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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 10, 2011

Resveratrol in Humans: Results of a Controlled Trial

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Posted by Derek

The effects of resveratrol have been controversial, to say the least. Arguments rage about whether (and how) it affects the various sirtuin pathways, what those various sirtuin pathways are and what they do, and what the compound does in animal models at all (whether you care about the mechanism or not). That last topic recently boiled over once more. I've spoken about the compound and these issues many, many times around here, as long-time readers will know - go here and just keep scrolling back if you're interested. GSK halted its development of resveratrol itself (as opposed to follow-up ligands) last year, it appears.

Get ready for more head-scratching. There's a new paper out from researchers in the Netherlands and Switizerland looking at the effects of resveratrol in obese human subjects. They ran a small (11-subject) double-blind crossover trial vs. placebo of 150mg of resveratrol per day, and found. . .well, let me quote the summary, because I can't put it in fewer words myself. If you're not a technical kind of person, that last line (emphasis added) tells the story:

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.

Well, that is interesting. What this (and some of the earlier data) seems to be telling us is that resveratrol may well be beneficial - but particularly so under conditions of metabolic stress, such as in obesity. As for the mechanism, when they looked at muscle tissue samples, they found over 400 genes with altered expression (some up, some down). These seem to have particularly concentrated in metabolic and inflammation pathways, particularly mitochondrial oxidative phosphorylation. These are quite similar results to those seen in obese rodents.

On the other hand, some things were very different indeed in the two species. Mice actually showed an increase in energy expenditure during reservatrol treatment - these humans showed a decrease. The plasma concentration reached in both experiments were similar, but mice needed a 200-fold higher dose of resveratrol to reach that, which has to be one confounding factor. (Another is the duration of treatment; the mice got the compound for several months, which is longer by the calendar but also a much higher percentage of their entire lives).

Still, the effects in the human subjects were quite impressive. Not all the changes were huge, but they all seem to point in the same direction: mimicking the effects of caloric restriction and exercise. This is exactly the sort of thorough, well-controlled study this field has been needing, and it makes all the questions in it take on that much more urgency. What does resveratrol do in humans, on a molecular level? Are sirtuins involved, and to what extent? Can other compounds do the same thing, or even more? What are the long-term effects of such compounds on human morbidity and mortality? Do these effects only manifest themselves in obese subjects? How much would happen in people who are under less metabolic stress to start with? And so on. . .

Comments (43) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. Curious Wavefunction on November 10, 2011 10:53 AM writes...

I was hoping you would blog about this paper. I didn't read the whole thing and the results certainly look relevant and promising, but when I glanced at it I worried about both the small sample size and duration of the trial (30 days). With something as complex as 400 genes contributing to the observed effects, I would hold out for lengthier trials before drawing concrete conclusions.

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2. Wile E. Coyote. Genius on November 10, 2011 11:05 AM writes...

A couple things really caught were the portions of the abstract that said (I've not read the paper):

1) "Resveratrol significantly reduced sleeping and resting metabolic rate."
2) "In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased."

These points suggest to me that resveratrol may not be beneficial in humans, as in point 2, fat is not being mobilized and removed from the adipose tissue. In fact, the opposite, might be taking place if adipose lipolysis is reduced and if fat deposition is unchanged. That agrees with the reduced metabolic rate in point 2. People with a high metabolict rate can eat like a horese, but not gain weight. For this stuff to be a benefit, seems to me that there should be increased lipolysis and an increased metabolic rate.

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3. Wile E. Coyote, Genius on November 10, 2011 11:08 AM writes...

For all the really snarky people out there, my last post should read: A couple of things really caught my eye which were....

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4. anchor on November 10, 2011 11:39 AM writes...

Derek; The jury is still out there as this trial size and the duration of it are small. In the same breadth did you hear the yesterday's news at NBC? I am always wary when major advances in science are reported in main stream news. Anyway the husband and wife team in Houston (some hospital) claimed that a drug named "Adipotide" reduced the body weight (BW) on monkeys (11% on rhesus, I suppose. The study lasted 28 days. Any idea about this story? I also welcome comments from the blogger's.

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5. a ha on November 10, 2011 11:51 AM writes...

My take,
Low dose resveratrol works. It does the job of numerous pharmaceuticals. It is non toxic and non patentable.

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6. Cellbio on November 10, 2011 12:38 PM writes...

