November 19, 2006
Resveratrol Increases Energy In Humans, Mice

Resveratrol increases energy production in humans and increases mouse endurance on treadmills.

CAMBRIDGE, MA and Strasbourg, France – November 16th, 2006 – Sirtris Pharmaceuticals and the University Louis Pasteur, Strasbourg announced that in an article published today in Cell, “Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α.” Lagouge et al., Cell. 2006; 127: 1–14, SIRT1 was shown for the first time in a human population to accelerate metabolic rate.

In a human population in Finland, SIRT1 was linked to increased energy expenditure as demonstrated by genetic studies of three variants of the SIRT1 gene. The study also showed that treating mice with resveratrol increased mitochondrial biogenesis leading to increased exercise endurance and protection from diet induced obesity. Activation of SIRT1, the best characterized of the recently-discovered family of sirtuin enzymes, was shown to be the mechanism by which these therapeutic benefits occur.

The doses used in mice, 200 mg/kg and 400 mg/kg, is milligrams per day per kilogram of body weight of the mice. Well, scale that to humans and it becomes clear the dose is very high. A 150 lb human is 68 kilograms. That works out to over 27 grams per day.

Mice were dosed with 200 mg/kg or 400 mg/kg of resveratrol daily in either normal chow or high fat chow. The mice on resveratrol lost weight due to decreased fat, and this was attributed to an increase in the number and function of mitochondria. The resveratrol-treated mice also exhibited improved insulin sensitivity and an increased metabolic rate. Notably, mice treated with resveratrol showed a two-times increase in exercise endurance. These effects were shown to be mediated through SIRT1 and PGC-1α.

The scientists who did the work are at prestigious research universities.

The authors of the Cell article include the teams of the principal investigator Johan Auwerx, M.D. Ph.D., Professor at the Medical Faculty in Strasbourg, at IGBMC (Unité mixte de recherche CNRS, Inserm, University Louis Pasteur), France, and of Pere Puigserver, Ph.D. from Johns Hopkins University School of Medicine in Baltimore (now at the Dana-Farber Cancer Institute/Harvard Medical School in Boston), both members of the Scientific Advisory Board of Sirtris Pharmaceuticals, and Sirtris scientists: Peter Elliott, Ph.D. Senior Vice President and Head of Development, Phil Lambert, Ph.D. Senior Director of Pharmacology, and Jill Milne, Ph.D., Senior Director of Biology.

It would be hard to get regulatory approval for a drug that increased life expectancy because it is a claim that is hard to prove in a clinical trial. But Sitris is chasing a more provable claim: That their modified resveratrol molecule, SRT501, will reduce the symptoms of old age and obesity such as high unhealthy blood lipids and insulin resistance in the form of type II diabetes.

“This work is significant because it shows that a SIRT1 activator can protect against metabolic disease, highlighting the therapeutic potential of sirtuins. Resveratrol a compound found in the skin of red grapes and hence in red wine, could very well explain the French Paradox,” said Johan Auwerx.

Sirtris has initiated a human Phase 1b clinical trial in diabetes with SRT501, a proprietary formulation of resveratrol with improved bioavailability. SRT501 is the first small molecule to enter human clinical trials that is designed to activate SIRT1. Sirtris has applied this scientific discovery to the development of SRT501, which activates SIRT1, for the treatment of diseases of aging such as metabolic and mitochondrial disorders. In addition, Sirtris has a robust pipeline of novel small molecule drug candidates that are potent SIRT1 activators and are chemically distinct from resveratrol.

“This important work highlights the significance of SIRT1 as a therapeutic target for metabolic disease. Based on the continuing scientific evidence, as shown in this most recent Cell article, we are continuing to advance drug candidates to translate the science of sirtuins into new treatments for diseases of aging, such as diabetes,” said Peter Elliott, Ph.D. Senior Vice President and Head of Development at Sirtris Pharmaceuticals.

“These new human data support SIRT1 as a therapeutic target for metabolic disease. Our broad pipeline of sirtuin modulators have potential in a number of diseases of aging,” said Christoph Westphal, M.D., Ph.D., Chief Executive Officer of Sirtris Pharmaceuticals.

Now for the qualifiers and caveats.

Back in March 2005 Sirtris co-founder David Sinclair of Harvard said that most commercial resveratrol preparations have no active resveratrol in them - with activity measured by the ability to activate the SIR2 enzymes.

