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MIT researchers link sirtuins to anxiety and mood control
CAMBRIDGE, Mass.—A little more than a year ago, scientists at the Massachusetts Institute of Technology (MIT) took public their groundbreaking work showing how the neuroprotective abilities of sirtuins could be applied to treating Alzheimer's disease. Now the same team, led by MIT biology professor Dr. Leonard Guarente, has published a new paper that explores the role this set of proteins plays in the psychological response to dietary restriction and its correlation to anxiety and panic disorder.
The paper, published Dec. 8 in the online edition of Cell, shows that sirtuins play a key role in the psychological response to dietary restriction. Specifically, mice become more anxious when their food intake is cut and sirtuins are elevated in the brain. In addition, in two large human genetic studies, the MIT researchers found that mutations which boost production of sirtuins are commonly associated with higher rates of anxiety and panic disorder.
In the mice study, Guarente's team examined two different groups: One with elevated levels of the SIRT1 protein in their brains, and a second group with none. To test the psychological consequences of these alterations, the mice were placed on a circular raised platform with two quadrants protected by a wall, and two unprotected quadrants. While normal mice spent a considerable amount of time venturing out into the unprotected region, mice with abnormally high sirtuin levels stayed close to the walls, suggesting they were more anxious, Guarente explains.
For the human study, Guarente's lab teamed up with researchers at the University of Lausanne in Switzerland who had identified mutations in the SIRT1 gene in humans associated with anxiety, panic disorder and social phobia. Investigating the molecular consequences of some of those SIRT1 mutations, the researchers found they led to sirtuin overactivity. Another group of collaborators at Virginia Commonwealth University found a strong correlation between one of those SIRT1 mutations and the risk of panic disorder.
"Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples," the researchers found. "Together, these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.
According to the researchers, this anxiety may be an evolutionary adaption that makes animals and perhaps humans more cautious under the stressful condition of having to forage more widely for scarce food. The physiological response provoked by low-calorie diets promotes survival, according to Guarente.
"Our paper suggests that anxiety could potentially be treated with drugs that inhibit sirtuins," he says.
Several sirtuins are currently in clinical trials for metabolic diseases and diabetes. Although these drugs can't pass through the blood brain barrier, some researchers are exploring the possibility of using sirtuin inhibitors to treat neurological disorders, and Guarente's research career has been marked by significant findings in this area. About 20 years ago, he was the first to discover that sirtuins prolong lifespan in yeast; since then, they have been shown to have similar effects in worms, mice and other animals. In July 2010, Guarente and his colleagues published another study in Cell suggesting that developing drugs that activate sirtuins may be a viable strategy to combat Alzheimer's disease.
"At the same time, however, we now know that we must be cautious when treating patients with drugs that activate sirtuins because anxiety may be a possible side effect," Guarente notes. "We're interested in the biology of sirtuins and what they do. That's important, because the more we understand about the biology, this will inform how we do clinical trials. Right now, there is nothing to treat many neurodegenerative diseases, but if you had something to control them, and the only side effect was anxiety, that is something that would at least be controllable."
The study, "SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive," was co-authored by Sergiy Libert, Kelli Pointer, Eric L. Bell and Abhirup Das from MIT's Paul F. Glenn Laboratory; Dena E. Cohen from both the Glenn Laboratory and the HHMI/Harvard Department of Stem Cell and Regenerative Biology; John M. Asara from the Beth Israel Deaconess Medical Center and Department of Medicine and Harvard Medical School; Karen Kapur and Sven Bergmann from the University of Lausanne; Martin Preisig from the Centre Hospitalier Universitaire Vaudois in Lausanne; Takeshi Otowa, Kenneth S. Kendler, Xiangning Chen, Edwin J. van den Oord and John M. Hettema from Virginia Commonwealth University; and Justin P. Rubio from GlaxoSmithKline PLC, a longtime pharma partner of MIT.