La Jolla, CA In studies going back to the 1930s, mice and many other species subsisting on a severely calorie-restricted diet have consistently outlived their well-fed peers by as much as 40 percent. But just how a diet verging on the brink of starvation extends lifespan has remained elusive.

Now, researchers at the Salk Institute for Biological Studies have cracked open the black box of how persistent hunger promotes long life and identified a critical gene that specifically links calorie restriction (CR) to longevity.

After 72 years of not knowing how calorie restriction works, we finally have genetic evidence to unravel the underlying molecular program required for increased longevity in response to calorie restriction, says Andrew Dillin, Ph.D., an associate professor in the Molecular and Cell Biology Laboratory, who led the study published online in the May 2 issue of Nature.

Having identified a key link between calorie restriction and aging also opens the door to development of drugs that mimic the effects of calorie restriction and might allow people to reap health benefits without adhering to an austere regimen that only ascetics can endure.

Initially, researchers thought that the effect of calorie restriction on aging was mediated through insulin-like signaling pathways in the roundworm Caenorhabditis elegans (C. elegans), but experiments by graduate student Siler Panowski in Dillins lab suggested otherwise.

In the worm, signals passed down the insulin/IGF-1 pathway regulate a DNA-binding protein called DAF-16 that belongs to what is called the forkhead family. It was believed that DAF-16 then regulated expression of genes associated with longevity. Dillin had also identified a co-regulator in the pathway called SMK-1 that apparently worked with DAF-16 to regulate longevity.

When we asked whether DAF-16 and SMK-1 proteins were both necessary for CR-mediated longevity, DAF-16 turned out to b
'"/>

Contact: Gina Kirchweger
kirchweger@salk.edu
858-453-4100 x1340
Salk Institute
2-May-2007