Harvard Medical School (HMS) researchers have discovered a way to genetically mimic the life-extending effects of calorie restriction – without the severe food deprivation that method entails.

The study was done in yeast, a simple life form that is easy to manipulate in the laboratory. But scientists believe the same longevity regulatory pathway – a molecular clock that determines how fast the body ages – has passed through evolution to all complex organisms, including humans. Thus, the findings might someday lead to drugs that give people longer, healthier lives.

Previous studies have shown that a key component in the longevity pathway is the Sir2 protein, “one of the most exciting molecules in aging research,” says David Sinclair, Medical School assistant professor of pathology, and senior author of the new research. The precise functions of Sir2 and its equivalents in other species are not fully understood, but in the yeast Saccharomyces cerevisiae it delays aging by protecting the cell against genome instability – a buildup of mutations that typically results in cell death. Building on earlier work with yeast, scientists at the Massachusetts Institute of Technology found that giving tiny roundworms an extra copy of the worm version of Sir2 extends their lives by 50 percent. And SIRT1, the human version of Sir2, was recently found to promote cell survival by deactivating the cell-death regulator gene p53.

In the new study, Sinclair’s group, including first author Rozalyn Anderson, a research fellow in Sinclair’s lab, and colleagues at HMS and Washington University in St. Louis, inserted extra copies of the NPT1 gene into S. cerevisiae. This gene makes a protein required to synthesize or recycle the important metabolic regulator nicotinamide adenine dinucleotide (NAD+), which, in turn, controls the activity level of Sir2.

One explanation of the link between caloric restriction and Sir2 is that when yeast’s (or another organism’s) metabolic activity is slowed down through reduced caloric intake, NAD+ levels increase, stimulating Sir2 activity. The new findings refine this theory: While overall levels of NAD+ remained steady, its rate of recycling – and thus, its availability to Sir2 – were speeded up with help from extra copies of NPT1. One additional copy increased the replicative lifespan (the number of daughter cells produced by an individual mother cell) in various yeast strains by an average of 40 percent, while four extra gene copies increased lifespan by 60 percent.

Scientists have known about the longevity benefits of caloric restriction since experiments conducted in the 1930s showed that rats lived much longer if their food intake was severely restricted. Broadly speaking, the reason is stress. Although usually viewed as the enemy of good health, stress can actually boost longevity, driving an organism to slow down metabolism and conserve scarce resources. Caloric restriction is one form of stress that does this very effectively. But to see the longevity benefits, animals must eat only about half the calories in a normal diet, resulting in constant hunger.

“Caloric restriction has been shown to extend lifespan in almost every organism it has been tried on, from rats to fish to spiders, all the way down to worms and yeast,” Sinclair said, and it is now being tested in monkeys, with preliminary positive results. “If we can understand the molecular basis of what’s going on in the lower organisms, we might have a chance to understand how it works in humans, too. What we really want to do is to be able to mimic calorie restriction without having to starve ourselves.” Most importantly, the goal is not simply to extend life, but to extend health. Calorie-restricted animals remain remarkably free of the common ailments of old age, including heart disease and cancer. Applied to humans, “Instead of combating one disease at a time, we could potentially tackle numerous ones, slowing down or preventing their occurrence.”

The new findings, the authors write, show that NPT1 and other proteins needed to make NAD+ “are attractive targets for small molecules that may mimic the beneficial effects of caloric restriction.” The authors envision testing libraries of small molecules to find ones that can increase NPT1 levels or recycling rates, and in turn increase availability of Sir2 and decrease cell death. The article appears in the May 24 Journal of Biological Chemistry.