60 replies to this topic

[mikeinnaples]

Is plausible to think that a certain serum level or saturation level is require to cause SIRT expression, but lesser doses are still benficial for other reasons sans SIRT expression?

[niner]

Is plausible to think that a certain serum level or saturation level is require to cause SIRT expression, but lesser doses are still benficial for other reasons sans SIRT expression?

It's certainly plausible. Resveratrol "activates" sirtuins by participating in substrate binding or catalysis. It could have this effect regardless of whether or not expression was upregulated. The EC50 for this is fairly high though, so if it's happening significantly at low doses we may need to invoke some sort of concentrating mechanism. Maxwatt posted some evidence of active transport a long while back.

[Shannon Vyff]

I haven't been convinced of its efficacy, as resveratrol's activation of sirtuins may not help humans that much, unless they have major metobolic issues or diabetes. http://www.benbest.c....html#silencing It is all very interesting, and I'm sure there will be great developments in the next decade

[VP.]

Nicholas Wade of the NYT was able to interview some of the leading scientists in the field and get their opinions on the study:

June 4, 2008
New Hints Seen That Red Wine May Slow Aging
By NICHOLAS WADE
Red wine may be much more potent than was thought in extending human lifespan, researchers say in a new report that is likely to give impetus to the rapidly growing search for longevity drugs.

The study is based on dosing mice with resveratrol, an ingredient of some red wines. Some scientists are already taking resveratrol in capsule form, but others believe it is far too early to take the drug, especially using wine as its source, until there is better data on its safety and effectiveness.

The report is part of a new wave of interest in drugs that may enhance longevity. On Monday, Sirtris, a startup founded in 2004 to develop drugs with the same effects as resveratrol, completed its sale to GlaxoSmithKline for $720 million.

Sirtris is seeking to develop drugs that activate protein agents known in people as sirtuins.

“The upside is so huge that if we are right, the company that dominates the sirtuin space could dominate the pharmaceutical industry and change medicine,” Dr. David Sinclair of the Harvard Medical School, a co-founder of the company, said Tuesday.

Serious scientists have long derided the idea of life-extending elixirs, but the door has now been opened to drugs that exploit an ancient biological survival mechanism, that of switching the body’s resources from fertility to tissue maintenance. The improved tissue maintenance seems to extend life by cutting down on the degenerative diseases of aging.

The reflex can be prompted by a faminelike diet, known as caloric restriction, which extends the life of laboratory rodents by up to 30 percent but is far too hard for most people to keep to and in any case has not been proven to work in humans.

Research started nearly 20 years ago by Dr. Leonard Guarente of the Massachusetts Institute of Technology showed recently that the famine-induced switch to tissue preservation might be triggered by activating the body’s sirtuins. Dr. Sinclair, a former student of Dr. Guarente, then found in 2003 that sirtuins could be activated by some natural compounds, including resveratrol, previously known as just an ingredient of certain red wines.

Dr. Sinclair’s finding led in several directions. He and others have tested resveratrol’s effects in mice, mostly at doses far higher than the minuscule amounts in red wine. One of the more spectacular results was obtained last year by Dr. John Auwerx of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France. He showed that resveratrol could turn plain vanilla, couch-potato mice into champion athletes, making them run twice as far on a treadmill before collapsing.

The company Sirtris, meanwhile, has been testing resveratrol and other drugs that activate sirtuin. These drugs are small molecules, more stable than resveratrol, and can be given in smaller doses. In April, Sirtris reported that its formulation of resveratrol, called SRT501, reduced glucose levels in diabetic patients.

The company plans to start clinical trials of its resveratrol mimic soon. Sirtris’s value to GlaxoSmithKline is presumably that its sirtuin-activating drugs could be used to treat a spectrum of degenerative diseases, like cancer and Alzheimer’s, if the underlying theory is correct.

Separately from Sirtris’s investigations, a research team led by Tomas A. Prolla and Richard Weindruch, of the University of Wisconsin, reports in the journal PLoS One on Wednesday that resveratrol may be effective in mice and people in much lower doses than previously thought necessary. In earlier studies, like Dr. Auwerx’s of mice on treadmills, the animals were fed such large amounts of resveratrol that to gain equivalent dosages people would have to drink more than 100 bottles of red wine a day.

