Do Sirtuin Molecules Hold the Key to Antiaging Drugs?

A recent discovery showing that a family of enzymes called sirtuins can significantly extend life in organisms such as yeast, worms, and flies has led experts to believe that they may also be able to control age-related metabolic disorders, including obesity and type 2 diabetes in humans.

Various naturally occurring substances are known to activate sirtuins, including the red wine component called resveratrol—although one would need to drink about 2 cases of wine every day to receive a clinically effective dose of resveratrol. These findings have prompted a search for drugs that could boost sirtuin activity.

A new study points to one strategy for activating sirtuins and unleashing their antiaging properties (Mol Cell. 2007; 25:463-472). Applying strategies from structural biology, the investigators demonstrated that a component of niacin (vitamin B₃), nicotinamide, binds to a specific site on the sirtuin molecule to inhibit its activity.

This observation suggests that drugs designed to prevent nicotinamide from binding at this site could have the effect of activating sirtuins. Any such drug would basically block the inhibitory effect of nicotinamide.

“Our findings suggest a new avenue for designing sirtuin-activating drugs,” says senior investigator Ronen Marmorstein, PhD, of the Wistar Institute, Philadelphia. “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 2 diabetes.” Future research will focus on use of rational drug design techniques to create such a drug.

The nicotinamide-binding site may be a particularly appealing drug target for other reasons too, according to Dr Marmorstein. “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. 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.”

This research also helps explain 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,” Dr Marmorstein says. “Recent research has shown that the connection works at least in part through these sirtuin molecules.”