21 replies to this topic

[cortex]

(linked from mind and muscle forum)

http://www.mindandmu...pe=post&id=5231

[tintinet]

Yabut:

1. Can't access post without registration and login...and

b.) No one really knows what the effects of the resveratrol conjugate metabolites might be, as the cited study notes.

[cortex]

Sorry people, here´s the abstract of the study from pubmed.

1: Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52. Links
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.
Cancer Biomakers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester University, Leicester LE2 7LX, United Kingdom.

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 of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol 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]



Basically even 5g per day isn´t even near effective according to the authors - any comments ?

[krillin]

SIRT1 activation doesn't need a long soak time. You just need a spike dose to flip the gene switches.

[maxwatt]

additionally, there may be an active transport mechanism via red blood cells in humans; the abstract was posted in another thread that discussed this same topic.

[craigb527]

Cortex, the article states you must reach the 5 micromol/L in order to fight cancer, whereas Resveratrol is supposed to have other health benefits at lower doses. I don't think
the metabolites are cancer preventive, it seems it would have been proven in vitro already. I guess the question is, why are you taking resveratrol? If it is indeed to fight
cancer then, to me, it would seem you have three choices if you want success (A) determine a way to make your current dose more bioavailable, I don't think that was done in the experiment you quote (B) increase your dose to an amount that would make your blood level over 5 micromol/L which would seem to be a dose in excess of 100 mg/kg. As far as I know studies have not been released on human doses this high, but resveratrol is generally claimed to be non toxic. © combine resveratrol with another drug(s) to create a synergy amongst the drugs, thereby allowing resveratrol to work at a reduced concentration.
Additionally, resveratrol is an antioxidant, which are thought to help prevent cancer by elimination of free radicals, even at small doses.

Edited by craigb527, 13 October 2007 - 11:09 PM.

[inawe]

PMID: 17548692 reports on some results from the "Resveratrol in
Preventing Cancer in Healthy Participants" clinical trial sponsored by
the National Cancer Institute. The only purpose was to give
participants increasing doses and see when 5 micromol/L can be
reached. This was based on some older research (in vitro) claiming that
was the minimum concentration required to have some effect on cancer
cells.
What resveratrol does to cancer cells is far from clear and the effect
can be more positive. In a newer paper, PMID: 17848600, it is reported
that resveratrol attacks breast cancer cells on several fronts
including their mitochondria. In a murine model in vivo, tumor
reduction was observed at a dose of 50mg/Kg a day (8mg/Kg for
humans?). Sirtuins are not even mentioned.

[cortex]

Any thought on dose needed for SIRT1 effect as opposed to cancer prevention ? PMIDS ?

[craigb527]

Once Sirt 1 is activated, would discontinuing use of Resveratrol deactivate it in humans? I realize there isn't much info on this, but what about in animal trials?

[VP.]

Sorry people, here´s the abstract of the study from pubmed. 

1: Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52. Links
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.
Cancer Biomakers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester University, Leicester LE2 7LX, United Kingdom.

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 of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol 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]



Basically even 5g per day isn´t even near effective according to the authors - any comments ?

This study has been discussed earlier but I'll re-post some info on it.:

Scant research on people Most studies of resveratrol have been done in vitro -- outside of any living organism -- or in animals. But two early clinical trials in people give reason for optimism, and uncertainty, about its possible medical benefits.

One, published in June in Cancer Epidemiology, Biomarkers & Prevention, looked at resveratrol's bioavailability, i.e., how much of it is absorbed, unchanged, into the blood.

"That's a very important question," says Brenner, lead author of the study. "You can take grams and grams, and if none of it gets absorbed, it's moot."

The researchers gave single doses of resveratrol in uncoated immediate-release caplets to 10 volunteers at each of four dose levels -- 0.5, 1, 2.5 and 5 grams -- and then analyzed their blood to see how much resveratrol was absorbed.

Even at the highest dose, peak levels were only about half as high as the level determined in earlier studies to have cancer-preventive effects in vitro. But various resveratrol metabolites -- forms the antioxidant changes into when digested -- were present in very high levels. It's possible, Brenner speculates, that these have cancer-preventive effects themselves, perhaps being re-converted to resveratrol after they're absorbed into tissues.

"There are all kinds of questions," he says. "All we know right now is that resveratrol is absorbed, but it's not absorbed very much."

In a second clinical trial described this year by a team of researchers at UC Irvine, nine colon cancer patients took resveratrol for about two weeks between their diagnosis and their surgery. It was given either in pill form (20 milligrams a day) or as freeze-dried grape powder (mixed in water, either two or three times a day, at doses corresponding to either two-thirds or one pound of fresh grapes).

Part of the tissue from the patients' diagnostic biopsies was saved and later compared with tissue removed during surgery. The researchers were looking for changes in cellular metabolism that occur in more than 85% of patients with colon cancer. Earlier lab studies had indicated that resveratrol might inhibit these changes.

Preliminary results from six patients -- presented in a poster at the meeting of the American Assn. for Cancer Research in Los Angeles this April -- showed that the changes were indeed inhibited by about 50%, with more inhibition occurring in healthy tissue than in cancerous tissue.

"This doesn't prove that resveratrol definitely prevents colon cancer," says principal investigator Holcombe. "But it provides a rationale for doing more studies. . . . And it suggests that resveratrol may be more useful in prevention than in treatment."

http://www.latimes.c...rack=crosspromo


All we can do is sit back and wait. Many studies on resveratrol in humans are in progress or planned. You could use SIRT's stock price as a rough and imperfect proxy for resveratrol's effectiveness. If SIRT drops below it's IPO price then resveratrol may be useless (or SIRT has patent problems). As of Friday SIRT is near it closing high so no problems so far.