Resveratrol is not an easy molecule to protect from oxidation. Most commercially available supplements I have tested have no ability to stimulate SIR2 enzymes.

Longevinex sells resveratrol to many researchers. But their commercial resveratrol preparation has only 100 mg of resveratrol per capsule and costs more than $1 per capsule. But the recent study by David Sinclair and Rafael de Cabo showing resveratrol protected mice from the harms of obesity used a dose of resveratrol that would be the equivalent of 1600 mg for a 150 lb human. Whereas the study above on mice used the equivalent of 27 grams (27,000 milligrams) of resveratrol for a 150 lb human.

Bulk sources of resveratrol from knotweed can be found on the internet. But which of those sources is selling real active resveratrol? Your guess is as good as mine.

Then there's the question of whether this stuff is safe. We do not know. Okay? Really, we do not know. We need a big study of large numbers of people taking a gram of resveratrol a day with all sorts of checks done on them to look for bad signs. My guess is we are not going to see such a study on resveratrol because the money is in making a patentable commercial variation of resveratrol into a marketable drug. That'll take 6, 7, 8 years more and hundreds of millions of dollars.

In the comments section of my post on the David Sinclair and Rafael de Cabo study on resveratrol you'll see a reader who claims he's taking over 1 gram of resveratrol a day with very beneficial effects. He thinks he has a good trustworthy source for large doses.

Where do resveratrol and the Sirtris drug SRT501 fit into the larger picture of anti-aging treatments and life extension? If they work then they probably work by slowing down aging the same way that calorie restriction does. The interest in the Sir1 and similar sirtuin genes comes from studies on calorie restriction's effects on gene expression in yeast and rodents. But we do not know for sure that calorie restriction will increase human life expectancies.

Now, if resveratrol and SRT501 do extend life that's a good thing because they'll help keep us alive until rejuvenation therapies such as gene therapies and stem cell therapies become available. That companies are trying to develop drugs that mimic the effects of calorie restriction is a good thing. I wish them luck and watch their progress closely.

But we still need the rejuvenation therapies and we need even greater efforts to develop rejuvenation therapies. For more on that read about Strategies for Engineered Negligible Senescence (SENS). We won't need to slow the rate of aging when we can reverse aging. Though slowing the rate of aging will still let us go longer between rejuvenation therapy episodes.

Share |      Randall Parker, 2006 November 19 05:04 PM  Aging Diet Resveratrol


Comments
cathy said at November 20, 2006 9:22 AM:

I have a great crop of giant knotweed in my backyard - it's considered a noxious weed. Does anyone know which part of the plant contains resveratrol and how it can be extracted?

Kurt said at November 20, 2006 10:11 AM:

Randall,

Its a matter of cost savings. Obviously, if you can take something to slow aging, you have more time between each application of SENS therapies. Say, the first time you undergo SENS might be in 2030. It could be expensive the first time around. The second time around will be cheaper. If you can delay having to undergo SENS the second time around to say, 2060 or 2070, rather than 2050, it will be that much cheaper because the technology will be more mature and any patents will have run out. By 2070 we will have bodies based completely on synthetic biology that will not age at all or very slowly.

Perry E. Metzger said at November 20, 2006 1:11 PM:

The doses used in mice in a couple of recent studies have been on the order of 20-25mg/kg, not 200-400mg/kg. This translates to 1.5g for humans, a perfectly acceptable dose. I'm not sure that press release was accurate even for this study -- 400mg/kg is a heroic dose even for mice.

michael vassar said at November 20, 2006 6:45 PM:

The more I read about resveratrol, the more it worries me. It seems to a-priori improbable that such a substance should exist. If it doesn't impair fertility, stunt growth, or have any other deleterious effect why would we not have evolved metabolitic pathways to duplicate its effects.

Randall Parker said at November 20, 2006 8:53 PM:

Michael Vassar,

I think the exactly same thing. It does not make sense. How can resveratrol provide benefits without some downsides? It'd be too easy for the Sir enzymes to just be upregulated due to some genetic mutation. So why wasn't that mutation already selected for?

I figure resveratrol must have downsides. The question I have is whether those downsides are ones that we would find acceptable if we only knew what they were.

But maybe resveratrol does lower fertility. Do you really know that it does not?