The Wisconsin scientists used a dose on mice equivalent to just 35 bottles a day. But red wine contains many other resveratrol-like compounds that may also be beneficial. Taking these into account, as well as mice’s higher metabolic rate, a mere four, five-ounce glasses of wine “starts getting close” to the amount of resveratrol they found effective, Dr. Weindruch said.
Resveratrol can also be obtained in the form of capsules marketed by several companies. Those made by one company, Longevinex, include extracts of red wine and of a Chinese plant called giant knotweed. The Wisconsin researchers conclude that resveratrol can mimic many of the effects of a caloric-restricted diet “at doses that can readily be achieved in humans.”

The effectiveness of the low doses was not tested directly, however, but with a DNA chip that measures changes in the activity of genes. The Wisconsin team first defined the pattern of gene activity established in mice on caloric restriction, and then showed that very low doses of resveratrol produced just the same pattern.

Dr. Auwerx, who used doses almost 100 times greater in his treadmill experiments, expressed reservations about the new result. “I would be really cautious, as we never saw significant effects with such low amounts,” he said Tuesday in an e-mail message.
Another researcher in the sirtuin field, Dr. Matthew Kaeberlein of the University of Washington in Seattle, said, “There’s no way of knowing from this data, or from the prior work, if something similar would happen in humans at either low or high doses.”

A critical link in establishing whether or not caloric restriction works the same wonders in people as it does in mice rests on the outcome of two monkey trials. Since rhesus monkeys live for up to 40 years, the trials have taken a long time to show results. Experts said that one of the two trials, being conducted by Dr. Weindruch, was at last showing clear evidence that calorically restricted monkeys were outliving the control animals.

But no such effect is apparent in the other trial, being conducted at the National Institutes of Health.

The Wisconsin report underlined another unresolved link in the theory, that of whether resveratrol actually works by activating sirtuins. The issue is clouded because resveratrol is a powerful drug that has many different effects in the cell. The Wisconsin researchers report that they saw no change in the mouse equivalent of sirtuin during caloric restriction, a finding that if true could undercut Sirtris’s strategy of looking for drugs that activate sirtuin.

Dr. Guarente, a scientific adviser to Sirtris, said the Wisconsin team only measured the amount of sirtuin present in mouse tissues, and not the more important factor of whether it had been activated.
Dr. Sinclair said the definitive answer would emerge from experiments, now under way, with mice whose sirtuin genes had been knocked out. “The question of how resveratrol is working is an ongoing debate and it will take more studies to get the answer,” he said.
Dr. Robert E. Hughes of the Buck Institute for Age Research said there could be no guarantee of success given that most new drug projects fail. But, he said, testing the therapeutic uses of drugs that mimic caloric restriction is a good idea, based on substantial evidence.

Sardi's got love the plug for Longevinex.

[sUper GeNius]

Sardi's got love the plug for Longevinex.

Makes you kind of wonder why he would even get a plug. And an exclusive one at that.


Edit: Removed long double quote of the NYT article

Edited by Technosophy, 06 June 2008 - 03:08 AM.

[porthose]

Sardi's got love the plug for Longevinex.

Makes you kind of wonder why he would even get a plug. And an exclusive one at that.


Edit: Removed long double quote of the NYT article

ok. despite his less than reputable marketing and his overpriced resveratrol supps, is his formulation any good?

[maxwatt]

Sardi's got love the plug for Longevinex.

Makes you kind of wonder why he would even get a plug. And an exclusive one at that.


Edit: Removed long double quote of the NYT article

ok. despite his less than reputable marketing and his overpriced resveratrol supps, is his formulation any good?

It has never been tested in any meaningful way for efficacy in mice, much less humans.

[malbecman]

Wow, nice thread to have popped up in my absence, sorry I missed all the good discussions and it sounds like you've hammered out many of the doseage issues. I will continue to take my ~1 gram/day with hypermellulose.


Now 35 bottles a day I could almost handle:

"The Wisconsin scientists used a dose on mice equivalent to just 35 bottles a day. But red wine contains many other resveratrol-like compounds that may also be beneficial. Taking these into account, as well as mice’s higher metabolic rate, a mere four, five-ounce glasses of wine “starts getting close” to the amount of resveratrol they found effective, Dr. Weindruch said. "


Robert Mondavi (God rest his soul), who just passed away at 95, was also known to be to split a bottle of red wine pretty much every night with his wife and family.

[kismet]

Experts said that one of the two trials, being conducted by Dr. Weindruch, was at last showing clear evidence that calorically restricted monkeys were outliving the control animals.

But no such effect is apparent in the other trial, being conducted at the National Institutes of Health

Ok, I know there are 2 ongoing studies on primates, rhesus (NIA-trial) and squirrel monkeys (NIH-trial) afaik, but does that quote imply that one of them did not show any evidence yet or that it probably won't show any life extension at all?

