehow to continue my Sirtuin gene but not invoke the ?AMP pathway?

Nope. Particularly not in a capsule. You could get higher blood levels if you did repeated buccal dosing from an ethanol solution, but you might be a little bit drunk all the time too... Even at that, it's pretty hard to know what's going on at the level of gene activation.

so the whole approach seems more like gambling as long as we cannot test for the right values in humans..

But we can test for blood levels in humans; we do this all the time. Maxwatt posted a paper above where they did just that. In the early days of resveratrol, one of our members had his own blood drawn after a dose of resveratrol, and analyzed it himself, as he had access to a lab with a liquid chromatograph.

[maxwatt]

I don't think you need ethanol; I don't have it handy, but a recent study used a one milligram dose, with a few cc's of water. Subjects held it in their mouths for a minute before swallowing. Their blood levels after two minutes were twice the highest value reported from oral dosing. It was a short lasting peak, the liver made short work of it, but the levels were briefly high enough to have some of the anti-cancer effects seen in in vitro experiments. The solubility of resveratrol in water is about 3 mg per 100 ml.

I've been taking up to 400 mg of 98 to 99% powder, holding it under my tongue, sipping a good bit of water, and holding it as long as I can before swallowing, swishing it amoung in my cheeks to get maximal buccal absorption. The first blood peak is followed by the blood levels brought about by ingestion which peaks after about 45 minutes (depending on what else you eat) and gradually tapers off. Another peak level occurs eight hours later due to hepatic recirculation....

I believe I do not need quite as high a dose as I had been taking for anti-arthritic and endurance enhancing effects. Recently I've been incredibly busy, and have been unable to take my accustomed exercise. But when I do get out and ride, I don't seem to have lost any endurance.

[CaptainFuture]

But we can test for blood levels in humans; we do this all the time. Maxwatt posted a paper above where they did just that. In the early days of resveratrol, one of our members had his own blood drawn after a dose of resveratrol, and analyzed it himself, as he had access to a lab with a liquid chromatograph.

That sounds good but do we have a way to measure SIRT1 activity directly? Is it fine to say that higher Resveratrol levels equal higher SIRT1 activity?

[bixbyte]

But we can test for blood levels in humans; we do this all the time. Maxwatt posted a paper above where they did just that. In the early days of resveratrol, one of our members had his own blood drawn after a dose of resveratrol, and analyzed it himself, as he had access to a lab with a liquid chromatograph.

That sounds good but do we have a way to measure SIRT1 activity directly? Is it fine to say that higher Resveratrol levels equal higher SIRT1 activity?

______________
YES, that was Hedgehog? and he asked me if I was willing to FEDEX my blood after RES.
Unless you have your own Lab to take the blood or work for a Big Pharma.
Nobody else really knows where to have their Plasma levels tested?
I think Hedgehog had a couple friends allow him to test their plasma levels?
RES is measured in Milliliters per Mole?

[CaptainFuture]

______________
The Edit function does not work.
YES, that was Hedgehog? and he asked me if I was willing to FEDEX my blood after RES.
Unless you have your own Lab to take the blood or work for a Big Pharma.
Nobody else really knows where to have their Plasma levels tested?
I think Hedgehog had a couple friends allow him to test their plasma levels?
RES is measured in Milligrams or Micrograms per Mole?

That sounds very good. So you connect plasma levels of Resveratrol to SIRT1 activity. Is there a way to measure SIRT1 activity?

[niner]

So you connect plasma levels of Resveratrol to SIRT1 activity. Is there a way to measure SIRT1 activity?

No, resveratrol levels don't tell you anything about SIRT1 activity. I don't know of any way to measure SIRT1 activity in a whole animal. There might be some sort of ex-vivo way of doing it, like taking cells out of the organism, lysing them, and then either looking for products of SIRT1 or using a commercial SIRT assay. But to what point? Why do you want to measure SIRT1 activity?

