It has been known for 72 years—and demonstrated in a range of organisms, including yeast, fruit flies, mice and dogs—that a restricted diet, typically amounting to less than half of the usual number of daily calories, can increase life span. The biological mechanism underlying this effect, however, has continually eluded longevity researchers.
A new study involving roundworms appears to have isolated one gene—a transcriptional factor (or gene that controls the regulation of other genes in the genome)—that appears to be an essential member of the pathway that translates reduced caloric intake into a longer life span. The report, appearing online today, is published by the journal Nature, and could lead to therapies that lead to longer lives without requiring a starvation diet.
"This may be the primordial gene that regulates nutrient sensing and helps an animal overcome stressful conditions—and helps an animal live a long time through dietary-restriction conditions," says the study's senior author, Andrew Dillin, an associate professor of molecular and cell biology at the Salk Institute in La Jolla, Calif.
Previously, longevity researchers believed dietary restriction was regulated via an insulin-signaling pathway, where the levels of the nutrient-sensing hormone would fall in response to lowered food intake, activating a DNA-binding protein called daf-16 that would then confer longevity through the regulation of genes under its control. Earlier, Dillin's group fingered the protein smk-1 as a co-factor, which worked with daf-16 to increase the life spans of nematodes (Caenorhabditis elegans). Later, they discovered that only smk-1 was required for dietary restriction-mediated longevity, which meant that the protein was taking part in an independent pathway.
Dillin's team then screened 15 other genes from the forkhead family—transcriptional factors important to development and possibly longevity, to which the gene for daf-16 belongs—to see if any of them were necessary to increase longevity after dietary restriction. Only one, pha-4, fit the bill, says Siler Panowski, a graduate student in Dillin's lab. "So, removal of this gene could completely remove the longevity we see when we reduce feeding in the worm," he explains.
Pha-4 plays an essential role in the development of the pharynx, the throat section of the worm's digestive tract, between the mouth and the esophagus. Its effects in adult worms, however, were unknown, so Panowski used fluorescent probes to determine where the gene is expressed. He found that the gene is active in the worm's intestines, as well as in neurons in the animal's head and tail. When the researchers then overexpressed the gene in the intestines of the worms, they noted some increased longevity in normal animals, but highly increased life spans in animals whose production of daf-16 had been blocked. "This fact," says Panowski, "suggests that pha-4 [protein] and daf-16 may be competing in some way, perhaps for target genes that increase longevity or other coregulators or cofactors that may be required for this."
Marc Tatar, a professor of biology at Brown University, notes that pha-4 is not the first gene implicated in longevity stemming from caloric restriction. Another gene, sir-2, has also been linked to this kind of longevity, although its effects seem to influence several different pathways in the worm's body. In contrast, pha-4 is "the first direct transcriptional regulator of dietary restriction." Tatar also points out that Dillin's group is not entirely sure what the gene does in the worm. "They need to take away [its] downstream targets and see if pha-4 overexpression is still increasing life span."
Dillin notes that this work is already being done, adding that pha-4 has three mammalian homologues (similar genes serving similar functions) falling under the Foxa family of genes, which regulates the pancreatic hormone glucagon in the pancreas and liver. Glucagon counters the ill effects of fasting by increasing blood sugar and controlling energy balance. He cautions that the benefits of dietary restriction have yet to be proved in humans, although a 35-year (and running) study in lower primates seems to indicate that these close human relatives benefit from the calorie cutoff as well. "We think that the conservation that we're seeing from worms to mice [makes it] likely that it could play a role in the human condition," says Dillin. "Really figuring out what the three Foxas are doing in mice in response to dietary restriction will tell us the key targets downstream and if we can manipulate them."