Hunger gene behind longevity discovered

A recent research has found how constant hunger promotes long life and identified a crucial gene that particularly links calorie restriction (CR) to longevity.

Washington, May 3 : A recent research has found how constant hunger promotes long life and identified a crucial gene that particularly links calorie restriction (CR) to longevity.

The study, conducted by researchers at the Salk Institute for Biological Studies, has explained how a diet bordering on the edge of starvation extends the duration of life.

"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.

The identification of a key link between calorie control and aging also opens the door to expansion of drugs that imitate the effects of calorie restriction and might permit people to garner health benefits without adhering to a frugal routine that only ascetics can undergo.

At first, researchers thought that the outcome of calorie restriction on aging was arbitrated through insulin-like signaling pathways in the roundworm Caenorhabditis elegans (C. elegans), but experiments by graduate student Siler Panowski in Dillin's 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 connected with longevity. Dillin had also identified a co-regulator in the pathway called SMK-1 that apparently worked with DAF-16 to control longevity.

"When we asked whether DAF-16 and SMK-1 proteins were both necessary for CR-mediated longevity, DAF-16 turned out to be unnecessary but, somewhat surprisingly, SMK-1 was," says first author Panowski.

Given that 15 other forkhead-like factors are expressed in C. elegans, graduate student Suzanne Wolff and former post-doctoral fellow Hugo Aguilaniu, Ph.D., now an assistant professor at the �cole Normale Sup�rieure de Lyon, France, set off to find out if any of them collaborated with SMK-1 to delay aging in the CR-response.

They did this by knocking out each gene one by one and observing whether the genetically changed worms still showed improved longevity when calorie-restricted.

Loss of only one of the genes, a gene encoding the protein PHA-4, negated the lifespan-enhancing effect of calorie-restriction in worms. And, when researchers took on the reverse experiment, by over expressing pha-4 in worms, the longevity effect was enhanced.

"PHA-4 acts completely independent of insulin/IGF-1 signaling and turns out to be essential for CR-mediated longevity," says Panowski.

Till date, only one other gene, called sir-2, has been implicated in the life- and health-prolonging response to calorie restriction. Increased amounts of SIR-2 protein expand longevity of yeast, worms, and flies, but while loss of sir-2 upsets the calorie restriction response only in yeast, it has no effect on other organisms, such as worms.

"We know three distinct pathways that affect longevity: insulin/IGF signaling, calorie restriction, and the mitochondrial electron transport chain pathway, yet it is still not clear where sir-2 fits in. It seems to meddle with more than one pathway," says Dillin and adds that "PHA-4 is specific for calorie restriction as it does not affect the other pathways."

Humans have three genes greatly akin to worm pha-4, all belonging to what is called the Foxa family. All three play a central role in growth and then afterwards in the regulation of glucagon, a pancreatic hormone that unlike insulin boosts the concentration of blood sugar and maintains the body's energy equilibrium, particularly during fasting.

The probable recompense for cutting to 60 percent of normal while maintaining a healthy diet rich in vitamins, minerals, and other nutrients, is enormous. At present it is the only approach apart from direct genetic manipulation that constantly prolongs life and reduces the risk of cancer, diabetes, and cardiovascular disease, while staving off age-related neurodegeneration in laboratory animals from mice to monkeys.

Even though some people are by now imposing this harsh regimen upon themselves, it is too early to tell whether calorie restriction will have the same effect in humans.

ANI