[CaptainFuture]

No, resveratrol levels don't tell you anything about SIRT1 activity. I don't know of any way to measure SIRT1 activity in a whole animal. There might be some sort of ex-vivo way of doing it, like taking cells out of the organism, lysing them, and then either looking for products of SIRT1 or using a commercial SIRT assay. But to what point? Why do you want to measure SIRT1 activity?

SIRT1 is responsible for the benefits of Resveratrol. If Resveratrol targets SIRT1 at moderate doses in mice and other targets at higher doses, then how do we know what the optimal dose is? Even if plasma levels are high, can these be translated into a high SIRT1 activity? If not, measuring SIRT1 activity (measuring SIRT1 protein?), could eliminate this problem. Feel free to correct me, but we want maximum SIRT1 activity, not maximum Resveratrol levels?

[poolboy]

Looks like you can hit that level with just 150 mg.

http://www.ncbi.nlm....pubmed/22055504

' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/22055504']Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. (November 2011)
Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P.

Source
Top Institute Food and Nutrition (TIFN), Wageningen, The Netherlands.

Abstract
Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

→ source (external link)

Edited by poolboy, 07 May 2012 - 03:53 PM.

[niner]

Why do you want to measure SIRT1 activity?

SIRT1 is responsible for the benefits of Resveratrol. If Resveratrol targets SIRT1 at moderate doses in mice and other targets at higher doses, then how do we know what the optimal dose is? Even if plasma levels are high, can these be translated into a high SIRT1 activity? If not, measuring SIRT1 activity (measuring SIRT1 protein?), could eliminate this problem. Feel free to correct me, but we want maximum SIRT1 activity, not maximum Resveratrol levels?

Resveratrol has a lot of "off-target" activities, assuming SIRT1 is the "target". Apparently it doesn't even act directly on SIRT1, but rather through a roundabout pathway involving a phosphodiesterase. Basically, the biological activity of resveratrol is exceedingly complex, and can differ markedly depending on the dose. I think it would be a better idea to focus on the effects that are observed in humans under different dosage regimes, rather than try to optimize a marker like a particular enzyme activity.

[bixbyte]

Resveratrol has a lot of "off-target" activities, assuming SIRT1 is the "target". Apparently it doesn't even act directly on SIRT1, but rather through a roundabout pathway involving a phosphodiesterase. Basically, the biological activity of resveratrol is exceedingly complex, and can differ markedly depending on the dose. I think it would be a better idea to focus on the effects that are observed in humans under different dosage regimes, rather than try to optimize a marker like a particular enzyme activity.

The reason for the excitement of SIRTUIN Gene is for longevity.
Direct or indirect is not an important study.
Just that Res does work and makes you live longer.
So, the same question is continually posted.
What is the most effective way to supplement with Resveratrol to maximize our SIRT1 gene activation?
That is what I have been trying to figure out for years.
Swishing a mouthful of RES in liquid in my mouth for an hour?
Polydatin, EGCG and Bioperine to modulate the RES?
I just want to sustain a blood plasma spike forever if possible.
_______

Edited by Michael, 10 June 2012 - 12:28 AM.

[CaptainFuture]

What is the most effective way to supplement with Resveratrol to maximize our SIRT1 gene activation?

_______

That's the question I also want the answer for.

[2tender]

Theoretically, and after much research, practical personal use etc. daily morning ingestion, on an on-going basis, is the best way to maintain levels. So if you reach a good spike once a day, it should be enough. I suggest the tween80 type, although some have digestion problems that pass in time. IMO anything more than 250 mgs dly isnt really affordable. I feel its best to use first thing in the morning. Just my opinion and not advice.

That's the question I also want the answer for.

[Julia36]

Cant see why everyone's not just doing ADF?

the 2010 paper on sudden death i rats was alternate day fasting not 5o-600cals.

This regime is reasoned to turn on SiRt1 response at zero cost!

Am I missing something?