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NIH Researchers Determine Resveratrol’s Probable Health-Promoting Mechanism

Scientists have been studying resveratrol—a chemical that originates in grapes (Vitis spp., Vitaceae) and several other plants (e.g., Japanese knotweed [Polygonum cuspidatum, Polygonaceae])—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


  1. Baumbach N. Mouse au vin. The New Yorker. January 26, 2009. Available at: 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: 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: 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: Accessed February 17, 2012.