A short pubmed search revealed that they have seen 'attenuated Alzheimer's disease type brain amyloidosis' in the NIH trial (anno 2006), no mention of life extension. However, the trial on rhesus monkeys may have been more successful as suggested by the above quote.

[Michael]

All:

Experts said that one of the two trials, being conducted by Dr. Weindruch, was at last showing clear evidence that calorically restricted monkeys were outliving the control animals.

But no such effect is apparent in the other trial, being conducted at the National Institutes of Health

Ok, I know there are 2 ongoing studies on primates, rhesus (NIA-trial) and squirrel monkeys (NIH-trial) afaik, but does that quote imply that one of them did not show any evidence yet or that it probably won't show any life extension at all?

I just answered this here.

-Michael

[TianZi]

This paper by Weindruch et al. doesn't seem to jibe with previous
papers by the Sinclair group. Am I the only one bothered by this?
Furthermore, Weindruch and Sinclair get together at events and carry
on as if they were on the same page. There was a longevity event at
the New York University hall. Among others, both these guys were in
attendance and gave talks. From a report of the event:
[Weindruch said his research, which began by showing how consuming little food could
greatly increase the life spans of mice, moved on in 1989 to a
long-term study on monkeys that can live up to 40 years. "Just now
we're starting to see statistically significant improvements in
survival and resistance to disease and favorable effects on brain
aging," he said. He said his team hopes to publish these results soon.
Sinclair said that based on Weindruch's work, he set out a decade ago
to find the genes involved in caloric restriction and find a pill that
can provide the benefits "without you feeling hungry all the time." He
described how his research found that mice given large doses of
resveratrol "live longer, they're almost immune to the effects of
obesity. They don't get diabetes, cancer, Alzheimer's as frequently.
We delay the diseases of aging." Sinclair showed video of mice on
resveratrol running on a treadmill far more vigorously than those who
didn't get the substance. He called them "our Lance Armstrong mice."]
Now, if I understood anything from Weindruch's paper, one of the
conclusions was "neither CR nor resveratrol feeding significantly altered the
levels of SIRT1 protein in brain or liver of mice, and SIRT1 abundance
was actually significantly decreased in both heart and muscle of CR
mice".
So SIRT1 has nothing to do with what RSV is doing? Are Weindruch and
Prolla going to start a new company SIRTISN"T?

See my earlier post in this thread.

The authors of this study suggest they didn't use high enough doses of resveratrol to trigger SIRT1 activity, explaining the apparent discrepency (see my quote from the study on this point). SIRT1 activity triggered by higher doses of resveratrol may lead to effects different not only in magnitude but in kind.

[inawe]

This paper by Weindruch et al. doesn't seem to jibe with previous
papers by the Sinclair group. Am I the only one bothered by this?
Furthermore, Weindruch and Sinclair get together at events and carry
on as if they were on the same page. There was a longevity event at
the New York University hall. Among others, both these guys were in
attendance and gave talks. From a report of the event:
[Weindruch said his research, which began by showing how consuming little food could
greatly increase the life spans of mice, moved on in 1989 to a
long-term study on monkeys that can live up to 40 years. "Just now
we're starting to see statistically significant improvements in
survival and resistance to disease and favorable effects on brain
aging," he said. He said his team hopes to publish these results soon.
Sinclair said that based on Weindruch's work, he set out a decade ago
to find the genes involved in caloric restriction and find a pill that
can provide the benefits "without you feeling hungry all the time." He
described how his research found that mice given large doses of
resveratrol "live longer, they're almost immune to the effects of
obesity. They don't get diabetes, cancer, Alzheimer's as frequently.
We delay the diseases of aging." Sinclair showed video of mice on
resveratrol running on a treadmill far more vigorously than those who
didn't get the substance. He called them "our Lance Armstrong mice."]
Now, if I understood anything from Weindruch's paper, one of the
conclusions was "neither CR nor resveratrol feeding significantly altered the
levels of SIRT1 protein in brain or liver of mice, and SIRT1 abundance
was actually significantly decreased in both heart and muscle of CR
mice".
So SIRT1 has nothing to do with what RSV is doing? Are Weindruch and
Prolla going to start a new company SIRTISN"T?

See my earlier post in this thread.

The authors of this study suggest they didn't use high enough doses of resveratrol to trigger SIRT1 activity, explaining the apparent discrepency (see my quote from the study on this point). SIRT1 activity triggered by higher doses of resveratrol may lead to effects different not only in magnitude but in kind.

