November 02, 2006
Wine Compound Resveratrol Protects Mice From Obesity Damage
Resveratrol, a compound found in highest concentration in red wine, protected mice from the life shortening effects of a high calorie diet.
How the Study Was Done
This study examined three groups of mice, one on a standard diet (SD), another on a high calorie diet (HC) with 60 percent of calories coming from fat, and a third group of mice on the same high calorie diet but also treated with resveratrol (HCR). At middle age, or roughly 52 weeks of life, the researchers put the mice on the different diets.
At 60 weeks of age, the survival rates of HC and HCR fed mice groups began to diverge and remained separated by a three to four month span. At 114 weeks of age, 58 percent of the HC fed mice had died, compared to 42 percent of the HCR and SD groups. Presently, the team has found resveratrol to reduce the risk of death from the HC diet by 31 percent, to a point where it is not significantly increased over the SD group.(Note: Given that mice are still living, final calculations can't be made.) "The median lifespan increase we are seeing is about 15 percent at this point," says Sinclair. "We won't have final lifespan numbers until all of the mice pass away, and this particular strain of mouse generally lives for two-and-a-half-years. So we are around five months from having final numbers, but there is no question that we are seeing increased longevity.
Mice on resveratrol also are more coordinated.
The team also found that the HCR fed mice had a much higher quality of life, outperforming the HC fed mice on motor skill tests. "The mice on resveratrol have not been just living longer," says Sinclair. "They are also living more active, better lives. Their motor skills actually show improvement as they grow older."
The resveratrol fed mice also showed improved motor function with age over its HC fed counterparts. Researchers watched how well the mice did walking on a rotarod, similar to walking on a log in the water, a common measure of balance and motor coordination. At 24 months of age, the HC fed group would fall off the rotarod after 60 seconds, while the HCR group would stay on for nearly 120 seconds. The HCR group steadily improved their motor skills as they aged to the point where they were indistinguishable from the SD fed group.
The experiment they did not do: Feed resveratrol to mice on the standard diet. Why we need that experiment: For those of us who are not overweight would resveratrol increase our life expectancy? Maybe. Maybe not. It might emulate the effects of a calorie restriction diet and boost life expectancy even further.
Be careful about taking resveratrol as a supplement. Some preparations are not stable. Also, if you want to get resveratrol then wine made from muscadine grapes is the ticket.
The amount of resveratrol in food substances varies greatly. Ordinary non-muscadine Red wine contains between 0.2 and 5.8 mg/L , depending on the grape variety, whilst white wine has much less - the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Wines produced from muscadine grapes, however, both red and white, contain more than 40 mg/L.
It is not physically possible to get as much resveratrol from drinking red wine as these mice got from their diet.
The mice were fed a hefty dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-pound person would need to drink from 1,500 to 3,000 bottles of red wine a day to get such a dose. Whatever good the resveratrol might do would be negated by the sheer amount of alcohol.
That works out to about 1600 mg of resveratrol for a 150 lb human. Even muscadine grapes would give you about 40 milligrams per liter which is slightly more than a quart. The resveratrol supplements on sale that I've seen range as high as 25 mg resveratrol. But at least one scientific paper questions the stability of commercial resveratrol supplements. Does anyone know of recent research on resveratrol potency in commercial supplements?
Gene array studies would be useful here. Give obese mice various doses of resveratrol and see how high the dose has to be to deliver a big protection as measured by changes in gene expression (e.g. in sirtuins). Then do a clinical trial with humans at various doses and do gene expression tests to look for a human dose response curve.
Update: Experimental drug SRT501 is a more potent form of resveratrol and works works by activating the gene SIRT1 which is suspected of increasing life expectancy in animals on calorie restriction diets.
Sirtris Pharmaceuticals, the leading sirtuin therapeutics company, announced today that SRT501, its initial clinical candidate which is a proprietary formulation of resveratrol with improved bioavailability, has been administered to patients with Type 2 diabetes in a human Phase 1b clinical study. Sirtris is studying SRT501 as a drug candidate for Type 2 diabetes, based in part on the scientific evidence that sirtuin activation, by means of compounds like resveratrol, has been shown to have a positive effect on key clinical measures for diabetes. In an article published today in Nature, “Resveratrol improves health and survival of mice on a high-calorie diet,” resveratrol was shown in mice to promote normal cellular function and extend healthy lifespan, including an increase in insulin sensitivity, a decrease in insulin growth factor-1 levels, and an increase in the number of cellular mitochondria. The authors of the Nature article include principal investigator David Sinclair, Ph.D., Associate Professor of Pathology and Co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School and co-founder and Board member of Sirtris, and Olivier Boss, Ph.D., Associate Director of Pharmacology at Sirtris.
