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More resveratrol hoopla

Saturday, June 28, 2008

Resveratrol is in the news. Again.

My last major note about resveratrol is here, way back last September. How time flies. I also mentioned it more briefly here, in May, in connection with cancer. (Where its effect may involve facilitating apoptosis of tumor cells.)

But resveratrol's now back in the news again, so I guess it's time for an update.

As you recall, resveratrol seems to have a number of properties that confer health benefits. For example, it is thought to be an antioxidant, an anti-inflammatory, and perhaps to activate sirtuin enzymes, which may help produce an effect similar to calorie restriction.

The big question is whether you can get the benefits from the amount of the stuff you can get in a dose of reasonable size, for a reasonable price, and without having to drink gallons of wine per day (not a great idea).

Now we have recent reports of two more research results dealing with resveratrol. One suggests a benefit in countering obesity, and the other concerns anti-aging properties that mimic calorie restriction.

Here's the finding on obesity, the relation to which of resveratrol I cannot recall having heard bandied about before:

Red Wine's Resveratrol May Help Battle Obesity (6/16/08)
Resveratrol, a compound present in grapes and red wine, reduces the number of fat cells and may one day be used to treat or prevent obesity, according to a new study.

Past research found that resveratrol protected laboratory mice that were fed a high-calorie diet from the health problems of obesity, by mimicking the effects of calorie restriction. Researchers at the University of Ulm in Germany wanted to know if resveratrol could mimic the effects of calorie restriction in human fat cells by changing their size or function. The German team used a strain of human fat cell precursors, called preadipocytes. In the body, these cells develop into mature fat cells. ...

In the cell-based study, they found that resveratrol inhibited the pre-fat cells from increasing and prevented them from converting into mature fat cells. Also, resveratrol hindered fat storage.

One would certainly expect effects like that, if they can be reproduced in living humans, to be helpful in countering obesity. But there were two other beneficial effects as well:
[R]esveratrol reduced production of certain cytokines (interleukins 6 and 8), substances that may be linked to the development of obesity-related disorders, such as diabetes and clogged coronary arteries. Also, resveratrol stimulated formation of a protein known to decrease the risk of heart attack. Obesity decreases this substance, called adiponectin.

We've discussed both of these subjects before: IL-6 and inflammation were discussed here, while adiponectin was discussed here and here.

But the intriguing connections don't even stop there. Another report on the same research suggests that the effects related to fat cells may be mediated through sirtuin proteins:

Red wine component resveratrol might fight obesity, lab tests show (6/16/08)
Resveratrol’s mechanism of action is not entirely clear, but the compound seems to activate at least one member of a family of proteins called sirtuins. While also poorly understood, some sirtuins show up in fat cells.

Previous work showed that low levels of sirtuins allowed fat cells to add fats and to proliferate freely from nascent to mature stages, a recipe for weight gain. Conversely, that work also showed that an increase in sirtuins — in that case the compound Sirt2 — kept stem cells from maturing into full-fledged fat cells and inhibited mature fat cells from filling with fats.

In the new study, resveratrol’s good effects failed to emerge in either nascent or mature fat cells engineered to lack a sirtuin called Sirt1, Wabitsch said.

As potential therapeutics, “the sirtuins are a new class in the armamentarium of diabetes and pre-diabetes management,” says Henry Anhalt, a pediatric endocrinologist at Animas Corp. in West Chester, Pa., who wasn’t involved in this study. Sirtuins seem to curb the risk of obesity, cardiovascular disease and inflammation, all of which have been correlated with development of diabetes and its complications. The finding that resveratrol seems to work through a sirtuin (Sirt1) opens up new research opportunities, he says.

As previously noted, I've had a lot to say about sirtuins, which you can refer to here.

The second recent study, which appeared about two weeks before the one just discussed, involved experiments with mice that explicitly compared the effects of resveratrol and calorie restriction:

Substance In Red Wine, Resveratrol, Found To Keep Hearts Young (6/4/08)
[T]he researchers report that low doses of resveratrol in the diet of middle-aged mice has a widespread influence on the genetic levers of aging and may confer special protection on the heart.