No, I prefer to get it directly from the horses mouth. Unless you can prove to me that you know more about this than Weindruch.
More important than what RSV is doing is what the CR effect is. Contrary to claims by other authors, Weindruch et al. didn't see any
SIRT1 overexpression caused by CR. As a layman, I believe Weindruch microchip technique is more reliable than what Sinclair et al. used.
Did you read the paper? Are you going to tell me they should have used higher doses of CR?

[lhobbs1]

On a side note, I wonder if a heads up on this is what led the Sincalir group to sell to GSK. If low dosages of a readily available nutritional supplement can achieve a CR mimetic role, who needs 501? Well there were the NCE's, so .....

As one who likes a good conspiracy theory, I wonder if Sirtris was taken out because the results they were getting were just too good and GSK recognized a risk to current and future drug development, i.e., profits.
Perhaps this takeover buys them some time to suppress the information so they can continue developing drugs that cause complications they can treat.
Call me cynical but I will be watching for a Sirtris clone to see how long it lasts before being bought.
I will continue with 500 mg./day or so of resv.

[sUper GeNius]

On a side note, I wonder if a heads up on this is what led the Sincalir group to sell to GSK. If low dosages of a readily available nutritional supplement can achieve a CR mimetic role, who needs 501? Well there were the NCE's, so .....

As one who likes a good conspiracy theory, I wonder if Sirtris was taken out because the results they were getting were just too good and GSK recognized a risk to current and future drug development, i.e., profits.
Perhaps this takeover buys them some time to suppress the information so they can continue developing drugs that cause complications they can treat.
Call me cynical but I will be watching for a Sirtris clone to see how long it lasts before being bought.
I will continue with 500 mg./day or so of resv.

Very interesting conjecture. T-res is found to be very effective against several diseases of aging, company decides it needs time to formulate a product that a) shows efficacy similar to t-res, and b) is patentable.

Very possible IMO.

[niner]

This paper by Weindruch et al. doesn't seem to jibe with previous
papers by the Sinclair group. Am I the only one bothered by this?
Furthermore, Weindruch and Sinclair get together at events and carry
on as if they were on the same page. There was a longevity event at
the New York University hall. Among others, both these guys were in
attendance and gave talks. From a report of the event:
[Weindruch said his research, which began by showing how consuming little food could
greatly increase the life spans of mice, moved on in 1989 to a
long-term study on monkeys that can live up to 40 years. "Just now
we're starting to see statistically significant improvements in
survival and resistance to disease and favorable effects on brain
aging," he said. He said his team hopes to publish these results soon.
Sinclair said that based on Weindruch's work, he set out a decade ago
to find the genes involved in caloric restriction and find a pill that
can provide the benefits "without you feeling hungry all the time." He
described how his research found that mice given large doses of
resveratrol "live longer, they're almost immune to the effects of
obesity. They don't get diabetes, cancer, Alzheimer's as frequently.
We delay the diseases of aging." Sinclair showed video of mice on
resveratrol running on a treadmill far more vigorously than those who
didn't get the substance. He called them "our Lance Armstrong mice."]
Now, if I understood anything from Weindruch's paper, one of the
conclusions was "neither CR nor resveratrol feeding significantly altered the
levels of SIRT1 protein in brain or liver of mice, and SIRT1 abundance
was actually significantly decreased in both heart and muscle of CR
mice".
So SIRT1 has nothing to do with what RSV is doing? Are Weindruch and
Prolla going to start a new company SIRTISN"T?

See my earlier post in this thread.

The authors of this study suggest they didn't use high enough doses of resveratrol to trigger SIRT1 activity, explaining the apparent discrepency (see my quote from the study on this point). SIRT1 activity triggered by higher doses of resveratrol may lead to effects different not only in magnitude but in kind.

No, I prefer to get it directly from the horses mouth. Unless you can prove to me that you know more about this than Weindruch.
More important than what RSV is doing is what the CR effect is. Contrary to claims by other authors, Weindruch et al. didn't see any
SIRT1 overexpression caused by CR. As a layman, I believe Weindruch microchip technique is more reliable than what Sinclair et al. used.
Did you read the paper? Are you going to tell me they should have used higher doses of CR?

The horse's mouth? Are you going to email Weindruch? Weindruch's chip looks at expression levels, but it can't tell you anything about how the activity of the existing SIRT1 is altered, either by RSV or by NAD+/NADH ratios and levels. Expression is only part of the total activity. The rest is determined by molecular events at or near the active site of the enzyme. I think that Tian Zi makes a good point.

[inawe]

I think that Tian Zi makes a good point.

