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Pathways Underlying the Benefits of Calorie Restriction

Calorie restriction leads to increased production of the gas hydrogen sulfide.

Calorie restriction is the process of reducing food intake—typically by at least 30% from a normal diet—without malnutrition. Researchers have known since the 1930’s that this regimen, also referred to as dietary restriction, has numerous health benefits. It can extend the lifespan of yeast, worms, flies, and some mice. Calorie restriction can also improve tolerance to certain metabolic stresses to the body.

A team led by Drs. Christopher Hine and James Mitchell at the Harvard School of Public Health set out to determine the molecular mechanisms by which calorie restriction can bring health benefits. The study was funded in part by NIH’s National Institute on Aging (NIA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Cancer Institute (NCI). Results appeared online on December 23, 2014, in Cell.

The researchers induced surgical stress in mice by temporarily halting blood flow to the liver. When blood flow is restored to the tissue, it shows damage and inflammation. This injury model, known as ischemia reperfusion, is similar to what occurs during organ transplantation, stroke, or heart attack in humans.

The team found that mice that had their diet restricted by 50% for a week before the surgery showed less liver damage than mice provided with unlimited food. The beneficial effects of the calorie restriction could be blocked, however, by providing the mice with extra methionine and cysteine. These 2 amino acids are notable because they both contain sulfur.

The scientists determined that restricting these 2 sulfur-containing amino acids activated a metabolic pathway called the transsulfuration pathway, which resulted in increased production of the gas hydrogen sulfide (H₂S). When they deleted a gene for an H₂S-producing enzyme in mice, the protective effects of dietary restriction were lost. Conversely, mice genetically manipulated to make more of the gas had less surgical damage, even without dietary intervention. Thus, production of the gas was important for the benefits of calorie restriction against surgical stress.

Further experiments showed that H₂S production played a role in calorie-restricted models of longevity in yeast, worms, fruit flies, and mice. This implicates an evolutionarily conserved metabolic pathway in several of the benefits of calorie restriction.

“This finding suggests that H₂S is one of the key molecules responsible for the benefits of dietary restriction in mammals and lower organisms as well,” Mitchell says. “While more experiments are required to understand how H₂S exerts its beneficial effects, it does give us a new perspective on which molecular players to target therapeutically in our efforts to combat human disease and aging.”

—by Carol Torgan, Ph.D.