Why Calorie Restriction Might Prolong Life

(Page 2)

Near-starving mice and other species outlive better fed organisms by as much as 40 percent. But dietary restriction is a fine balance between dying of starvation and succumbing to obesity and related ills.

"Dietary restriction is really a sweet spot between the two that is empirically determined, a 60 to 70 percent reduction in normal food intake," Dillin said. "It's very difficult to adhere to, from what I understand. It takes some real discipline."

Before embarking on this study, Dillin and his team already knew of three pathways linked to longevity: the insulin/IGF pathway, the mitochondrial electron transport pathway, and the dietary restriction pathway. All work independently of each other and may work in humans as well, the authors stated.

In the C. elegans roundworm, genes involved in the first two pathways turned out not to be implicated in the dietary restriction pathway.

Surprisingly, a protein in the insulin/IGF pathway called DAF-16 was not associated with longevity. But another factor which works with DAF-16 did seem to be involved. That factor was called SMK-1.

DAF-16 is one of 16 factors expressed in C. elegans roundworms. Team members knocked out each of genes one by one to see if any of them worked with DAF-16 to affect longevity in the worms.

Only one gene -- pha-4 -- had an effect on life span.

"This led to the hypothesis that maybe by overexpressing the protein pha-4, we could mimic dietary restriction and increase longevity, and this is exactly what we found," said Siler Panowski, a graduate student in Dillin's lab and lead author of the paper. "This suggests that pha-4 and DAF-16 may be competing in some way over perhaps target genes that increase longevity or other co-regulators or cofactors that may be required for this."

Pha-4 has nothing to do with the insulin/IGF signaling pathway, something the researchers stressed, but it is critical for longevity related to caloric restriction.

"Pha-4 was required for this dietary restriction response," Panowski said. "Removal of this gene could completely remove the longevity we see when we reduce feeding in the worms."