Anchor,

I don't know a lot about adipotide, but one of the authors spent time in Ruoshlati's lab, which might be the source of the homing peptide, which is purported to bind to blood vessels specific to fat tissue. Conjugated to that is a toxin (not sure of the nature). Interesting and bold idea. Don't think I'd have the guts to develop this, but it could work? Hope the homing peptide has remarkable specificity and that preclinical species are predictive of humans. Wonder about clearance and associated tox too. Arrowhead research had a nice day with a 38% stock gain.

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7. Morten G on November 10, 2011 1:00 PM writes...

So healthier but fatter? Less CVD, less diabetes, more sweaty fat people next to me on the plane. Okay.

Adipotide is a daily injectable and a bit of a strain on the kidneys. When the fat monkeys where taken of it and returned to their cages they started gaining weight again after 2 weeks.

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8. Vader on November 10, 2011 1:12 PM writes...

Double-blind crossover study: Good.

11 subjects: I have a tough with a study that small, no matter what the formal statistical significance is claimed to be.

But I'm not a methodologist.

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9. dori on November 10, 2011 1:32 PM writes...

Fatter? The human subjects did not gain weight. Moreover, mice on high doses of resveratrol lost weight. And mice on moderate doses did not lose weight but had a better muscle to fat ratio.

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10. Bill Sardi on November 10, 2011 1:32 PM writes...

Re: First human resveratrol study

Yes, certainly, the results were modest in the short-term but greater response can be anticipated over longer term since significant gene differentiation in calorie-restricted mice increases from 198 genes at 12 weeks to 831 genes (Weindruch & Prolla research) at ~2-3 years. This is the first time a gene array in human tissue has been reported and 459 genes is certainly a broad epigenetic effect. That male humans achieved a blood concentration of resveratrol equal to that achieved in rodents with 133-266 fold greater dose points to a reason why prior studies may not have been conclusive. Resveratrol is posed as a hormetic agent, that is a low-dose toxin activates internal defenses in the body. This may explain why the Sirtris trial employing 5000 mg among multiple myeloma patients had to be halted due to kidney failure. At low dose resveratrol is an antioxidant, high-dose it is a pro-oxidant. High-dose res pills out to be outed from the marketplace.

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11. luysii on November 10, 2011 2:04 PM writes...

Did the subjects lose weight? 30 days of calorie restriction should produce some weight loss.

Back in the day, Garfield Duncan was hospitalizing (because nobody knew what would happen)the morbidly obese and totally fasting them (with vitamin supplementation, daily electrolytes, EKGs, etc. etc.). After the initial burst of weight loss, subjects went into ketosis and weren't even hungry. The maximum weight loss on this regimen was about 1/2 pounds/daily.

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12. Bgarrett on November 10, 2011 2:49 PM writes...

Thank you for the article. I am willing to believe in resveratrol but my faith breaks down when I get to the store.
Lots of products claim to be Resveratrol but which are worthy of my dollars?

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13. lord garth on November 10, 2011 3:33 PM writes...

The study involved only 11 people.

The only thing the study really shows is that it may be worthwhile to do a study with more people for a longer period and without the crossover.

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14. DA Burden on November 10, 2011 3:38 PM writes...

FWIW, it is an inhibitor of the catalytic activity of DNA toposiomerase II (alpha isoform; haven't tested beta). This is not to be confused with a topo II poison, but the effects of blocking the catalytic activity of topo II (as opposed to poisoning it) are less well-known. I would expect that at low levels (in vitro) it would tend to be cytostatic. High levels, who knows? I just know that I wouldn't go jacking around with my topo II unless I really, really need to (like I have cancer, for instance). There's no telling what someting like a 20 yr time frame will reveal for people taking it. It might be great, but it wouldn't surprise me in the least if people taking it long-term developed cancers (I'm not asserting they will, mind you).

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15. G8rDaVe on November 10, 2011 4:10 PM writes...

Not a doctor, not a statistician but I'd say
a) too small a sample
b) too short a time frame
c) don't know enough of what happens to people when the drug is no longer taken.

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16. dori on November 10, 2011 4:37 PM writes...

Fatter? The human subjects did not gain weight. Moreover, mice on high doses of resveratrol lost weight. And mice on moderate doses did not lose weight but had a better muscle to fat ratio.

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17. johnnyboy on November 10, 2011 5:10 PM writes...

These results are probably interesting, from the standpoint of a researcher in cell metabolism. From a medical perspective though, we're quite far from something that indicates significantly beneficial effects.

In addition to the already pointed out very small n (which I guess can be excused by the extent and the complexity of assays done), I would also underline the fairly minor extent of most of the differences seen, and their lack of medical significance. Tell an atherosclerosis specialist that your one month treatment caused a decrease in ALT from 31.9 to 28.1, and a decrease in triglycerides from 2.29 to 2.16, and some other changes on in vitro cell assays that have unknown medical predictive value, without inducing any changes in cholesterol values or in body weight and fat, and you'll see the longest yawn ever.

