Antiaging Enzyme Target Found

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Finding shows how to activate sirtuin to flip longevity switches

A drug that flips on longevity switches is a step closer following the discovery of how to activate a key antiaging enzyme.

The discovery, by researcher Ronen Marmorstein and colleagues at The Wistar Institute in Philadelphia, Pennsylvania, sheds light on the workings of a family of enzymes called sirtuins that are critical to such processes as metabolism, aging and cancer development.

They also point scientists towards interventions that might boost the activity of the sirtuin Sir2, which has previously been linked to life extension in yeast and worms.

"We know that the Sir2 sirtuin silences gene expression and stabilizes the genome in yeast," says Marmorstein. "We also know that sirtuins are highly conserved in humans. The idea researchers are exploring is that if we could activate sirtuins, perhaps we could promote genomic stability and decrease cancer as well as other aging-related problems."

Stress-activated

Researchers have hypothesized that sirtuins are activated as a response to stressful conditions and that they help cells survive damage.

Studies have shown that sirtuins can increase the lifespan of yeast and human cells in laboratory dishes, as well as the lives of flies and worms.

Last year, Marmorstein and colleagues found that sirtuins influence longevity by flipping genetic switches.

They appear to promote genomic stability, a process that goes awry in cancer and aging.


Sir2 boost

Marmorstein's research team has been focusing on the molecular details of how sirtuins work.

For this study, they used a yeast sirtuin as a model and captured 3D images of it to gain a structural picture of its enzymatic activity.

This led them to a binding site that when blocked activated the sirtuin.

Using virtual libraries of molecules, they are now identifying molecules with structures that might bind to this site and serve as Sir2 activators.

The research is reported in the Proceedings of the National Academy of Sciences.