The good point is what?
Weindruch et al. didn't detect any overexpression of SIRT1 in the CR mice. So what's the point of claiming something is a CR mimetic because it does something to SIRT1? The pathways by which CR is life extending (if at all) might be completely different.
Also, Sinclair and collaborators first noticed activation of Sir2 by RSV in yeast. But it was contested by Kaeberlein and Kennedy:
"We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo".
The connection between CR and RSV via Sirtuins was never proven in any conclusive way.

I take RSV everyday because I think it provides small benefits for many different things. I'm sort of glad it doesn't have any large effect on Sirtuins. Overexpression or upregulation of Sirtuins increases histone deacetylation. This tightens up the chromatin and restricts transcription. I don't know if it's a good idea to have this systemically.

[krillin]

For a person 150lbs, 68inchs and wants 4.9mg/kg this FDA calculator says you need a dose of 334.09mg of

Based on a rat model that took 50mg/kg you get a plasma concentration of 548ng/mL and if you scale it down you could assume you get a plasma concentration of 53.68ng/mL if you give a rat a 4.9mg/kg dose.

Assume that the boocock paper (human plasma data) is correct which in a 500mg dose they achieved a 72ng/mL level. If we assume the average person in the study is 150lbs or 68kg then the dosage per kg is 7.4mg/kg. This also achieves a higher plasma concentration then what is seen in the rat model. If you do the conversion you need to take about 350mg dose to achieve a plasma concentration of 53ng/mL.

The FDA formula suggested 334mg human dose would be equivalent. So IMO it is pretty close

This math assumes lots of things.... (mainly weight of a person and of the rats they used)

If this calculation is correct, the rat's higher metabolism is almost exactly canceled out by its lower conjugation of resveratrol, so we don't even need a conversion factor to apply rat studies to humans. So here's a range of results to expect.

5 mg/kg: replicate the effects of CR on gene expression for about half the genes affected by CR, but not enough to activate SIRT1
20-25 mg/kg: overcome effects of bad diet (PMIDs 18356487, 17086191), NFkB inhibition (Maxwatt's toe)
400 mg/kg: more mitochondria (PMID 17112576)

[niner]

I think that Tian Zi makes a good point.

The good point is what?

It's exactly what he said in the post we were talking about:

The authors of this study suggest they didn't use high enough doses of resveratrol to trigger SIRT1 activity, explaining the apparent discrepency (see my quote from the study on this point). SIRT1 activity triggered by higher doses of resveratrol may lead to effects different not only in magnitude but in kind.

Weindruch et al. didn't detect any overexpression of SIRT1 in the CR mice. So what's the point of claiming something is a CR mimetic because it does something to SIRT1? The pathways by which CR is life extending (if at all) might be completely different.

There doesn't have to be overexpression of SIRT1 for CR to involve SIRT1. Expression is not the only determinant of activity. (I think this is the fourth time this concept has been put forth in this thread.) The Weindruch article shows that a low dose of resveratrol alters the expression of many of the same genes as CR. That's all. It's a fair question as to whether or not this constitutes being a "CR mimetic". I think it's at least safe to say that it's a partial CR mimetic.

Also, Sinclair and collaborators first noticed activation of Sir2 by RSV in yeast. But it was contested by Kaeberlein and Kennedy:
"We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo".
The connection between CR and RSV via Sirtuins was never proven in any conclusive way.

I thought that the fluor de lys issue had been put to bed. Could it be that K&K were using a low dose? The EC50 for enhancement of acetylation by resveratrol is pretty high, like 40+ uM.

[niner]

For a person 150lbs, 68inchs and wants 4.9mg/kg this FDA calculator says you need a dose of 334.09mg of

Based on a rat model that took 50mg/kg you get a plasma concentration of 548ng/mL and if you scale it down you could assume you get a plasma concentration of 53.68ng/mL if you give a rat a 4.9mg/kg dose.

Assume that the boocock paper (human plasma data) is correct which in a 500mg dose they achieved a 72ng/mL level. If we assume the average person in the study is 150lbs or 68kg then the dosage per kg is 7.4mg/kg. This also achieves a higher plasma concentration then what is seen in the rat model. If you do the conversion you need to take about 350mg dose to achieve a plasma concentration of 53ng/mL.

The FDA formula suggested 334mg human dose would be equivalent. So IMO it is pretty close

This math assumes lots of things.... (mainly weight of a person and of the rats they used)

If this calculation is correct, the rat's higher metabolism is almost exactly canceled out by its lower conjugation of resveratrol, so we don't even need a conversion factor to apply rat studies to humans. So here's a range of results to expect.

