Posted Nov 28, 2010

In a remarkable demonstration of the ability of calorie restriction to blunt the effects of aging, scientists at the University of Wisconsin-Madison have succeeded in delaying age-related hearing loss in mice.

Reporting Thursday in the journal Cell, the researchers described experiments with mice showing that a 25% reduction in calories activated a single enzyme, Sirt3, that helped preserve hearing.

Although small numbers of people practice strict caloric restriction — consuming just 1,000 to 1,500 calories a day — scientists concede that such a diet is exceedingly difficult. But there may be other ways to achieve the same benefits.

“If we can find compounds that activate Sirt3, we may be able to obtain some of the benefits of caloric restriction without having to restrict our calories,” said Tomas A. Prolla, a professor of genetics at UW and senior author of the new paper.

The idea that extremely low-calorie diets might extend life dates back to the early 1930s when two Cornell University scientists found that rats fed such a diet lived up to twice the normal life span.

Decades later others began investigating the science of caloric restriction in greater detail, including another UW professor, Richard Weindruch, and Roy Walford, a gerontologist at University of California, Los Angeles. Walford went so far as to put himself on such a diet in an effort to reach the age of 120. He died in 2004 at age 79 of complications from Lou Gehrig’s disease.

Last year, Weindruch and other UW researchers reported in the journal Science on a 20-year study of rhesus monkeys that found caloric restriction led to fewer deaths from natural causes and fewer cases of diabetes, cancer, cardiovascular disease and brain shrinkage.

The new UW study looked at age-related hearing loss, an ideal target for experiments to curb aging because it is so common.

“It has prevalence that approaches 100 percent,” said Leonard Guarente, a professor of biology at the Massachusetts Institute of Technology.

Guarente discovered the family of enzymes called sirtuins, which includes Sirt3. These enzymes, first found in yeast, appear strongly linked to the aging process.

Guarente, who did not work on the new Cell paper, called the UW study “striking because the effects are so profound.”

Prolla and his colleagues carried out experiments with normal mice and mice without the Sirt3 enzyme. In one experiment both groups were fed the 25% reduced calorie diet for 10 months. The diet had the same weight loss effect on both groups.

Although the diet delayed hearing loss at various frequencies in the normal mice, it did not work at all in the mice lacking Sirt3.

The experiments also suggested how the benefits of caloric restriction play out at the molecular level.

“What seems to happen that drives caloric restriction is that the organism senses it is under stress,” Prolla explained. “There are then metabolic changes that favor self-preservation.”

Under normal conditions, he said, levels of Sirt3 are low. Caloric restriction appears to boost levels of Sirt3 and the boost helps the cells’ energy factories, called mitochondria.

The mitochondria make not only the energy, but also atoms called free radicals, which damage cells and advance the effects of aging. When Sirt3 levels rise, however, they reduce production of the harmful free radicals. One result is less damage to cells, including the cells of the inner ear.

In humans, age-related hearing loss generally begins around middle age as higher-pitched sounds become more difficult to distinguish.

“We need to find out which are the main mediators of caloric restriction,” Prolla said, explaining that the current study indicates Sirt3 is one of them. “Once we’ve identified them we can come up with interventions that mimic caloric restriction.”

Within five to 10 years, he said, “we’ll have a very good understanding of which ones are the main players.”

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Copyright © 2010, Milwaukee Journal Sentinel

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