In recent years, scientists have discovered that a family of enzymes called sirtuins can dramatically extend life in organisms as diverse as yeast, worms, and flies. They may also be able to control age-associated metabolic disorders, including obesity and type II diabetes.
Naturally occurring substances have been shown to activate sirtuins, including a constituent of red wine called resveratrol -- although an individual would need to drink about two cases of wine a day to derive a clinically effective dose of resveratrol. Still, the findings have energized a number of scientific groups and biotechnology companies, all of which are now eagerly searching for drug candidates able to boost sirtuin activity. The public-health benefits of such an "anti-aging" drug would be substantial -- as would the economic returns.
Now, a new study from scientists at The Wistar Institute points to another strategy for activating sirtuins to unleash their anti-aging powers. A report on the research will appear in the February 9 edition of Molecular Cell, and a podcast interview with the study's senior author, Ronen Marmorstein, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar, will be available on the Institute's web site (http://www.wistar.org) on the same date.
Using the techniques of structural biology, the Wistar team demonstrated that a component of the common vitamin B3, also known as niacin, binds to a specific site on the sirtuin molecule to inhibit its activity. This observation suggests that drugs designed to prevent the vitamin B3 component, nicotinamide, from binding at this site could have the effect of activating sirtuins. Any such drug would, in essence, inhibit the inhibitory effect of nicotinamide. As in mathematics, the two negatives would create a positive result -- activation of sirtuins.
"Our findings suggest a new avenue for designing sirtuin-activating drugs," says Marmorstein. "The jury is still out as to whether a drug of this kind might result in longer life in humans, but I'm equally excited by the possibility that such interventions might help counteract age-related health problems like obesity and type II diabetes."
The nicotinamide binding site may be a particularly attractive drug target for other reasons too, according to Marmorstein. His group now hopes to use rational drug design techniques to create such a drug.
"Many drugs have unwanted side effects because in addition to the intended target, the drugs also hit other biologically active molecules that you don't want to affect," he says. "This nicotinamide-binding site we've identified appears to be unique to the sirtuins, so that if we're able to design a molecule to target it, it should be very specific for these sirtuin molecules."
Marmorstein's research on sirtuins also links to a long line of observations concerning calorie-restricted diets and longevity.
"People have known for some time that low-calorie diets result in life extension in many organisms, but they didn't know why," he says. "Recent research has shown that the connection works at least in part through these sirtuin molecules."
The lead author on the Molecular Cell study is Brandi D. Sanders at The Wistar Institute. Kehao Zhao, Ph.D., formerly at Wistar and now at the Novartis Institutes for Biomedical Research Inc. in Cambridge, Massachusetts, is also a coauthor, as is James T. Slama, Ph.D., with the College of Pharmacy at the University of Toledo, Ohio. Funding to support the research was provided by the National Institutes of Health and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.
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