“This study indicates that SIRT1 is associated with extension of healthy lifespan in obese mice and if this is translated into humans, it could have an enormous impact on medicine.” said David Sinclair. “I believe that the measures of health improvement in this study, such as increased insulin sensitivity and decreased IGF-1 levels, show the potential for sirtuin activation to treat metabolic diseases, such as diabetes.”
SRT501 is the first small molecule to enter human clinical trials that is designed to target SIRT1, the best characterized of the recently-discovered family of sirtuin enzymes. Activation of SIRT1 is believed to be a key pathway by which resveratrol regulates such processes as glucose and insulin production, fat metabolism, and cell survival. 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 small molecule drug candidates that are potent SIRT1 activators and are chemically distinct from resveratrol.
Compounds that slow down the rate of aging will give us more time to wait for actual aging reversal and rejuvenation therapies.
Until the studies are completed, I think the safest thing to do is drink a bottle of red wine every day.
I have been using a reveratrol supplement called Longevinex for about 2 years at a 1mg/kg dose. This is about 20% of the level that Dr. Sinclair is taking and about 4% of the mice dose. Do I feel different? Not really. My health is excellent though. I did compare my blood work from my pre-resveratrol days to last month and did see some differences. My HDL went from 43 to 87. My triglycerides went from 105 to 65. My blood pressure is 105/60. (age45) Does it work? I don't know. It doesn't seem to be harming me. I will continue to take it and I will double my dose. Dr. Sinclair stated that he is in early trials of a Resveratrol type drug that is 1000X better at activating the SIRT1 gene. I believe this is really going to turn the world upside down. What happens to the actuary tables? I will be watching this closely.
Another company, Elixir, is also working on sirtuins, with similar indications (PDF) for diabetes.
Besides these two--Sirtis and Elixir--, does anybody know of more? It'd be nice to see competition, but it's great that we already have two companies committed to what seems to be unusually promising research.
Larry, why do we suppose that a 4% dose is going to do a lot of good? If those numbers (HDL and TG) are attributable to the resveratrol, that's remarkable. But I don't see how it's possible with such a low dose. I'm now experimenting with 100% of the murine dose (extrapolated), with a natural extract of extremely high purity.
The Harvard mouse experiments represent the best relative dosage to date. Since we use mice and rats for toxicity, LD50 and safety studies, I'm comfortable with the safety of this dose for self-experimentation.
Everyone is different, but I think it's improbable that one could take this dose and not feel distinct effects. This stuff kicks butt. In this increasingly healthy and responsive laboratory (my 50-year-old body), I'm convinced that if something is powerful enough to make you live longer, you'll be able to tell when you take it. If it doesn't make you feel great- if it doesn't dramatically improve the quality of your life- the question of whether it extends your life seems to me less important.
My wife, on the same dosage for two weeks, reports an "effortless" weight loss of 12 lbs. I don't know if I've lost weight or not. This makes sense if the sirtuin gene mimics CR.
I'm not only NOT waiting until there's a pharmaceutical, I probably won't take it. There's much to be said for purity, but the track record of natural chemicals altered to patentable pharmaceuticals is fairly disastrous. Detach the dollar signs, and I don't see the need to reinvent what nature has provided. Purify it, yes. Study it, absolutely. But these benefits can be had, right now, in pure form and adequate dosage.
I can't decide what's most exciting- the discovery that we can actually alter the expression of our own genes with foods and natural extracts, or that Harvard scientists, the Wall Street Journal, and the New York freakin' Times are talking about polyphenols extending human lifespan.
David L. Kern,
In what form are you getting the resveratrol? Capsule? Powder? What dosage? Are you taking a large number of pills to get hundreds of milligrams per day?