I'm figuring maybe resveratrol has some of the downsides of calorie restriction. For example, maybe we become less able to handle temperature extremes for example. Well, I'd be willing to give up that in exchange for aging more slowly.

rsilvetz said at November 20, 2006 9:39 PM:

Huh? It's all about function and dosing. But addressing probability of exogenous substances first:

Is it a-prior improbable that a prostaglandin pathway inhibitor should exist? Of course not, as aspirin [willow bark extract] is in fact that substance. At 80 mg per day it will crush heart attack rate and drastically reduces colon cancer. Is it a-priori improbable that an NFKappab inhibitor should exist? Of course not, as curcuminoids universally are that inhibitor. 900 mg/day is a potent cancer preventor. There's nothing improbable about Sirts being responsive to resveratrol. Cells are concentration-based computers and we are locked into the natural order that produced us (which includes grapes!), so it's unsurprising such substances are found on a regular basis.

And of course we have metabolic pathways that duplicate their effects, otherwise the body could not function nor would the substances have the effects we so greatly desire. Sirts exist and thus we can manipulate them beyond their otherwise normal levels and outside the normal feedback cycles.

Which brings us to dosing. 8000 mg/day aspirin will tank your kidneys in short order and crush platelet function (bleeding). 18000 mg/day curcumin will induce gastric bleeding, blow your liver and probably shut down nitric oxide pathways.

So yes, we do indeed need a dosing study for resveratrol.

Brett Bellmore said at November 21, 2006 9:41 AM:

"why would we not have evolved metabolitic pathways to duplicate its effects."

Because it doesn't really start to have beneficial effects until you're a couple times older than most people would have gotten during the majority of our evolutionary existance? The evolutionary drive to age slower didn't kick in until we'd dramatically reduced disease, predation, and accidents as causes of early mortality.

the_alpha_male said at November 21, 2006 11:38 AM:

I read this comment on Wikipedia's resveratrol entry:

"The amounts used in the mouse study were approximately 22.4 mg/kg body weight per day. Scaling this amount to human body weights would imply an "equivalent human dose" of 1.5 to 2.0 grams/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to the range of 150 to 200 mg/day"


Does anyone know if that is true?

rsilvetz said at November 21, 2006 5:06 PM:

The Wikipedia entry is, well, wrong. Metabolic rate scales to mass at approximately scale-difference to 3/4 power. A human is roughly 7000x a mouse, so our metabolic rate is loosely 765x that of the mouse. Thus the human dose on metabolic considerations would 22.5 * 765 ~= 17.1 grams.

rsilvetz said at November 21, 2006 5:16 PM:

DAMN, DAMN, DAMN!!!: Off by a factor of 10. A man is 700x times a mouse. Metabolic rate scales to 3/4 power of the scale difference. So our metabolic rate is roughly 136 times that of the mouse. Thus, the human does on metabolic considerations is 22.5 * 136 = 3060 mg/d or 3 grams/day.

rsilvetz said at November 21, 2006 6:07 PM:

Great little chart comparing metabolic rates.

Kurt Miller, MD said at November 21, 2006 9:56 PM:

BW (body weight) in Kg to the 3/4 power is a suprisingly good first estimate, and a starting point for dosage studies across mammalian species, per the late great Herr Doktor Professor Max Klieber, an expert in animal energetics. Critically, this is an estimate of metabolic rate, which in turn gives a good estimate of caloric need. His work might directly apply, as pointed out by rsilvetz, as this appears to be an energy related issue. I think Kleiber did this work about 75 years ago. Some drugs (not nutrients) have dosages which seem wholly independent of this rule of thumb regarding energy, as they are not metabolic rate/energy related.

So, if you had a giant mouse at 50 grams and he daily recieved revasterol 20 mg / kg of body weight (not 20 mg / kg of diet; interestingly and obviously, nutrient density of foods is about the same across species, in that afterall we are eating mostly the same things) his daily dose would be a single milligram. This is in the range of many vitamins and some minerals for a mouse. [the calculation being 50g/1000g x 20 mg, where 50g is the mouse weight times the quantity 20mg/1000g; grams cancel out, 50 x 20 is 1000, and 1000/1000 = 1; leaving 1 mg]. So, if the mouse was given 200 mg / kg, then the dose would be 10 mg per day and 400 mg/kg would be 20 mg.

20 mg to the 3/4 power in kg would be [2 X 10(neg 5 power)3/4 power... sorry no calculator available to do the math. Anyway, I hope this helps.

rsilvetz said at November 21, 2006 11:22 PM:

DAMN. Blew the units in the post above - 3 gr/kg/day which implies a gross 210 gr total dose in humans! Thanks Randall for the catch. Egads...