5 mg/kg: replicate the effects of CR on gene expression for about half the genes affected by CR, but not enough to activate SIRT1
20-25 mg/kg: overcome effects of bad diet (PMIDs 18356487, 17086191), NFkB inhibition (Maxwatt's toe)
400 mg/kg: more mitochondria (PMID 17112576)

Wait, something's funky here. Hedgehog, if you're reading, where did you find that rat data? Marier's rats at 50 mg/kg had a Cmax of 6.6uM, while 548ng/ml * (4.386nM/ng/ml) = 2.4uM. So Marier's rats are hitting three times the Cmax on the same dose. They were dosed orally, so I don't see where the discrepancy comes from. Marier is http://pmid.us/12065739

Comparing large oral doses of resveratrol between rats and humans, looking at Cmax, I get:

Marier (rat) 6.6 uM/50 mg kg(-1) = 0.132
Boocock (human) 2.4 uM/71 mg kg(-1) = 0.0338

0.132/0.0338 = 3.9 So the rats are seeing a Cmax that is 4 times that of the human Cmax on the same mg/kg dose. So to see the blood levels of rats getting 5mg/kg, we probably want more like 20mg/kg, or ~1.4 g/day. That's not too hard to do. Overcoming a bad diet? A bit over 5 grams per day. More mitochondria? If it really takes 400mg/kg to do it in rats (it might take quite a bit less), then at 1600mg/kg, a 70 kg human would need to eat 112 grams a day, which is decidedly not on for most of us. In reality, I think the more mitos application probably takes a lot less. Sirtris has a trial going for MELAS, a mitochondrial defect disorder. If the goal there is to generate more mitos, then we should be able to find out the dose they used in the trial eventually.

[VictorBjoerk]

Does resveratrol have any toxic effects when consumed in very large amounts?

[VictorBjoerk]

I've not heard any but isn't everything toxic in large doses just like Vitamin C

[maxwatt]

Does resveratrol have any toxic effects when consumed in very large amounts?

I think you can kill a rat by hitting it over the head with a jar of the stuff.

[krillin]

Does resveratrol have any toxic effects when consumed in very large amounts?

Toxicol Sci. 2004 Dec;82(2):614-9.
Resveratrol-associated renal toxicity.
Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS.
Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland 20892-7322, USA. jc94h@nih.gov

Resveratrol, (3,5,4'-trihydoxystilbene) a compound found in grapes, mulberries, and peanuts, has antimycotic, antiviral, and beneficial cardiovascular and cancer preventive activities. It is being developed for several clinical indications. To evaluate the potential toxicity of resveratrol, rats were administered by gavage 0, 300, 1000, and 3000 mg trans-resveratrol per kilogram body weight per day for 4 weeks. Most of the adverse events occurred in the rats administered 3000 mg per kilogram body weight per day. These included increased clinical signs of toxicity; reduced final body weights and food consumption; elevated BUN, creatinine, alkaline phosphatase, alanine aminotransferase, total bilirubin, and albumin; reduced hemoglobin, hematocrit, and red cell counts; and increased white cell counts. Increases in kidney weights and clinically significant renal lesions, including an increased incidence and severity of nephropathy, were observed. Diffuse epithelial hyperplasia in the bladder was considered, equivocal and of limited biological significance. No histological effects on the liver were observed, despite the clinical chemistry changes and increased liver weights in the females. Effects seen in the group administered 1000 mg resveratrol per kilogram body weight per day included reduced body weight gain (females only) and elevated white blood cell count (males only). Plasma resveratrol concentrations in blood collected 1 h after dose administration during week 4 were dose related but were relatively low given the high dosage levels; conjugates were not measured. Under the conditions of this study, the no observed adverse effect level was 300 mg resveratrol per kilogram body weight per day in rats.

PMID: 15329443

[Hedgehog]

For a person 150lbs, 68inchs and wants 4.9mg/kg this FDA calculator says you need a dose of 334.09mg of

Based on a rat model that took 50mg/kg you get a plasma concentration of 548ng/mL and if you scale it down you could assume you get a plasma concentration of 53.68ng/mL if you give a rat a 4.9mg/kg dose.

Assume that the boocock paper (human plasma data) is correct which in a 500mg dose they achieved a 72ng/mL level. If we assume the average person in the study is 150lbs or 68kg then the dosage per kg is 7.4mg/kg. This also achieves a higher plasma concentration then what is seen in the rat model. If you do the conversion you need to take about 350mg dose to achieve a plasma concentration of 53ng/mL.

