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 undertook the opposite experiment—by overexpressing 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.
“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 possess three genes highly similar to worm pha-4, all belonging to what is called the Foxa family. All three play an important role in development and then later on in the regulation of glucagon, a pancreatic hormone that unlike insulin increases the concentration of blood sugar and maintains the body’s energy balance, especially during fasting.
The potential payoff for cutting to 60 percent of normal while maintaining a healthy diet rich in vitamins, minerals, and other nutrients, is huge. Currently it is the only strategy apart from direct genetic manipulation that consistently 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. Although some people are already imposing this strict regimen upon themselves, it is too early tell whether calorie restriction will have the same effect in humans.