Discovery by NHLBI Researchers
BY JUSTIN CHEN, NICHD
Many believe that resveratrol—a chemical found in red wine as well as in grapes, peanuts, and other plants—protects against aging-associated diseases such as type 2 diabetes. But no one has fully understood how it works. In February, senior investigator Jay H. Chung and colleagues at the National Heart, Lung, and Blood Institute published a paper explaining how resveratrol affects enzymes that increase the activity of the aging-associated protein Sirtuin 1 (Sirt1). (Cell 148:421-433, 2012).
Over the years, resveratrol and Sirt1 have been the subjects of intense debates that have thrown reputations, grants, and the biology of aging into question. At the heart of the resveratrol story is the human desire for good health and longevity. Resveratrol mimics the effects of calorie restriction (CR), which since the 1930s has been known to stretch, and even double, the lifespans of mice. CR can also prevent cancer, heart disease, neurodegenerative diseases, age-related loss of muscle mass, and type 2 diabetes in mice. But most humans will not tolerate the kind of restricted diets that have been imposed on mice. Instead scientists are looking to resveratrol and other CR-mimicking compounds that show promise as anti-aging agents.
PHOTO BY: BILL BRANSON
Jay Chung, NHLBI
A major breakthrough occurred in 2000 when scientists at the Massachusetts Institute of Technology (Cambridge, Mass.), who were working with yeast, proposed that CR worked through the Sir2 protein (the yeast version of mammalian Sirt1). Then, in 2003, Harvard (Cambridge, Mass.) researchers reported that resveratrol increased the activity of Sirt1, in a test tube, and extended the lifespan of yeast. Suddenly, it seemed possible that resveratrol might be a cure for aging. Unfortunately, laboratories in the United States and England have failed to replicate the original breakthrough results.
Chung—who earned an M.D.-Ph.D. from Harvard, trained in internal medicine at Brigham and Women’s Hospital (Boston), and first came to the NIH as an endocrine fellow in the National Institute of Diabetes and Digestive and Kidney Diseases—was initially interested in resveratrol because of its antidiabetic effect in mice. “The problem with resveratrol is that it interacts with many proteins and by itself would probably not be a good drug,” he explained. “To translate resveratrol research into the clinics, we need to find the target of resveratrol that produced its antidiabetic effect.”
In the Cell study, Chung’s lab used tissue culture and mouse models to demonstrate that resveratrol doesn’t directly affect Sirt1 but instead inhibits a group of enzymes known as phosphodiesterases (PDEs), particularly PDE4. PDEs normally decrease the concentration of cyclic adenosine monophosphate (cAMP), a signaling molecule whose levels increase with CR and exercise and plays a key role in metabolic regulation. When PDEs are inhibited, however, cAMP concentrations rise, leading to a cascade of protein-protein interactions that activate Sirt1. Treating obese mice with a PDE4 inhibitor reproduced all the metabolic benefits of resveratrol, including its antidiabetic effects.
NIH’s unique environment of “allow[ing] one to take on risky projects even without having significant background or expertise in an area” made it possible to do the kind of work that has led to Chung’s discovery. “Prior to this work, I had no background in animal research,” he explained. Chung plans to continue his investigation of resveratrol through clinical trials that will use PDE inhibitors to treat people at risk for type 2 diabetes.
The Cell paper has “certainly raised the profile of PDEs as the target for a number of diseases,” Chung said. Researchers working with mice have shown that PDE inhibitors can improve memory, prevent obesity, and protect against aging-related diseases such as Alzheimer disease and Parkinson disease. “The next chapter in resveratrol research is to identify the specific targets for whatever indication you’re looking at—whether it’s diabetes or neurodegeneration.”
Although Chung is excited about the potential of PDEs, he is more reserved when discussing the anti-aging properties of the sirtuin family of proteins. Despite these uncertainties, Chung’s finding suggests that PDEs may be the missing link in the resveratrol-Sirt1 story—but it may not be the end of the story
All the NHLBI researchers on the Cell paper: Sung-Jun Park, Faiyaz Ahmad, Alexandra L. Brown, Myung K. Kim, Michael A. Beaven, Vincent Manganiello, and Jay H. Chung