The FDA formula suggested 334mg human dose would be equivalent. So IMO it is pretty close

This math assumes lots of things.... (mainly weight of a person and of the rats they used)

If this calculation is correct, the rat's higher metabolism is almost exactly canceled out by its lower conjugation of resveratrol, so we don't even need a conversion factor to apply rat studies to humans. So here's a range of results to expect.

5 mg/kg: replicate the effects of CR on gene expression for about half the genes affected by CR, but not enough to activate SIRT1
20-25 mg/kg: overcome effects of bad diet (PMIDs 18356487, 17086191), NFkB inhibition (Maxwatt's toe)
400 mg/kg: more mitochondria (PMID 17112576)

Wait, something's funky here. Hedgehog, if you're reading, where did you find that rat data? Marier's rats at 50 mg/kg had a Cmax of 6.6uM, while 548ng/ml * (4.386nM/ng/ml) = 2.4uM. So Marier's rats are hitting three times the Cmax on the same dose. They were dosed orally, so I don't see where the discrepancy comes from. Marier is http://pmid.us/12065739

Comparing large oral doses of resveratrol between rats and humans, looking at Cmax, I get:

Marier (rat) 6.6 uM/50 mg kg(-1) = 0.132
Boocock (human) 2.4 uM/71 mg kg(-1) = 0.0338

0.132/0.0338 = 3.9 So the rats are seeing a Cmax that is 4 times that of the human Cmax on the same mg/kg dose. So to see the blood levels of rats getting 5mg/kg, we probably want more like 20mg/kg, or ~1.4 g/day. That's not too hard to do. Overcoming a bad diet? A bit over 5 grams per day. More mitochondria? If it really takes 400mg/kg to do it in rats (it might take quite a bit less), then at 1600mg/kg, a 70 kg human would need to eat 112 grams a day, which is decidedly not on for most of us. In reality, I think the more mitos application probably takes a lot less. Sirtris has a trial going for MELAS, a mitochondrial defect disorder. If the goal there is to generate more mitos, then we should be able to find out the dose they used in the trial eventually.

You are using a dosing information of a formulation (cyclodextrin) not pure resveratrol.... The Cmax is significatnly higher for that formulation. However, T1/2 is very short compared to pure resveratrol.

Cyclodextrin causes a fast high Cmax but blood levels don't last long... This is also noted in a patent. So you can't really use that Cmax because it has been formulated....

[TianZi]

Inawe said:

"No, I prefer to get it directly from the horses mouth. Unless you can prove to me that you know more about this than Weindruch.
More important than what RSV is doing is what the CR effect is. Contrary to claims by other authors, Weindruch et al. didn't see any
SIRT1 overexpression caused by CR. As a layman, I believe Weindruch microchip technique is more reliable than what Sinclair et al. used.
Did you read the paper? Are you going to tell me they should have used higher doses of CR?"


Yes, I did read the study, as would be obvious if you had read my initial post in this thread, which quoted extensively from it.

I definitely don't know as much, or even a fraction as much, about this subject as compared to someone like Weindruch. However, I do have some small confidence in my ability to read and understand simple statements he himself makes about the subject. From the horse's mouth (again):

"It is likely that the effects of resveratrol feeding at lower doses reported here are distinct than [sic] those observed with higher doses, with particular relevance to the induction of SIRT1 activity."

This was said by Weinbruch himself in the context of explaining why many other studies by his peers have shown SIRT1 activation with higher doses of resveratrol, and perhaps why other studies have shown beneficial effects not seen in his study, e.g. cancer protective effects. His conclusion therefore clearly seems not to argue that resveratrol given at any dose won't stimulate increased SIRT1 enzyme activity, or that increased SIRT1 activity in and of itself provides no beneficial effects in test subjects, but rather that at low doses resveratrol provides significant health benefits (that partially mimic CR) without induction of SIRT1 activity.

Perhaps an implicit assumption in your post is that if resveratrol triggers increased SIRT1 activity, we should see changing levels of SIRT1 activity commensurate with increases and decreases in dose. But such an assumption is incorrect--sometimes a "threshold" dose of a substance is required to trigger activity like this.

Edited by TianZi, 18 June 2008 - 08:42 AM.

[sUper GeNius]

Hey, didn't LEF do this a while back? I remember reading a blurb about how their product was tested and was shown to show similar gene expression as CR.

[malbecman]

Just for curiosities sake, what is the highest dose that anyone has taken or who knows that someone else has taken? Either 1 time or consistently. Come on, don't be shy.

Maybe we need a poll. I'll start it off: I've taken 2 grams at once of 99% with HPMC ( I was shootin for ~25 mg/kg).

I know Missminni's dogs have likely outdone us all.....

