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Rewriting Life

A Clue to Living Longer

According to a study with mice, restricting calories may boost longevity – by altering growth hormone and insulin.

Scientists have long known that a very low-calorie diet can increase life span in organisms as diverse as yeast, flies and mice. One of the most puzzling questions in aging research, however, is how it works. If they can figure out the molecular processes underlying the boost in longevity, scientists think they might be able to harness the life-extending benefits without restricting diet.

An adult mouse lacking the ability to respond to the growth hormone (right) has a longer life span than a normal mouse (left). Scientists believe this hormonal change may mimic the life-extending effects of calorie restriction. (Courtesy of Michael Bonkowski.)

A new study offers evidence that a decline in growth hormone and a corresponding boost in sensitivity to insulin may be the reason why mice live longer when they eat less – and that those two hormones may be critically important in controlling aging and longevity.

The study opens up new questions about the role of growth hormone in aging. In humans, growth-hormone levels decline with age, and artificial growth hormone has been touted as an anti-aging drug. But at least in mice, high levels of growth hormone reduce life span, says Andrzej Bartke, a physiologist at Southern Illinois University School of Medicine, who led the study. And these results suggest that lowering growth hormone in mice can mimic the benefits of calorie restriction without the diet.

Within the last few years, biologists have found that mutating certain genes in lower organisms can make them live longer. These discoveries helped fuel the idea that life span is directly controlled by a genetic program in the body – a program that scientists may be able to manipulate. But, so far, none of these genes have explained the remarkable effects of calorie restriction.

The current study, published in the May 16 Proceedings of the National Academy of Sciences, examined a line of mice who was resistant to growth hormone, which promotes childhood growth and has several other functions in the body. These mice, who are smaller than normal, lack the growth hormone receptor, a molecule that sits at the surface of cells and binds to growth hormone circulating in the blood. Without the receptor, the body’s tissues are deaf to the hormone’s signal.

Scientists have previously shown that caloric restriction can increase life span in mice by 25 to 30 percent. In the new study, the researchers found that mutant mice, which lack the growth hormone receptor, live just as long as caloric-restricted mice – even though they ate a normal amount of food. The results suggest that lack of growth hormone triggers a molecular reaction similar to caloric restriction.

Cynthia Kenyon, biochemist at University of California San Francisco, says it seems as if the mutant mice are “eating as much as they want, but reaping the benefits of calorie restriction,” including greater insulin sensitivity and longer lives.

The findings are puzzling to some scientists, since growth hormone was not predicted to have this effect. They aren’t yet sure how lack of growth hormone extends life, but Bartke believes it may work by improving insulin function. In the mutant mice, a lack of the growth hormone receptor made them more sensitive to insulin. Insulin sensitivity is necessary in humans to prevent metabolic diseases like diabetes. Caloric restriction also improves insulin sensitivity by lowering insulin levels.

Kenyon says that it makes sense that chemicals such as insulin – which is affected by food intake – might be the signal responsible for calorie restriction’s effects.

Molecules similar to insulin have recently been shown to affect aging and life span in many organisms. Brian Kennedy, biochemist at the University of Washington, has found that insulin-like chemicals control longevity in yeast. “There are a small number of these nutrient-responsive pathways, and calorie restriction may be going through them,” he says. And if that’s true, he adds, “the challenge for the whole field is to start working downstream,” to figure out what the signals control. Because hormones control an array of functions in the body, they make poor targets for drugs. But if scientists could isolate a more specific chemical that the hormones are targeting, they would have a better target for drugs that would mimic the benefits of calorie restriction.

Several companies, including Elixir Pharmaceuticals and Sirtris in Cambridge, MA, have been launched to hunt for chemical compounds that can extend life span, and Bartke says his study adds to evidence that insulin and its related pathways are a good place to start.

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