We really do seem to be turning a corner of scientific and popular awareness on the idea that natural compounds can do a major change to human metabolism and extend lifespan as a result.
I'm taking a 98% resveratrol extract from knotweed, the purest I can find from a supplier I know well. At a dose of 24 mg/kg, it works out to just over 2 grams, or 4 pills. My partner is taking 3 g, and seeing rapid fat loss effects, irrespective of food intake, 6 kg in 2 weeks. The number of pills is easy with the purified extract, but the cost is a bit high. Since resveratrol's bioavailability is low due to rapid metabolization, we're taking divided doses.
Safety is a question, of course, but one way to judge this (besides watching the mice) is body response. If something is toxic, it will eventually make you feel sick. It makes me feel stronger, more alert, more energy. Not a poison response.
You're right, we're turning a corner, but ever-so-slowly. The unifying principle is still Dr. Harman's free radical theory of aging, published over 50 years ago. It explains how CR could extend life span quite elegantly. What's challenging with the resveratrol is this: it seems to increase cellular energy metabolism, which in theory would increase oxidative stress. I suspect it may be improving energy metabolism, rather than accelerating it as current theory holds. Otherwise, it's inconsistent with Harman, at least on the surface.
And as always, there are lots of companies selling fairy dust. 10 mg? 40 mg? Enough for a mouse.
I just did some googling on resveratrol and knotweed. Found 10% to 98% resveratrol from knotweed. Even Wikipedia mentions it as a source. I had no idea.
Curiously, Japanese knotweed is an invasive species in the northwest.
As for bioavailability, I found a paper which used carbon-14 labelling with human volunteers that said absorption is not the main problem:
The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 ± 90 ng/ml (about 2 µM) and a plasma half-life of 9.2 ± 0.6 h. However, only trace amounts of unchanged resveratrol (
Though with your higher dose absorption might be much lower. More info here.
BTW, I read a Denman Harman interview about 10 years ago where he described how when he took very large doses of antioxidants he got to the point of feeling lethargic. He said too much antioxidants will dampen down needed oxidation. That cogs with my own experience. It was great hearing that from him.
Could you be more specific about the supplement that you are taking... Possibly naming the supplier or the brand that you are using, where it can be purchased, etc.. Thanks.
Not to be too suspicious or anything, but it's interesting that clicking on 'David L. Kern' takes you to a website selling another supplement. It would be good to get full disclosure on all of this, Mr. Kern...
If your "HDL went from 43 to 87" that's a GIGANTIC increase!! Very very difficult to do; meds may cause a 10% increase, and that significantly reduces heart disease. HDL is highly protective against heart disease, and the biggest problem people have with HDLs of 80+ is outliving their money.......
My HDL did go from 43 to 87. The tests were 9 years apart though. I will do another test next September and post my results on the Immi boards. Dukenukem has had similar results (read Immi Inst boards on supp) I have thought about how drugs might affect retirement. I was planning to retire at 55. I have 10 years to see how things pan out.
"I'm taking a 98% resveratrol extract from knotweed, the purest I can find from a supplier I know well"
David, could you please name product or supplier?
I am taking Resveratrol and drinking muscadine Red wine every evening. So far I am not getting the headaches that I get with grape wine and I'm losing about a pound a day. Hay fever isn't bothering me this year and my relatives are dropping like flies. I just feel better.
I see a lot people making the same leap - assuming that the mouse study dose of 24 mg/Kg is optimal, and then claiming that the amount found in wine is too small to do any good. That may be true but the study data is silent on that. What should have been done is to do the study with enough mice and with at least four different doses so that a dose vs effect curve could be developed. A similar study could be done with normal mice. And micro-array technology could be used to examine their DNA rather than rely soley on gross physical changes. With the venture capital these guys probably have on hand I can't believe money would be an obsticle.
If you are still monitoring this site, I'd like to know how your more recent blood tests of HDL came out. You had mentioned that you were going to have a new set of blood tests that Sept. (2007 ?)..
This online communication is the only place I have seen any comments about resveratrol (or natural versions) having affect on HDL.
I am very interested in this as a method of getting my HDL (now at 28) up to more reasonable levels..... before my heart doctor puts me on those darn drugs I do not care to use.
Thank you, I look forward to your reply.