Exciting Research On Resveratrol (REZ-V)

Diet and Nutrition
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Red wine may protect heart from aging�??s toll

Study in mice finds natural compound blocks decline in cardiac function

updated 8:30 p.m. ET, Tues., June. 3, 2008
WASHINGTON - A natural compound found in red wine may protect the heart against the effects of the aging process, researchers said on Tuesday.

In their study, mice were given a diet supplemented with the compound known as resveratrol starting at their equivalent of middle age until old age.

These mice experienced changes in their gene activity related to aging in a way very similar to mice that were placed on a so-called calorie restriction diet that slows the aging process by greatly cutting dietary energy intake.

Most striking was how the resveratrol, like calorie restriction, blocked the decline in heart function typically associated with aging, according to Tomas Prolla, a University of Wisconsin professor of genetics who helped lead the study.

Scientists seek fountain of youth
Much as Spaniard Juan Ponce de Leon once searched for the mythical fountain of youth, researchers now are seeking ways to extend the quality and length of human life.

In some studies, animals given a diet with greatly reduced caloric intake have lived longer than animals with normal diets. But perpetual hunger is a steep price to pay for greater longevity, some researchers say.

Resveratrol, found in abundance in grapes and in red wine, has drawn a lot of interest from scientists and some companies, including GlaxoSmithKline, which in April said it would pay $720 million to buy Sirtris Pharmaceuticals Inc, a company that is developing drugs that mimic the effects of resveratrol.

Some studies have shown that in high doses, resveratrol extended the life span of fruit flies and worms and prevented early death in mice fed a high-fat diet.

In this study, mice were given relatively low doses compared to the earlier research, and still experienced important aging-related benefits, the researchers said.

The researchers began giving the resveratrol diet to the mice when they were 14 months old �?? their middle age �?? and followed the animals until they were about 30 months old. The researchers then conducted tests on cardiac function and on gene activity related to aging.

�??Resveratrol at low doses can retard some aspects of the aging process, including heart aging, and it may do so by mimicking some of the effects of caloric restriction, which is known to retard aging in several tissues and extend life span,�?? added Prolla, whose study was published in the scientific journal PLoS ONE.

Using a method that permits simultaneous analysis of thousands of genes at the same time, the researchers found a huge overlap in the genes whose activity were changed by resveratrol and caloric restriction.

They looked at the heart, brain and muscles, and said that the effect of resveratrol was strongest in the heart but did prevent some aging-related changes in the other tissues.

Just because mice had these benefits does not mean people also would, although Prolla said, �??I think there�??s a high likelihood that our findings are applicable to humans.�??

He said he expected to see a lot of studies in the coming years on the effects of resveratrol supplementation in people.

Very interesting! Very sad though that pharmaceutical companies are looking at “drugs to mimic the effects of resveratrol”! Of course, naturally occurring compounds can’t be patented.

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The problem with resveratrol is that it is extremely impotent at SIRT1 activation. It is a very small molecule and surely has great access to tissue throughout the body, but the potency is still an issue.

The compounds made by Sirtris Pharmaceuticals (there are a few, published in Nature 12/07) are orders of magnitude more potent at activating SIRT1.

I do not think it is sad at all that a start-up company sought to find compounds to mimic resveratrol. Sirtris was founded by David Baltimore, who was the researcher at Harvard that first discovered the anti-aging properties of resveratrol and its link to SIRT1 activation (in C. elegans). Essentially, he deserves every bit of that 720$ million. And will probably be getting more if their compound(s) prove efficacious and safe in humans.

There is an obvious question of “How much SIRT1 activation is safe?” Resveratrol may be the “perfect SIRT1 activator” because it is low potency, and has been speculated to have other biological effects on other proteins due to its extremely small and generic, aromatic structure. The compounds made by Sirtris might turn out to provide too much SIRT1 activation that may in turn lead to major health problems. Of course time will only tell, but the bottom line is that a small start-up company like Sirtris Pharm. has no capacity to push their compounds through large scale clinical trials. But by selling their soul, ahem I mean licensing rights to a few molecules, to GSK, Sirtris will be able to see their molecules in humans much quicker and we will all benefit.