[steelheader]

SIRT's stock price, research, theories, and anecdotal accounts (other people's experience) have little influence on me at this point. My own experiece (correctly just anecdotal to you folks) in taking resveratrol for almost a year is more important to me than all that. For me resveratrol is extremely effective.

[geo12the]

Once Sirt 1 is activated, would discontinuing use of Resveratrol deactivate it in humans?  I realize there isn't much info on this, but what about in animal trials?

My understanding is that resveratrol alters the activity of Sirt1 protein. I'm not sure if it's known exactly how long this effect lasts, I don't remember if it's mentioned in any of the papers I've read. However, I would surmise that you need to continue taking resveratrol, since new proteins are continuously being made by your cells and old ones are being degraded.

Regarding the SIRT1 activation, I'm not 100% convinced that it is responsible for all of the beneficial effects of resveratrol. It’s been established that SIRT1 is activated by resveratrol and also by caloric restriction. But might it be a side effect that has nothing to do with the beneficial effects? The correlation of SIRT1 with beneficial health effects is there, so SIRTRIS may be on the right track by looking at factors that activate it, but it seems to me like there has to be more to the story than just the SIRTs.

[neogenic]

In the top study it simply states "resveratrol"...what source? What purity? Trans or mixed/racemic? That has some bearing. Anyone have access to the full study. I hate always discussing "abstracts" that are keenly written to leave out information that negates the author's (and more likely the fund sources) opinions. Very few studies are unbiased these days.

[tintinet]

Agree with geo12the, there's likely much more to resveratrol than Sirt1 activation alone:


1: Mol Nutr Food Res. 2005 May;49(5):405-30.Click here to read Links
Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications.
de la Lastra CA, Villegas I.

Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain. calarcon@us.es

Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan.

PMID: 15832402 [PubMed - indexed for MEDLINE]

[maxwatt]

SIRT's stock price, research, theories, and anecdotal accounts (other people's experience) have little influence on me at this point.  My own experiece (correctly just anecdotal to you folks) in taking resveratrol for almost a year is more important to me than all that.  For me resveratrol is  extremely effective.

Care to elaborate?

My own admittedly subjective experience includes greatly reduced or eliminated arthritic symptoms, increased exercise endurance, sense of physical well-being, fewer colds than normal (or is that the Vitamin D?) faster healing of minor cuts, a feeling greater mental acuity.

[steelheader]

Maybe the effects of resveratrol are more dramatic for older subjects. At 71 (in a couple of weeks) I feel like I'm back in my early 60s. I've lost 20 pounds, chronic pains in back and legs have vanished, I have better balance, better endurance, and lot's more "get up and go". And I'm happier! All of which is rock solid evidence for resveratrol, but only to me. The point of my post is that personal experiment trumps all, but only for the person doing the experiencing.

[resveratrol]

Maybe the effects of resveratrol are more dramatic for older subjects.  At 71 (in a couple of weeks) I feel like I'm back in my early 60s.  I've lost 20 pounds, chronic pains in back and legs have vanished, I have better balance, better endurance, and lot's more "get up and go". And I'm happier! All of which is rock solid evidence for resveratrol, but only to me.  The point of my post is that personal experiment trumps all, but only for the person doing the experiencing.

That's fantastic ... congratulations!

[sUper GeNius]

Maybe the effects of resveratrol are more dramatic for older subjects.  At 71 (in a couple of weeks) I feel like I'm back in my early 60s.  I've lost 20 pounds, chronic pains in back and legs have vanished, I have better balance, better endurance, and lot's more "get up and go". And I'm happier! All of which is rock solid evidence for resveratrol, but only to me.  The point of my post is that personal experiment trumps all, but only for the person doing the experiencing.

But how did you feel a few months ago? Maybe you are simply bipolar.

[steelheader]

Maybe the effects of resveratrol are more dramatic for older subjects.  At 71 (in a couple of weeks) I feel like I'm back in my early 60s.  I've lost 20 pounds, chronic pains in back and legs have vanished, I have better balance, better endurance, and lot's more "get up and go". And I'm happier! All of which is rock solid evidence for resveratrol, but only to me.  The point of my post is that personal experiment trumps all, but only for the person doing the experiencing.

But how did you feel a few months ago? Maybe you are simply bipolar.

Or maybe I'm lying or it's a placebo effect. I know that's not the case but you can't know that.

I felt the same way a few months ago as I feel now. Changes were most noticable shortly after I started taking resveratrol last winter and have long since leveled out. I would like to lose some more weight but that's not happening.

[kenj]

>>> I would like to lose some more weight but that's not happening. <<<

Seems resveratrol is making it very hard to shed weight, beyond what the body is naturally comfortable with!? *I'm* also more prone to whatever vira is around, when I'm on resv, higher doses.

[HighDesertWizard]

My own admittedly subjective experience includes greatly reduced or eliminated arthritic symptoms, increased exercise endurance, sense of physical well-being, fewer colds than normal (or is that the Vitamin D?) faster healing of minor cuts, a feeling greater mental acuity.

I just began Resveratrol a few weeks ago and I have sensed increased energy and sense of physical well-being. My wife and a friend have noticed this in me too. I have a similar problem too in that I began higher dosage Vitamin D supplementation at the same time as Resveratrol and so I can't pinpoint the source of this goodness.

[resveratrol]

I just began Resveratrol a few weeks ago and I have sensed increased energy and sense of physical well-being.  My wife and a friend have noticed this in me too.  I have a similar problem too in that I began higher dosage Vitamin D supplementation at the same time as Resveratrol and so I can't pinpoint the source of this goodness.

It's almost certainly the resveratrol. I've never seen vitamin D to cause that kind of effect, and I didn't notice anything like that once I went from 1000 IU to a higher dosage.