Heart, Lung, and Blood Institute (NHLBI)
February 2, 2012
NIH study uncovers probable mechanism underlying resveratrol health
Findings may settle scientific debate surrounding this chemical found in
red wine and other foods
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 pharmaceutical companies
for its potential to combat diabetes, inflammation, and cancer. The study
appears in the Feb. 3 issue of Cell.
"Resveratrol has potential as a therapy for diverse diseases such as type
2 diabetes, Alzheimer’s disease, and heart disease," 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 metabolic
activity in cells treated with resveratrol and identified PDE4 in the
skeletal muscle 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 health benefits 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 red wine.
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 PDE4 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
Part of the National Institutes of Health, the National Heart, Lung, and
Blood Institute (NHLBI) plans, conducts, and supports research related to
the causes, prevention, diagnosis, and treatment of heart, blood vessel,
lung, and blood diseases; and sleep disorders. The Institute also
administers national health education campaigns on women and heart
disease, healthy weight for children, and other topics. NHLBI press
releases and other materials are available online atwww.nhlbi.nih.gov.
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and is a component of the U.S. Department of Health and Human Services.
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causes, treatments, and cures for both common and rare diseases. For more
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