Resveratrol

Resveratrol, of course, is somewhat famous as the substance in red wine that is widely believed to be able to retard aging and promote longevity. There are various hypotheses as to how it might do this, and several may turn out to be correct, as they are not mutually exclusive. There is experimental evidence supporting several of these hypotheses.

Ironically, however, it may be that the amount of resveratrol available in red wine is not sufficient to account for the experimentally supported effects, and there may be other substances in red wine that account for whatever anti-aging properties red wine may have.

Among the properties of resveratrol that might explain an ability to promote longevity are its antioxidant characteristics or other abilities to impede cancer. Resveratrol also has anti-inflammatory properties. Yet another hypothesis is that resveratrol is able to stimulate sirtuin proteins. These proteins are hypothesized to promote longevity, and they may also explain the known longevity-enhancing effects of calorie restriction.

I plan to write about both sirtuins and calorie restriction soon, but right now let's just focus on resveratrol. The most recent news about resveratrol concerns its anti-cancer properties:

Red Wine Compound Shown To Prevent Prostate Cancer

Researchers at the University of Alabama at Birmingham (UAB) have found that nutrients in red wine may help reduce the risk of developing prostate cancer.

The study involved male mice that were fed a plant compound found in red wine called resveratrol, which has shown anti-oxidant and anti-cancer properties. Other sources of resveratrol in the diet include grapes, raspberries, peanuts and blueberries.

The magnitude of the observed effect was substantial:

In the study resveratrol-fed mice showed an 87 percent reduction in their risk of developing prostate tumors that contained the worst kind of cancer-staging diagnosis. The mice that proved to have the highest cancer-protection effect earned it after seven months of consuming resveratrol in a powdered formula mixed with their food.

Other mice in the study, those fed resveratrol but still developed a less-serious form of prostate cancer, were 48 percent more likely to have their tumor growth halted or slowed when compared to mice who did not consume the compound, the UAB research team said.

Unfortunately, the amount of resveratrol (in proportion to body weight) the mice received to achieve these effects would not be very practical for humans to get from wine:

The amounts used in the UAB mice studies were the equivalent of one person consuming one bottle of red wine per day, which is not advisable. Since drinking alcohol in excessive amounts can have harmful health effects, doctors generally recommend moderate red wine consumption, which is an average of two drinks a day for men and one drink a day for women.

Actually, the amounts used are the equivalent of far more than one bottle of wine per day – see further discussion on this below.

Unfortunately, too, this research doesn't address various questions we'd really like answers to. Does resveratrol have a similar effect with other cancers? What is the mechanism by which resveratrol affects cancer?

Here's a blog post at Futurepundit with more on this research, and in particular some suggestions about connection with sirtuins: Resveratrol Reduces Prostate Cancer In Mice

Let's now go back a little way in time, to November 2006, when resveratrol made a big splash with apparent longevity-enhancing effects of a different kind.

Red Wine Molecule Extends Lifespan Of Fat Mice Lives By Reversing Obesity-Related Gene Pathways (11/2/06)

Researchers have used a single compound to increase the lifespan of obese mice, and found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets--some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small molecule resveratrol has been shown to offer survival benefits in a mammal.

Importantly, one of the other principal investigators in this research is David Sinclair, who has been one of the main researchers studying sirtuins (see references in the Futurepundit post mentioned above), has done previous work with resveratrol (in non-mammals), and whose research has also been somewhat controversial. Some relevant background:

Resveratrol is found in red wines and produced by a variety of plants when put under stress. It was first discovered to have an anti-aging properties by Sinclair, other HMS researchers, and their colleagues in 2003 and reported in Nature. The 2003 study showed that yeast treated with resveratrol lived 60 percent longer. Since 2003, resveratrol has been shown to extend the lifespan of worms and flies by nearly 30 percent, and fish by almost 60 percent. It has also been shown to protect against Huntington's disease in two different animal models (worms and mice).

Here's what the researchers say about the sirtuin connection:

Investigators identified resveratrol while looking for compounds that activate Sir2, an enzyme linked to lifespan extension in yeast and other lower organisms. For the last 70 years, scientists have been able to increase the lifespan of a variety of species by reducing their normal food consumption by 30 to 40 percent - a diet known as calorie restriction. Through this research, scientists identified Sir2 as a key contributor to life extension. Without Sir2, for example, fruit flies see none of the benefits from either calorie restriction or treatment by resveratrol. The mammalian version of the Sir2 gene is SIRT1, which has the same enzymatic activity as Sir2, but modifies a wider variety of molecules throughout cells. Indicators in this study show that resveratrol might also be activating SIRT1 in mice, as well as other known longevity pathways.

The experiments divided their mice into three categories: standard diet (SD), high-calorie diet (HC), and high-calorie diet with resveratrol (HCR). Among other findings, there were some which looked specifically at standard indicators of diabetes.

