New study uncovers probable mechanism underlying resveratrol activity

February 2, 2012

National Institutes of Health researchers and their colleagues have identified how resveratrol, a naturally occurring chemical found in red wine and other plant products, may confer its health benefits. The authors present evidence that resveratrol does not directly activate sirtuin 1, a protein associated with aging. Rather, the authors found that resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.

These findings may help settle the debate regarding resveratrol's biochemistry and pave the way for resveratrol-based medicines. The chemical has received significant interest from for its potential to combat diabetes, inflammation, and cancer. The study appears in the Feb. 3 issue of Cell.

" has potential as a therapy for diverse diseases such as , Alzheimer's disease, and ," said lead study author Jay H. Chung, M.D., Ph.D., chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute. "However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells."

Several previous studies suggested that resveratrol's primary target is sirtuin 1. Chung and colleagues suspected otherwise when they found that resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1.

In this study, the researchers methodically traced out the in cells treated with resveratrol and identified PDE4 in the as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1.

To confirm that resveratrol attaches to and inhibits PDE proteins, Chung's group gave mice rolipram, a drug known to inhibit PDE4. Rolipram reproduced all of the biochemical effects and health benefits of resveratrol, such as preventing diet-induced obesity, improving glucose tolerance, and increasing physical endurance.

Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use. He added that the levels of resveratrol found in wine or foods are likely not high enough to produce significant or problems. Convincing clinical studies in humans have used about 1 gm of resveratrol per day, roughly equal to the amount found in 667 bottles of .

The study results also suggest that inhibitors of PDE4 may offer the benefits of resveratrol without the potential toxicities arising from resveratrol's interactions with other proteins. One inhibitor called roflumilast has already been approved by the FDA for the treatment of COPD (chronic obstructive pulmonary disease).

"This result underscores the need for careful, well-controlled studies to illuminate how these natural products operate," said Robert Balaban, Ph.D., director of the NHLBI Division of Intramural Research. "As Dr. Chung's work suggests, the effects of resveratrol seem to be more complicated than originally thought. However, this new insight into the phosphodiesterases might prove an interesting avenue to pursue."

In addition to Dr. Chung's lab at the NHLBI, other contributors to this study included collaborators in the Cardiovascular Pulmonary Branch of the NHLBI; the University of California, Davis; the University of North Carolina, Chapel Hill; University of Texas Southwestern Medical Center, Dallas; Sun Yat-sen University, Guangzhou, China; University Medical Center, Utrecht, The Netherlands; and Emerald BioStructures, Bainbridge Island, Wash.

Explore further: Red wine ingredient resveratrol stops breast cancer growth

Related Stories

Red wine ingredient resveratrol stops breast cancer growth

September 29, 2011
Cheers! A new research report appearing in the October 2011 issue of The FASEB Journal shows that resveratrol, the "healthy" ingredient in red wine, stops breast cancer cells from growing by blocking the growth effects of ...

Red wine: Exercise in a bottle?

June 30, 2011
As strange as it sounds, a new research study published in the FASEB Journal, suggests that the "healthy" ingredient in red wine, resveratrol, may prevent the negative effects that spaceflight and sedentary lifestyles have ...

First clinical trial of red wine ingredient shows metabolic shifts

November 1, 2011
When obese men take a relatively small dose of resveratrol in purified form every day for a month, their metabolisms change for the better. In fact, the effects appear to be as good for us as severe calorie restriction. Resveratrol ...

Recommended for you

Make way for hemoglobin

August 18, 2017
Every cell in the body, whether skin or muscle or brain, starts out as a generic cell that acquires its unique characteristics after undergoing a process of specialization. Nowhere is this process more dramatic than it is ...

Bio-inspired materials give boost to regenerative medicine

August 18, 2017
What if one day, we could teach our bodies to self-heal like a lizard's tail, and make severe injury or disease no more threatening than a paper cut?

Are stem cells the link between bacteria and cancer?

August 17, 2017
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, ...

Two-step process leads to cell immortalization and cancer

August 17, 2017
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally ...

Female mouse embryos actively remove male reproductive systems

August 17, 2017
A protein called COUP-TFII determines whether a mouse embryo develops a male reproductive tract, according to researchers at the National Institutes of Health and their colleagues at Baylor College of Medicine, Houston. The ...

New Pathology Atlas maps genes in cancer to accelerate progress in personalized medicine

August 17, 2017
A new Pathology Atlas is launched today with an analysis of all human genes in all major cancers showing the consequence of their corresponding protein levels for overall patient survival. The difference in expression patterns ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Argiod
1 / 5 (1) Feb 03, 2012
If resveratrol inhibits aging, and it comes from red wine, then how come Italians aren't the longest lived people on the planet?
gmurphy
5 / 5 (1) Feb 03, 2012
@Argiod, Average Italian lifespan is 81.1 years, amongst the longest on the planet.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.