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18. WJ on November 10, 2011 5:23 PM writes...

who funded the study?

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19. terl on November 10, 2011 5:37 PM writes...

@johnnyboy, u must work in an industry sustained by patent protection.

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20. terl on November 10, 2011 5:38 PM writes...

@johnnyboy, u must work in an industry sustained by patent protection.

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21. Really? on November 10, 2011 6:28 PM writes...

I just glanced over the paper and I cannot for the life of me understand how it got published.
Most importantly, the markers they look at are not changed. Their p values may say they are different but this doesn't change the fact that they, from what I have seen so far, are inconsequential. This seems to hold true for most of what I've seen of the paper.

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22. johnnyboy on November 10, 2011 6:48 PM writes...

@ 20-21 teri (are you related to dori ?): you say that like it's a bad thing.

I'm guessing that you work in an industry that's sustained by Orrin Hatch ?

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23. rb on November 10, 2011 7:56 PM writes...

re FWIW, DNA toposiomerase II (alpha isoform)

I was under the impression that high expressions of alpha topoII were characteristic of nasty cancers, and that inhibiting alpha topoII might be a good thing...

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24. DA Burden on November 10, 2011 9:27 PM writes...

rb,
High levels of topo II generally correlate with cells dividing more quickly, and for this reason poisoning of topo II tends to affect cancer cells more than normal cells. Obviously, the problem is that normal cells that rapidly proliferate are also sensitive to the poisons (myelosuppression is usually the dose-limiting toxicity, IIRC). Inhibiting the catalytic activity of the enzyme should prevent cells from dividing, and when you treat cells with topo II inhibitors they will arrest (at metaphase, and in some cases prior to mitosis) as topo II is absolutely required for separation of daughter chromatids in mitosis. The problem is that they won't arrest forever, and if you keep them blocked they will eventually attempt mitosis anyway. This results in things such as chromosome nondisjunction (and some other bad things as well), which itself can result in the death of the daughter cells after a catastrophic mitosis. OTOH, such gross chromosomal abnormalities are the sorts of things that can actually result in cancers. I don't know that anyone has determined the extent to which inhibitors could be carcinogenic (not as up on the literature as I used to be), but the poisons (which ideally are acting as anticancer drugs, some of which are in fact used clinically) are in some cases known to cause secondary leukemias.

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25. Anonymous on November 10, 2011 9:34 PM writes...

rb,
Much shorter nonpedantic answer: messing with topoisomerases is a good thing, if you do it just right. And even then, you're playing with fire (secondary leukemias). Don't get me wrong. I absolutely adore topo II, but sometimes good enzymes go bad (credit Osheroff for that line).

Also, resveratrol is a fairly weak catalytic inhibitor of topo II compared to the "standard" topo II inhibitors, so even high doses might not pose a topo-related danger. Still...

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26. DA Burden on November 10, 2011 9:37 PM writes...

Sorry, #25 was me.

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27. Rob on November 11, 2011 8:43 AM writes...

What is interesting about this study is not so much its conclusions, which are (rightly) to be taken with a large grain of salt as the sample size is small and the time short. The study defines how to construct a larger safe study. It defines what range of dosages is enough (150mg is a lot less than 5000mg), what effects to look for, and shows that at least over a short time this dosage is safe for the participants.

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28. passerby on November 11, 2011 10:44 AM writes...

(#11 by luysii)
> Garfield Duncan was hospitalizing (because nobody knew what would happen)the morbidly obese and totally fasting them [...]

I misinterpreted this as implying dire consequences of the fasting (I now suppose it meant they were just being cautious with subjects' health) and got curious.

I found the 1963 paper, which is pretty interesting reading, and even has a final discussion section:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2249073/

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29. Anonymous on November 11, 2011 1:12 PM writes...

Looks like resVida is a DSM product. The address is Maastricht, which is close to DSM's headquarters in the Netherlands. So I'd assume it's a DSM trial to support their resVida product.

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30. George Henderson on November 11, 2011 4:06 PM writes...

Why do these studies always reference calorie restriction? mightn't that be a red herring?
CR on a junk chow diet might bear no relation to CR on a natural ad lib diet. CR could even be harmful on an ideal natural diet in the wild; that's never been tested.
It may be that the "benefits" of CR or resveratrol are those of an antidote to a toxic, high carbohydrate and/or PUFA diet, and are not seen at all on a better diet, and are perhaps replaced by harm or at least inefficiency.

