Less Insulin In the Brain Key to a Long Life

The investigators created mutant mice that over-ate, got fat and even had symptoms of diabetes, and yet lived 18 percent longer than normal lab mice. The secret: they lacked a certain key gene that affects insulin, the hormone that regulates glucose.

The genetic engineering mimicked the effects of eating less and exercising, the researchers report in the journal Science.
"This study provides a new explanation of why it's good to exercise and not eat too much," said Dr. Morris White, a Howard Hughes Medical Institute investigator at Children's Hospital in Boston who led the study.

The findings also raise questions about how desirable it is to use insulin to treat type 2 diabetes, said the researchers.
Doctors know that people who exercise regularly live longer on average. Researchers have also learned that putting animals on a strict diet makes them live longer, although this has not yet been shown to work in people.

So White's team sought to see if the two effects were linked. They looked at insulin, because both fasting and exercise make cells more insulin-sensitive, meaning they respond more efficiently to the effects of insulin. They looked at the entire insulin pathway -- a series of actions in the cell that control the body's use of insulin.

White's team engineered mice that had no working copies of one of the genes involved in this pathway, called insulin receptor substrate 2 (Irs2). Mice with no copies of Irs2 had defective brains and diabetes. But mice with one working copy lived 18 percent longer than normal mice.

"What's more, the animals lived longer even though they had characteristics that should shorten their lives such as being overweight and having higher insulin levels in the blood," White said in a statement.

They were also more active than normal mice, and after eating, their brains had higher levels of a compound called superoxide dismutase, an antioxidant that protects cells from damage.

"Diet, exercise and lower weight keep your peripheral tissues sensitive to insulin," White said. That means the body needs to make less insulin. "Since insulin turns on Irs2 in the brain, that means lower Irs2 activity, which we've linked to longer life span in the mouse," he said.

One obvious question is whether drugs can mimic the effects of having less Irs2, perhaps by interfering with its action. The researchers note that people who live to be 100 or more often have reduced insulin levels and their cells show better insulin sensitivity.

New diabetes drugs that increase insulin sensitivity may help, too, White said. But, he added: "The easiest way to keep insulin levels low in the brain is old-fashioned diet and exercise."