In humans, high calorie diets can increase glucose and insulin levels leading to diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. In the HC fed mice, researchers found biomarkers that might predict diabetes, including increased levels of insulin, glucose and insulin-like growth factor-1 (IGF-1). Conversely, the HCR fed group had significantly lower levels of these markers, paralleling the SD group. For example, a standard diabetes glucose test on the HCR fed group found considerably higher insulin sensitivity, meaning the HCR group had a lower disposition toward diabetes than the HC fed group. Lower insulin levels also predict increased lifespan in mice.

All-in-all, this appears to be a pretty comprehensive piece of research. However, there are a couple of flies in the ointment. Most importantly, as with the prostate cancer research reported above, the mice received rather high doses of resveratrol – much higher, even, in Sinclair's study. The following article by Nicholas Wade explains it pretty well:

Yes, Red Wine Holds Answer. Check Dosage. (11/2/06)

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-lb person would need to drink 750 to 1,500 bottles of red wine a day to get such a dose.

Dr. Richard Hodes, director of the National Institute on Aging, which helped support the study, also said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses, Dr. Hodes said.

One person who is not following this prudent advice, however, is Dr. Sinclair, the chief author of the study. He has long been taking resveratrol, though at a dose of only five milligrams per kilogram. Mice given that amount in a second feeding trial have shown similar, but less pronounced, results as those on the 24-milligram-a-day dose, he said.

So Sinclair is taking about one fifth the dose as his mice – still something like the equivalent of 150 to 300 bottles of wine per day. It's probably a good idea not to expect that drinking even a bottle a day will provide any significant protection against diabetes. The recognized fact that there does appear to be some health benefit to people who consume moderate amounts of wine must therefore be due either to other effects of resveratrol (anti-oxidant, anti-inflammatory, for example), or else to other substances in wine.

It is possible that dietary supplements containing more concentrated resveratrol might help, but probably not any currently on the market, as Wade notes:

Many companies sell the substance, along with claims that rivals’ preparations are inactive. One such company, Longevinex, sells an extract of red wine and knotweed that contains an unspecified amount of resveratrol. But each capsule is equivalent to “5 to 15 5-ounce glasses of the best red wine,” the company’s Web site asserts.

A couple of other problems are that the longevity-enhancing effects of resveratrol – or even calorie restriction, for that matter – have not yet been demonstrated in human trials, and that the lack of human trials also leaves open the question of possible harmful side-effects at high dosage, given the other properties of resveratrol (anti-oxidant, anti-inflammatory).

And if all that weren't enough to worry about, the connection between resveratrol and sirtuins is still not clearly demonstrated to general scientific satisfaction. As Wade writes,

“It hasn’t really been clearly shown, the way a biochemist would want to see it, that resveratrol can activate sirtuin,” said Matt Kaeberlein, a former student of Dr. Guarente’s who does research at the University of Washington in Seattle. Sirtuin is the protein produced by the SIRT-1 gene.

Dr. Sinclair said experiments at Sirtris had essentially wrapped up this point. But they have not yet been published, so under the rules of scientific debate he cannot use them to support his position. In his Nature article he therefore has to concede that “Whether resveratrol acts directly or indirectly through Sir-2 in vivo is currently a subject of debate.

Sinclair is working with a start-up biotech company (Sirtris Pharmaceuticals) that is developing pills containing resveratrol and similar molecules for eventual use in humans. But it almost always takes 5 to 10 years to guide a new drug – which must show measurable beneficial effects for specific diseases as well as safety – through clinical trials in humans, in order to gain approval from the FDA.

Other reports on this research: here, here, here, here, here, and here.

Results of this study were followed closely by those of another study, which apparently was funded by Sirtris:

Red wine compound boosts athletic endurance (11/16/06)

High doses of a compound found naturally in grape skins and red wine can improve muscle endurance in mice, and the compound also keeps them slim, a new study shows. ...

Johan Auwerx at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France, and colleagues placed mice on a high-fat diet. Half of those mice received daily amounts of up to 400 milligrams of resveratrol per kilogram of body weight. ...

After three weeks, the mice on the resveratrol supplements weighed only about 20% more than mice on a standard diet. But those on the high-fat diet that did not receive the supplement weighed 60% more than the control mice. The resveratrol also improved the rodents endurance in fitness tests, and seemed to have no toxic side effects.

Mice on the high-fat diet that also took resveratrol were able to run twice as far on a treadmill as those on the same diet but without the supplement, even after the animals’ weight differences were taken into account.

Note that the dose of 400 mg per kg of body weight is about 17 times as much as was used in Sinclair's study. One has to wonder whether these dosage levels have been reported correctly. It would seem to make more sense to use similar dosages so that similar studies of this sort would be more comparable to each other.

Another report on this research suggests a possible explanation for the results:

A Second Pour of Good News About Substance in Red Wine (11/17/06)

Additional experiments on the animals' cells indicate the substance works by increasing the activity of an enzyme known as SIRT1, boosting the number and activity of structures inside cells called mitochondria, the researchers said. Mitochondria are like power plants inside cells, burning fat and providing energy. They tend to get revved up by exercise, and deteriorate with age.

Mice fed resveratrol had more muscle tissue resembling that of a trained athlete, sharply increasing their endurance. They could run twice as far before collapsing as mice that did not receive the substance.