-Malbec

edit for typos

For a person 150lbs, 68inchs and wants 4.9mg/kg this FDA calculator says you need a dose of 334.09mg of

Based on a rat model that took 50mg/kg you get a plasma concentration of 548ng/mL and if you scale it down you could assume you get a plasma concentration of 53.68ng/mL if you give a rat a 4.9mg/kg dose.

Assume that the boocock paper (human plasma data) is correct which in a 500mg dose they achieved a 72ng/mL level. If we assume the average person in the study is 150lbs or 68kg then the dosage per kg is 7.4mg/kg. This also achieves a higher plasma concentration then what is seen in the rat model. If you do the conversion you need to take about 350mg dose to achieve a plasma concentration of 53ng/mL.

The FDA formula suggested 334mg human dose would be equivalent. So IMO it is pretty close

This math assumes lots of things.... (mainly weight of a person and of the rats they used)

If this calculation is correct, the rat's higher metabolism is almost exactly canceled out by its lower conjugation of resveratrol, so we don't even need a conversion factor to apply rat studies to humans. So here's a range of results to expect.

5 mg/kg: replicate the effects of CR on gene expression for about half the genes affected by CR, but not enough to activate SIRT1
20-25 mg/kg: overcome effects of bad diet (PMIDs 18356487, 17086191), NFkB inhibition (Maxwatt's toe)
400 mg/kg: more mitochondria (PMID 17112576)

Wait, something's funky here. Hedgehog, if you're reading, where did you find that rat data? Marier's rats at 50 mg/kg had a Cmax of 6.6uM, while 548ng/ml * (4.386nM/ng/ml) = 2.4uM. So Marier's rats are hitting three times the Cmax on the same dose. They were dosed orally, so I don't see where the discrepancy comes from. Marier is http://pmid.us/12065739

Comparing large oral doses of resveratrol between rats and humans, looking at Cmax, I get:

Marier (rat) 6.6 uM/50 mg kg(-1) = 0.132
Boocock (human) 2.4 uM/71 mg kg(-1) = 0.0338

0.132/0.0338 = 3.9 So the rats are seeing a Cmax that is 4 times that of the human Cmax on the same mg/kg dose. So to see the blood levels of rats getting 5mg/kg, we probably want more like 20mg/kg, or ~1.4 g/day. That's not too hard to do. Overcoming a bad diet? A bit over 5 grams per day. More mitochondria? If it really takes 400mg/kg to do it in rats (it might take quite a bit less), then at 1600mg/kg, a 70 kg human would need to eat 112 grams a day, which is decidedly not on for most of us. In reality, I think the more mitos application probably takes a lot less. Sirtris has a trial going for MELAS, a mitochondrial defect disorder. If the goal there is to generate more mitos, then we should be able to find out the dose they used in the trial eventually.

Edited by malbecman, 18 June 2008 - 06:54 PM.

[krillin]

Hey, didn't LEF do this a while back? I remember reading a blurb about how their product was tested and was shown to show similar gene expression as CR.

http://www.lef.org/m...veratrol_04.htm

They compared CR, resveratrol, and grape extract, which included a little more resveratrol (1.74 mg/kg) than what the resveratrol group got(1.45 mg/kg).

Interestingly, scientists noted a significant overlap—about 65%—when they compared the gene-expression patterns of the resveratrol and grape extract groups. While expected, these results confirm the similar effects of pure synthetic resveratrol and grape extract-derived resveratrol on gene expression in animals.

The gene-expression effects of “low-dose” resveratrol were similar to those seen in calorie-restricted mice: about 55% similarity between the calorie-restricted and resveratrol groups, and 52% similarity between the calorie-restricted and grape extract-supplemented groups.

So by adding OPCs to resveratrol, you get a little less like CR and a lot less like resveratrol alone.

[TianZi]

Thought I'd mention that within approx. the past day or so a formal correction has been made to this study as regards errors originally reported in gene expression data.

Follow the link to the study in the OP, and you'll see the note about this correction highlighted prominently at the top. However, it is unclear to me what precisely was changed, and the broad significance if any of those changes.

Edited by TianZi, 19 June 2008 - 08:41 AM.

[maxwatt]

Thought I'd mention that within approx. the past day or so a formal correction has been made to this study as regards errors originally reported in gene expression data.

Follow the link to the study in the OP, and you'll see the note about this correction highlighted prominently at the top. However, it is unclear to me what precisely was changed, and the broad significance if any of those changes.

It appears to be an addendum rather than a textual correction, giving access to some of the data that were analyzed. Unless I am missing something.