***

Dr. Miller is correct, I remembered the scaling equation but not the author. Klieber was the first to show that energetics varied to the 3/4th power and not to the 2/3 power that surface_area/volume consideratons would indicate.

Dr. Miller is also correct that other substances do not follow that scale. In fact, if one is reasonably certain that blood volume/compartment distribution/kidney issues are applicable, things may scale differently, to the tune of -1/4th power. On that basis we get a more supplement possible of about 100 mg/kg or about 7 grams total dosing. (Either way Wiki article grossly underestimates...)

I'm suffering a cold. I will bone up on dosing estimate research and report back.

rsilvetz said at November 22, 2006 1:04 AM:

OK. Reviewed the state of the art. (Couldn't sleep.) Randall please blow away previous posts as they are grossly incorrect mathwise. Moral of the story: Don't take cold medicine and try to do math.

Have better numbers. Avg mouse is 35 gr or 0.035 kg. We'll use 70 kg for a human. Even though energetics vary to the tune of 3/4th power, it's sitting in the denominator, thus (70 kg/0.035 kg)^(1-3/4)= 2000^(1/4)=6.69 scaling factor.

This puts the human dosage based on the mouse studies at:

(Wiki) 22.4/6.69= 3.35 mg/kg/day = 234 mg/day

200/6.69= 29.9 mg/kg/day = 2093 mg/day = 2.093 gr/day

400/6.69= 59.8 mg/kg/day = 4186 mg/day = 4.186 gr/day

So it appears we can do this by supplementation. Dosage adjusts downward because our physiologic clock is slower than a mouses, even though our total energy requirements are much higher. Eg if you compare heart rates, mouse ~ 700, humans ~72

Brett Bellmore said at November 24, 2006 6:12 AM:

A point I'm curious about: This apparently works by activating a gene complex, which results in rebuilding your mitochondria. One presumes that mitochondria don't vanish the instant that gene complex goes inactive again; Would saving on dosage by cycling this supplement be feasible? And if so, what would be likely schedule be?

Kurt Miller, MD said at December 1, 2006 10:08 PM:

rsilvetz, strong work! Re: mitochondrial function, interested parties might want to look at the recent (meaning a few years old) work of Bruce Ames, currently at UCB, Biochem Dept. Intermediates, particulary alpha lipoic acid and acetyl carinitne showed inprovement in mitochondrial ultrastructure, function, and in whole animal-aged rats, memory and exercise capacity.

fp said at December 7, 2006 5:11 PM:

The range of dosage is quite wide between 250mg and 4g.

But the more important question is the active nature of the supplement and bioavailability. Any information on that beyond Sinclair's claim that no available supplement has active resveratrol?

Glen Rockwell said at December 17, 2006 1:38 PM:

Great discussion on a possible dosage range for the drug, but as someone else noted, any thoughts on quality sources either via supplement companies or suppliers? David Sinclair has been quoted as saying that he and have his lab currently take resveratrol, but at what dose? and what source? Can't trust the supplement companies, but I would love to be able to have access to a quality source. Thanks for any comments on the topic

Anthony said at January 28, 2007 5:08 PM:

Hey, I think we ought to start looking at some of this info from the online encyclopedia:

http://en.wikipedia.org/wiki/Resveratrol

There is info on the supplement aspects of it there that I dont see on this site.

Doug said at August 30, 2007 10:27 AM:

It is an interesting comment on if there is a chemical that significantly prolongs life, why hasn't our (and other animals') bodies evolved to produce it.

Well, I'm no expert, but here is my two cents worth of answer. A longer lifespan, while benificial to an individual animal, is not necessarily helpful to the propagation of a species. The evolutionary sweet spot is for an animal to live long enough to procreate a reasonable number of offspring and to aid those offspring to reach an age of independance from the parent. After that, the parent is useless to the offspring. In ancient times, man would likely not die of old age, but rather infection, disease, preditors, etc. Lifespans were in the 30's, so a biological limit of 70 years was moot. If you lived to 200, most likely you would have accumilated so many injuries and fraliaties that you would be a burden on your fellow tribe/clan/family and detrimental to their survival.