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31. Anon on November 11, 2011 4:18 PM writes...

@29: DSM is one of the industry partners of the TI Food and Nutrition, which funded the research.

According to the paper, DSM Nutritional Products Ltd. provided the resVida and placebo capsules for performing the resveratrol and DHR analysis, so you are probably correct.

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32. anonymous on November 11, 2011 5:02 PM writes...

Again, got to wonder how different these results would be from those obtained in humans dosed with lower (non-fatal) amounts of 2,4-dinitrophenol....isn't that one of the first "calorie restriction mimetic" drugs????

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33. anonymous on November 11, 2011 10:57 PM writes...

I agree with #8, 13, and 15. For such a controversial molecule, why bother with an 11 subject trial??? Are they trying to add smoke to clarify the fog?

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34. Big Mic on November 12, 2011 11:32 AM writes...

@33, its about money. Big Pharma and the slowpoke government have all the capital. And we know big pharma is not going to undercut itself. Look what happend at Sirtris - big proponents of resveratrol Sinclair & Westphal gone, the Healthy Lifespan Institute's (founded by Sincalir, Westphal, and Dipp) selling of Resveratrol, halted by GSK. Does any of this surprise anyone?

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35. cancer_man on November 13, 2011 12:52 AM writes...

We're not surprised over here in these parts, Big Mic.

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36. anony on November 13, 2011 7:19 AM writes...

If you search "Resveratrol" in Pubmed you get 4344 references, most of which involve examining the compound against the author(s) favorite target and finding, surprise, that it is active!!!

To the point made by #32, resveratrol is CLEARLY an indirect activator of AMPK (like many other natural products and DNP). See http://download.cell.com/cell-metabolism/pdf/PIIS1550413110001129.pdf?intermediate=true

Why are we still discussing this promicuous molecule????

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37. Iridium on November 14, 2011 8:20 AM writes...

Form a scientific point of view all the discussion is very interesting but I cannot really cope with:

"... mimicking the effects of caloric restriction and exercise."

What about eating less and exercising more?
Goverments, schools, churches (of any kind), friends, families should promote more that ...or not?

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38. ADB on November 14, 2011 1:42 PM writes...

It is interesting to see how many people stop by to say that the evil government and pharma industry have conspired to bury resveratrol's positive effects.

But do they realize that at best resveratrol is mimicing calorie restriction? Which mean mimicing eating less and exercising more? I do believe that is totally free! Basically, they seem to be arguing that pharma is keeping a drug off the market that would allow them to sit on the couch and do nothing. Wonderful conspiracy.

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39. cancer_rman on November 14, 2011 11:27 PM writes...

"Conspiracy" is a straw man. Several companies sell resveratrol but GSK will not allow SRT 501 to be market, which *might* be a better form of resveratrol.

Of course, that is their choice, but David Sinclair has made seemingly condradictory statements about people taking the supplement.

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40. big mic on December 3, 2011 8:00 PM writes...

Adm, your argument is absurd. Caloric restriction mimetics are a holy grale of anti aging medicines.

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41. ananthanarayanan on January 11, 2012 11:44 AM writes...

what ever be the techical jargon,contolled study etc. etc i write this in plain and simple language.
I am taking one 320 mg resveratrol caps alternate day for about 15 months and find excellent results in several health matters. Previously my cholestrol levels were high around 230+ but on taking statins they came down to around 170+. now i have totally stopped statins and taking the above dosage of resveratrol and my cholestrol levels are around 170 mark and my fasting sugar levels always around 75 to 80 levels.lot of body pains have disappeared totally and my level of mental sharpness is superb. around 58 years i am feeling right on top my health. ofcourse i keep playing badminton but with better levels of agility and speed.all due to one miracle drug "RESVERATROL"

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42. careful on April 29, 2012 3:56 PM writes...

I took Resveratrol for 3 months and I felt great body fat went down strength went up and no matter what I ate I continued to lose fat !

Downside is I had a host of bad side effects develop slowly

.Pain in kidneys
.feeling sick
.pain in liver area
.constant thirst
.discolored urine

And finally a tumor on the thyroid.

My message to people is to please please please look to your diet eat plenty of veggies and 0 sugar and plenty of lean protein.

The way to good health is not a old one no pill can help with this.

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43. Otis on January 4, 2014 5:47 PM writes...

No one cares anymore, but this study used a student t test for measuring statistics for a crossover study, which greatly increases the power. "It is incorrect to use a student-t test for a crossover study, and the conclusions are not likely evidence based."

Their are lies, damned lies, and statistics. -Mark Twain

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