The paper, published Dec. 8 in the online edition of Cell, shows that sirtuins play a keyrole in the psychological response to dietary restriction. Specifically, micebecome more anxious when their food intake is cut and sirtuins are elevated inthe brain. In addition, in two large human genetic studies, the MIT researchersfound that mutations which boost production of sirtuins are commonly associatedwith higher rates of anxiety and panic disorder.
In the mice study, Guarente's team examined two differentgroups: One with elevated levels of the SIRT1 protein in their brains, and asecond group with none. To test the psychological consequences of thesealterations, the mice were placed on a circular raised platform with twoquadrants protected by a wall, and two unprotected quadrants. While normal micespent a considerable amount of time venturing out into the unprotected region,mice with abnormally high sirtuin levels stayed close to the walls, suggestingthey were more anxious, Guarente explains.
For the human study, Guarente's lab teamed up withresearchers at the University of Lausanne in Switzerland who had identifiedmutations in the SIRT1 gene in humans associated with anxiety, panic disorderand social phobia. Investigating the molecular consequences of some of thoseSIRT1 mutations, the researchers found they led to sirtuin overactivity.Another group of collaborators at Virginia Commonwealth University found astrong correlation between one of those SIRT1 mutations and the risk of panicdisorder.
"Both common and rare variations in the SIRT1 gene wereshown to be associated with risk of anxiety in human population samples," theresearchers found. "Together, these data indicate that SIRT1 mediates levels ofanxiety, and this regulation may be adaptive in a changing environment of foodavailability.
According to the researchers, this anxiety may be anevolutionary adaption that makes animals and perhaps humans more cautious underthe stressful condition of having to forage more widely for scarce food. Thephysiological response provoked by low-calorie diets promotes survival,according to Guarente.
"Our paper suggests that anxiety could potentially betreated with drugs that inhibit sirtuins," he says.
Several sirtuins are currently in clinical trials formetabolic diseases and diabetes. Although these drugs can't pass through theblood brain barrier, some researchers are exploring the possibility of usingsirtuin inhibitors to treat neurological disorders, and Guarente's researchcareer has been marked by significant findings in this area. About 20 yearsago, 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 andother animals. In July 2010, Guarente and his colleagues published anotherstudy in Cell suggesting thatdeveloping drugs that activate sirtuins may be a viable strategy to combatAlzheimer's disease.
"At the same time, however, we now know that we must becautious when treating patients with drugs that activate sirtuins becauseanxiety may be a possible side effect," Guarente notes. "We're interested inthe biology of sirtuins and what they do. That's important, because the more weunderstand about the biology, this will inform how we do clinical trials. Rightnow, there is nothing to treat many neurodegenerative diseases, but if you hadsomething to control them, and the only side effect was anxiety, that issomething that would at least be controllable."
The study, "SIRT1 Activates MAO-A in the Brain to Mediate Anxiety andExploratory 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 fromboth the Glenn Laboratory and the HHMI/Harvard Department of Stem Cell andRegenerative Biology; John M. Asara from the Beth Israel Deaconess MedicalCenter and Department of Medicine and Harvard Medical School; Karen Kapur andSven Bergmann from the University of Lausanne; Martin Preisig from the CentreHospitalier Universitaire Vaudois in Lausanne; Takeshi Otowa, Kenneth S.Kendler, Xiangning Chen, Edwin J. van den Oord and John M. Hettema fromVirginia Commonwealth University; and Justin P. Rubio from GlaxoSmithKline PLC,a longtime pharma partner of MIT.
