Scientists have been studying
resveratrol—a chemical that originates in grapes (Vitis spp.) and several other plants (e.g., Japanese knotweed [Polygonum cuspidatum])—for its possible life-extending effects for
about a decade, and have spent many more years studying its other potential
health benefits. Inching toward household familiarity, research on the
substance has even inspired American fiction, a memorable example being the short,
comical chronicle of a wine-lapping lab rodent, “Mouse au Vin,” that ran in a late-2009
issue of The New Yorker.1
Up until the present, though, resveratrol’s precise mechanism of action has
eluded experts. It was widely held that resveratrol promoted health by directly
activating a protein related to caloric restriction called sirtuin 1, but
debate persisted in the scientific community as studies generated varying
results. (Unfortunately, an oeuvre of resveratrol journal articles by the
director of the University of Connecticut’s Cardiovascular Research Center,
Dipak K. Das, PhD, describing the chemical’s positive effects was recently
reported to be riddled with false or fabricated data, causing some to question the
veracity of resveratrol’s reported benefits).2
A new study may put to bed conjecture over resveratrol’s means of imbuing
positive health effects. On February 2, 2012, the US National Institutes of
Health (NIH) issued a press release stating that its researchers had pinpointed
the probable mechanism of action by which resveratrol promotes health, knowledge
that also may be useful in creating new approaches for treating heart disease,
type 2 diabetes, and Alzheimer’s disease.3
Principle study author—and Chief of the Laboratory of Obesity and Aging
Research at NIH’s National Heart, Lung, and Blood Institute— Jay H. Chung, MD, PhD,
has been researching resveratrol for 5 years. “It captivated my interest
because a simple, naturally occurring compound was able to mimic certain
healthful aspects of calorie restriction,” he said (e-mail, February 17, 2012).
Dr. Chung and the co-authors of the NIH study, which was published in the
journal Cell, “present evidence that
resveratrol does not directly activate sirtuin 1, a protein associated with
aging,” debunking conclusions from a number of preceding studies.3 Indeed,
according to the study authors, “resveratrol inhibits certain types of proteins
known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.”3
Chung et al. confirmed in an
early experiment that resveratrol could not be interacting directly with
sirtuin 1—previously postulated by Pacholec et
al. in 20104—because “resveratrol activity required another
protein called AMPK.” (AMPK is the acronym for an enzyme known as 5'
AMP-activated protein kinase.) By observing metabolic activity in
resveratrol-treated cells, the scientists discovered that the protein PDE4 is inhibited
by resveratrol. This inhibition starts a chain reaction that activates AMPK, which
leads to the activation of sirtuin 1 along the way.
“There was doubt about previous studies’ conclusions before we entered the
picture,” said Dr. Chung, “We suspected AMPK may be involved because activation
of AMPK leads to the benefits that are very similar to those of resveratrol.
When we discovered that the metabolic effects of resveratrol disappear without
AMPK, we knew that AMPK was the principal player in resveratrol action.”
The researchers tested their hypothesis by dosing mice with a drug called
rolipram, which also inhibits PDE4, and the positive health benefits were
identical to those associated with resveratrol, such as “preventing
diet-induced obesity, improving glucose tolerance, and increasing physical
endurance.”3
(FDA has approved roflumilast [marketed as Daliresp® by Forest
Pharmaceuticals, Inc., and Daxas® by Nycomed], another drug that inhibits PDE4,
for the treatment of obstructive pulmonary disease.)3
While the conclusions of the study represent a step forward in resveratrol
research, they also reveal a more complex chemical than previous studies have
shown. According to Dr. Chung, natural resveratrol affects many non-PDE
proteins, and because of that, high doses of resveratrol such as those used in
human clinical studies (1 gram/day, equivalent to 667 bottles of red wine) “may
cause not-yet-known toxicities as a medicine, particularly with long-term use.”3
“No one has done a good long-term study, either in animals or in humans, on
the potential toxicities of resveratrol… At this point,” said Dr. Chung, “we
don’t know enough to predict what types of toxicities may exist, if at all.”
Equipped with the data yielded from the rolipram study, Dr. Chung intends
to follow it up with a clinical trial.
“We will be testing PDE4 inhibitors in obese individuals at risk for
developing type 2 diabetes,” he said “[to] determine whether it can improve
insulin sensitivity.”
—Ashley Lindstrom
References
1. Baumbach N. Mouse au vin. The New Yorker. January 26, 2009.
Available at: www.newyorker.com/humor/2009/01/26/090126sh_shouts_baumbach#ixzz1mOJBtYzT. Accessed February 17, 2012.
2. Wade N. University suspects fraud by a
researcher who studied resveratrol. The
New York Times. January 11, 2012. Available at: www.nytimes.com/2012/01/12/science/fraud-charges-for-dipak-k-das-a-university-of-connecticut-researcher.html.
Accessed February 14, 2012.
3. NIH study uncovers probable mechanism underlying
resveratrol activity [press release]. National Institutes of Health News.
February 2, 2012. Available at: www.nih.gov/news/health/feb2012/nhlbi-02.htm. Accessed February 3, 2012.
4. Pacholec M, Chrunyk B, Cunningham D, et al. SRT1720,
SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 2010;285:8340–8351. Available at: www.jbc.org/content/285/11/8340. Accessed February 17, 2012.
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