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WEDNESDAY, May 2 (HealthDay News) -- Scientists have long known that eating less translates into longer life, at least in worms and mice. Now, researchers report that they think they know why this phenomenon of "dietary restriction" increases longevity: It all revolves around a gene known as pha-4, which is involved in the embryonic development of the intestine in the C. elegans roundworm. "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," said study senior author Andrew Dillin, an associate professor in the Molecular and Cell Biology Laboratory at the Salk Institute in La Jolla, Calif. "This suggests that there could be specific genetic pathways that modulate organisms' response to caloric restriction. If there are, we can now screen to find drugs to modulate," said Heidi A. Tissenbaum, an associate professor in the Program in Gene Function and Expression at the University of Massachusetts Medical School. "Also, very few people have looked at genes in embryogenesis and how they affect adult life span. Not only does this have an effect on what we understand about dietary restriction, but also what we understand about longevity. Genes that play critical roles in embryogenesis might be critically important in the aging process," she added. Dillin reported the findings, which were expected to be published in the May 2 online issue of Nature, at a news conference Tuesday. The discovery raises the possibility that drugs targeting this gene could confer the same health benefits as a near-starvation diet, possibly even in humans. "We don't know that yet, but we think the gene could play a role in humans," Dillin said. "There's a primate study going on, and it looks like primates are going to respond very well to reduced intake and live longer. We have a lot of work to do to see whether or not the things that look like pha-4 in humans and mice are doing the same thing." 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." "The discovery of pha-4 is the first gene required for dietary restriction, the first gene that's absolutely essentially and specific for the response of dietary restriction," added Dillin. "This lays down the cornerstone for defining the actual molecular pathways that respond to reduced food intake." "The key new thing about this paper is identification of a particular pathway," said Rajesh Miranda, an associate professor of neuroscience and experimental therapeutics at the Texas A&M Health Science Center College of Medicine. "This points out how you could maintain longevity by affecting different pathways." One other gene, sir-2, seems to be involved in caloric restriction and longevity, but it's unclear how it works. Humans have three genes similar to the pha-4 gene in C. elegans. These genes belong to the Foxa family, and all are involved in regulating glucagon, a hormone produced by the pancreas that contributes to maintaining the body's energy balance, especially while fasting. This is different from the role of another pancreatic hormone, insulin. "We think that the function of pha-4 will be highly conserved in mice and perhaps humans," Dillin said. And, it's possible it will. "So far, everything that's known about longevity in worms has gone on to be true, at least as far as they can tell, in mice," Tissenbaum said. "We hope it will be true [in humans]." If there is a similar gene in humans, the next question will be whether it can be modified so people can eat normal diets but still reap the benefits of eating less. "We think we're on the right path," Dillin said. "Can we actually manipulate glucagon levels, and is that the sole target that's going to regulate dietary restriction?" More information The American Aging Association can tell you about
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