Specifically, the researchers found that low doses of resveratrol mimic the effects of what is known as caloric restriction - diets with 20-30 percent fewer calories than a typical diet - that in numerous studies has been shown to extend lifespan and blunt the effects of aging.

This research sharpens results that have previously been found, and also shows that the required dose of resveratrol may not be unreasonable:
Previous research has shown that resveratrol in high doses extends lifespan in invertebrates and prevents early mortality in mice given a high-fat diet. The new study, conducted by researchers from academia and industry, extends those findings, showing that resveratrol in low doses and beginning in middle age can elicit many of the same benefits as a reduced-calorie diet.

"Resveratrol is active in much lower doses than previously thought and mimics a significant fraction of the profile of caloric restriction at the gene expression level," says Tomas Prolla, a UW-Madison professor of genetics and a senior author of the new report.

Another way this research differs from earlier work is that it looks specifically at the expression of genes known to be affected by aging in several important tissue types:
The group explored the influence of the agent on heart, muscle and brain by looking for changes in gene expression in those tissues. As animals age, gene expression in the different tissues of the body changes as genes are switched on and off.

In the new study - which compared the genetic crosstalk of animals on a restricted diet with those fed small doses of resveratrol - the similarities were remarkable, explains lead author Jamie Barger of Madison-based LifeGen Technologies. In the heart, for example, there are at least 1,029 genes whose functions change with age, and the organ's function is known to diminish with age. In animals on a restricted diet, 90 percent of those heart genes experienced altered gene expression profiles, while low doses of resveratrol thwarted age-related change in 92 percent. The new findings, say the study's authors, were associated with prevention of the decline in heart function associated with aging.

Another report stresses the overlap between the effects of calorie restriction and of resveratrol:

Red wine compound seen protecting heart from aging (6/4/08)
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.

A similar news release on this research mentions an upcoming Phase I human clinical trial that will study the effects of resveratrol on older humans:

Substance in red wine found to keep hearts young (6/5/08)
Resveratrol is currently sold over-the-counter as a nutritional supplement with supposed anti-cancer, anti-viral, anti-inflammatory and anti-aging benefits, although few scientific studies have verified these claims in humans. That may soon change: Researchers at the University of Florida hope to explore the effects of resveratrol on older people in a phase 1 clinical trial, set to begin this summer.

The study will assess the supplement's effects on memory, physical performance, inflammation and oxidative damage.

It also calls attention to the possible longevity-promoting effects of resveratrol on the mitochondria of cells:
Mitochondria, the tiny power plants that keep a cell functioning, are especially vulnerable to the oxidative damage that accumulates during the aging process.

"In animal studies, (resveratrol) seems to promote mitochondrial health," said Todd Manini, also a principal investigator of the upcoming trial and an assistant professor of aging and geriatrics in the UF College of Medicine. "Mitochondria are everywhere: They're in the brain, in the muscle, the liver. So it could have kind of a global impact on many different organ systems."

New York Times science writer Nicholas Wade (who, in earlier articles, had questioned the necessary dosage of resveratrol, see here) has a cautionary article that puts this research into context of other work on resveratrol and sirtuins. Among other points, he notes that there is still plenty of room to question whether resveratrol, or something similar, will actually have health benefits in humans, for example:

New Hints Seen That Red Wine May Slow Aging (6/4/08)
Dr. Auwerx, who used doses almost 100 times greater in his treadmill experiments, expressed reservations about the new result. “I would be really cautious, as we never saw significant effects with such low amounts,” he said Tuesday in an e-mail message.

Another researcher in the sirtuin field, Dr. Matthew Kaeberlein of the University of Washington in Seattle, said, “There’s no way of knowing from this data, or from the prior work, if something similar would happen in humans at either low or high doses.”


More news reports about this:


Update, 7/16/08: There's more recent news about resveratrol here.

Further reading:

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice – abstract and complete technical article describing the mouse study

Low-dose resveratrol as a calorie restriction mimetic – 6/12/08 blog post with further comments on the mouse study and associated issues

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