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Vol. LXVI, No. 1
January 3, 2014
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Mimicking Calorie Restriction
NHLBI’s Chung Seeks to Slow Aging

Dr. Jay H. Chung
Dr. Jay H. Chung
Right now, there are two ways to slow the aging process: eat less and exercise more. NHLBI’s Dr. Jay H. Chung may have identified a third way. His studies indicate how resveratrol, a naturally occurring compound found in red wine, may slow aging by mimicking the effects of calorie restriction.

A senior investigator in the Laboratory of Obesity and Aging Research, NHLBI, Chung reviewed progress made in understanding how certain compounds may mimic the effects of calorie restriction in a recent lecture held in Lipsett Amphitheater.

He described obesity as partly a “disease of aging.” As people grow older, the body’s ability to metabolize energy declines. This contributes to weight gain, particularly around the midsection. People with this type of fat, known as visceral fat, are at increased risk for type 2 diabetes, Alzheimer’s disease and heart disease, among others.

Twenty-one years ago, scientists surmised that resveratrol was responsible for red wine’s health benefits. It was thought that resveratrol activated sirtuin 1, a protein thought to protect against aging by repairing damaged DNA and to switch off certain genes. With age, SIRT1 levels decline.

Chung’s research indicated otherwise. He found that resveratrol inhibited phosphodiesterases (PDEs), enzymes that regulate cell energy use, and that resveratrol activated SIRT1 indirectly as a result of inhibiting PDEs.

Out of 11 PDEs, Chung focused on PDE4 because it is the dominant PDE in skeletal muscle, the main site of glucose metabolism. To confirm whether the metabolic benefits of resveratrol were mediated by inhibiting PDEs, Chung’s team gave mice rolipram, a PDE4 inhibitor. This led to an increase in levels of cyclic AMP, which normally rise when blood glucose levels are low such as in fasting. Essentially, inhibiting PDE4 mimicked the effects of a lowcalorie diet and increased the activity of SIRT1 in skeletal muscle.

Despite the promising results, Chung cautioned that a person would have to drink 667 bottles of wine to produce resveratrol’s benefits. Besides the compound’s low potency, resveratrol could affect many other biological pathways in the body. Some of these interactions could be detrimental.

Chung is initiating a clinical trial at the Clinical Center to evaluate the glucoselowering mechanism of roflumilast, the PDE4 inhibitor that is FDA-approved for another indication, in obese, pre-diabetic individuals.


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