Toni said at April 12, 2008 6:58 AM:

As per the last comment, evolution suggests that our brain was designed to enable us to manipulate our environment to accomdate our requirements. That being said, we often make mistakes but there are times where our brains have propelled us further in understanding our universe. Each generation builds on the knowledge of the next...bringing us closer to understanding how all of this cosmically fits together. Every atom, electron....etc., has a place and fits together within the Cosmos. Now, would'nt it be wonderful if Einstein lived to 150? What more could he have contributed to our understanding of our existance and the Universe ? I read a theory once that our planet is alive and we are feelers designed to reach out to the universe and connect. Extending our lives is the outcome of our "understanding on behalf of the planet" and the evolution of the human brain has an absolute purpose. Yes, we are meant to procreate offspring. But, to what end. I think... as with most things on this planet... this subject is much more complicated than it appears.

Rich said at June 7, 2008 1:21 PM:

Getting off topic here but the evolution and age comments are interesting. I would suggest that evolution has tuned our aging process to benefit individual populations. Culture of course makes us different than most animals -- women probably live long past their child bearing years because they can pass accumulated information to their offspring and thus increase their own fitness. I doubt that we age simply because we become a burden -- if we didn't age, those that survived the diseases, predation, and starvation would likely be very fit, and thus pass more of those genes forward. In addition, I would guess that the elderly usually were not supported at high cost ( I think of the Inuit tradition to choose or accept death by exposure upon reaching a certain age).

I hazard that the evolutionary costs of aging are either i) that germline mutations accumulate more rapidly in adults so that keeping adults around too long degenerates DNA or more likely ii), that there is a balancing act between preventing aging and cancer. Cancer is, in a sense, the antithesis of aging. Cancer cells proliferate rapidly and vigorously, and are immortal, no longer following the programmed route to death. I guess that mutations that would lead to slower aging would either lead to lack of vigor or cancer. Think dogs -- they heal exceptionally fast from wounds, have short life spans, and often die of cancer. Perhaps one can have either a vigorous short life or a tepid long one, cancer being the mediator.

Of course, humans have only been symbolic animals for a short evolutionary time, and though we already have unusually long life spans, it may be that most of the genetic space relating to aging has yet to be explored -- especially if death by other causes has been prevalent.

That is my major (but only theoretical) concern with any anti-oxidant supplement that may stabilize the mitochondria and inhibit apoptosis (appropriate cellular suicide). I see that resveratrol has been shown to promote apoptosis in some cancer lines, so perhaps it is of less concern than vitE. It is tempting to supplement. Who is going first?

Lyn said at November 30, 2008 8:37 AM:

As much as this subject interests me, I feel we (ordinary people) will not be allowed to live these great long lives, so forget the idea now.

The people who really run this planet, the ones who control banks & governments, the same ones who planned the financial crisis to the day, honestly believe a significant proportion of present people should be euthanized.

The idea of keeping what are essentially 'wasteful eaters' going is offensive to them.

If they get their way, we will all be sterile and died-off LONG before 'anti-aging' would dared be given to commoners.

Before you scoff, David Rockefeller and his elite ilk have repeatedly lectured about how good a depopulated earth would be. Do you think HE would be anything but appalled at the thought of you all living one day longer, never mind decades?

The UK Queen's husband, Prince Philip, is on record that he wants to reincarnate as a virus to wipe out most of humanity for the betterment of the planet.

They don't say these things just to pass the time, they are statements of intent by the people who run this planet.

Wake up my friends, research your enemies, or they will get you or your children long before old age will.

They are known as the New World Order, a shadowy group of elites that despise the ordinary people of our plant and want 80% of us killed as soon as possible.

Learn more at

www.infowars.com

www.prisonplanet.com

resveratrol said at November 29, 2010 10:00 AM:

The properties of resveratrol are intriguing, and it may turn out to be a useful drug. But so far the studies on resveratrol are pre-clinical studies. We have no data on its effects in humans. Few people would want to take a proposed prescription drug that had not yet undergone clinical trials: why should resveratrol be any different? In the absence of clinical trials, resveratrol might be recommended for obese mice, but not for men.

resveratrol plus said at July 6, 2012 10:58 PM:

For long, this substance was not taken into account until it was discovered that it contained relatively large amounts in red grapes and, importantly, in red wine. Specifically, resveratrol is secreted by the grapes from the vine when they are attacked by parasitic fungi and bacteria, originally it was, therefore, a substance with defensive end.

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