The researchers in this study also had something to say about the connection with sirtuins in humans:

In addition to the mouse experiments, the researchers also produced evidence supporting the theory that SIRT1 plays a key role in longevity in humans in an accompanying analysis of 123 Finnish adults. The subjects born with certain variations of the SIRT1 gene had faster metabolisms, naturally burning energy more efficiently, indicating the same pathway works in humans, too.

According to a third report, Sirtris has actually (as of last November) begun phase 1 clinical trials in humans of their more potent formulation of resveratrol:

Red Wine Compound Could Boost Endurance (11/17/06)

But if you think that drinking more wine or taking resveratrol supplements might turn you into a super-athlete, think again, said Sirtris CEO Dr. Christoph Westphal.

"Native resveratrol from red wine or nutraceuticals cannot reach therapeutic levels in man," he said. "You would need to drink hundreds of glasses of red wine or take hundreds of nutraceutical pills in a day to get a therapeutic dose."

According to Westphal, the company has completed two phase 1 studies with 85 human volunteers of an improved formulation of resveratrol which reaches therapeutic levels in man and is safe.

In addition, Sirtris has started giving diabetic patients its resveratrol compound in a 28-day phase 1 trial to test the safety of the drug and to see how it affects glucose levels.

Another report on this study: here.

Just about 10 days later additional cold water was thrown on the notion that resveratrol in red wine is responsible for the apparent benefits of wine drinking for cardiovascular health. Whatever virtues resveratrol may actually have, there simply isn't enough of it in wine to make a difference. Instead, other substances in wine are more likely to deserve the credit:

Forget Resveratrol, Tannins Key to Heart Health from Wine (11/29/06)

Resveratrol, a molecule found in the skin of red grapes, among other places, has been found to have a host of health effects, most recently prolonging the life spans of obese mice. But the natural wonder drug does not play a role in the beneficial effects of wine drinking, according to research published in the November 28 issue of Nature. "There are some fascinating effects of resveratrol in animal systems," notes plant biochemist Alan Crozier of the University of Glasgow. "To get similar doses into humans through red wine, you would have to consume more than 1,000 liters of red wine a day."

... Using the endothelial cells that line human artery walls, the researchers tested which compounds in wine had the greatest effect. The tests showed that flavonoids called oligomeric procyanidins--essentially condensed tannins, the compounds that impart bitterness to young reds--suppressed production of the peptide responsible for hardening arteries. Such procyanidins can make up as much as 50 percent of the bioactive compounds in a given wine, the researchers observed. "Resveratrol," Crozier notes, "is available at one one-hundredth or one one-thousandth of the levels of procyanidin." Corder adds: "The role of resveratrol in the health benefits of wine has been popularized without any scientific evidence to support it, given the amounts needed for these actions are approximately 1,000-fold greater than could be achieved by wine consumption."

Other reports of this research: here, here.

Unfortunately, some people have perhaps gone off the deep end where resveratrol is concerned. In spite of the tiny amount of it that's actually in red wine, some folks have actually invested their time in charting that amount in different wines and spinning fantasies about adding information on resveratrol content to wine labels:

Resveratrol Content Varies Among Red Wines (4/20/07)

“The long-term aim is for people to be able to go along to the supermarket and to be able to know at a glance the levels of resveratrol contained in the wines they are choosing,” said Dr Hoffman.

Such information, if ever provided, will serve no other purpose than (wine merchants hope) sell more wine, but otherwise be next to useless.

However, one should not conclude that resveratrol has been over-hyped and is nothing but one of the latest "neutraceutical" scams. The problem is that it's a natural substance that hasn't been specifically optimized as a therapeutic drug – especially while in the form of just one biologically active trace ingredient in wine.

Many researchers, including David Sinclair, are hard at work to find a better form or chemical analogue of resveratrol. Sirtris Pharmaceuticals is also working hard to that end. The following article from January of this year profiles the company and its CEO. The profile is mostly from a business perspective, but there's a lot about resveratrol itself in it, so it's worth reading, despite its length:

Can red wine help you live forever? (1/19/07)

[I]f [Sirtris] succeeds, its medicines may retard the onset or progression of a whole slew of age-related diseases, from diabetes to Alzheimer's to cancer. The drugs may also have an extremely provocative side effect: They might extend life span. You have to go back to the advent of antibiotics in the first half of the 20th century to find such broad therapeutic potential.

There's much more to say about Sirtris and about the related scientific issues of calorie restriction and sirtuin proteins. But that will have to wait for later.

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Further information:

Via Eye on DNA I see some new research by David Sinclair and others has just been reported, dealing with calorie restriction: New Clue To Why Eating Fewer Calories Can Help You Live Longer.

There's a lot of information on resveratrol, as well as the related topic of sirtuins, at the Ouroboros blog. In fact, the whole blog is about the biology of aging. For resveratrol see here, and for sirtuins see here.

Tags: resveratrol, sirtuins, aging, longevity, diabetes, cancer, calorie restriction, caloric restriction