The laboratory I work for has just made a similar collaboration with Merck & Co.:

http://www.drugs.com/news/marcadia-biotech-inc-merck-amp-co-inc-enter-strategic-collaboration-7882.html

I am personally very excited because the peptides I have been working on are guaranteed to be entered into quality human clinical studies with deals like this. It is not sad in any respect… neither is Baltimore’s 720$ million.

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Don’t get me wrong, pharmaceutical advancements are important, but, honestly, how many times have we seen drug companies try to “improve” on nature only to develop highly toxic compounds that either were not discovered to be so for many years, or questionable data concerning which was essentially buried.

The fact that resveratrol was able to retard some of the age-related decline in heart function even at low doses, tells me all I need to know.

I’m all for the drug companies doing further research into “compounds that mimic the effects of resveratrol”, I’m just not naive enough to believe in a free lunch; with pharmaceutical compounds there are usually significant saftey issues. Perhaps as a pharmeceutical intervention, these new drug compounds could have specific medical uses; however, my point relates to the use of resveratrol by the average person as a preventivite health measure. Furthermore, drug companies are ravenously greedy, and will try and market any compound they believe there is a market for–even if that market has to be created through deceptive advertising and “research”.

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Well certainly the small molecules they discovered through random screening and subsequent structural optimization processes have the potential to have all kind of side effects. This is the largest risk in small molecule drug development hands down.

The compounds made by Sirtris aren’t necessarily meant to mimic resveratrol either. They are meant to be specific SIRT1 activators. The problem with resveratrol is that it has a multitude of physiological effects arising through interactions with many proteins, most of which have yet to be fully explained. So you cannot start a study where people are given resveratrol, see that they become more healthy or live longer, and truly say why.

Thus if you are able to make a more potent and selective SIRT1 activator, you will at the very least, be able to engage in a more controlled study of the effect of SIRT1 activation in animals. This is extremely important if humans are to capitalize on the opportunities that resveratrol has opened up and down the road have the chemical & intellectual knowledge to allow themselves to live longer, healthier lives.

You should also check out the paper published in Nature a few months back that shows the development of the SIRT1 activators. I can send you PDF if you cannot access it and want to see it. A great deal of the paper shows the in vivo effects the compounds provide in the diet-induced obesity and db/db mouse models (diabetic mice). They do an amazing job of ameliorating the diabetic state of these mice.

And so what if they turn out to be busts? You never know unless you try. Sure money is a motivating factor for us all, but what happens if your family member comes down with diabetes at age 50? Do you want them to have the best treatments they could possibly have because of trial & error research? Or do you want to see them not have any good therapies, and they can struggle with what the doctor gives them (20th Century medicines) and die by age 70 after battling the painful ravages of diabetes for far too long?

I’m not going to defend Eli Lilly for making Prozac and overmarketing it. Clearly this sort of stuff bothers you, and it does me as well. Hell I am 23 and drug development is what I am doing now and will probably be doing forever. But some of the pharmaceutical industry is garbage and you just have to deal with it. It’s a product of capitalist economy and world we live in. But there is quality research with quality intention, and this is a perfect example of it.

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Do people like this purely because of its anti-aging effect, or because it’s a rationale for drinking? You don’t hear anyone saying, “Wow, calorie restriction!” or rushing out to buy red grapes.

Anyway, I know the answer to that, it just seems like there will be more harm than good that comes out of this.

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I agree with most everything you said Rusty; again, I’m all for this research in terms of intervention in specific medical populations. My comments were really directed toward the average person using resveratrol for general preventative health benefits.

Prozac is not the only compound I’m thinking of here. I’m sure you’re well aware of the game drug companies play with NNT (number needed to treat) in drug advertisements.

Further, it’s more the end result of this “quality research and quality intention” that concerns me. Often times when a compound turns out to be questionable–from any number of perspectives–this information is buried and marketing proceeds at full pace if the company believes there has been a sufficient interest/market created, or there is the potential to do so.

However, having said this I simply can’t disagree with your basic position–scientific/medical research MUST and will continue. I just don’t want to see the average person become lulled into believing that their health can be safeguarded through preventive pharmaceutical interventions; I believe these compounds should only be used in specific medical populations.

Unless compounds are developed that are completely unlike all other pharmaceutical compounds developed to this point, people should stick to naturally occurring compounds (yes, purified and extracted, even modified to provide increased bio-availability), for their preventative health concerns.

I’d really like to take a look at the article you were talking about.

Thanks for the interesting discussion,

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