Shielding The Brain From Too Much Insulin Can Prolong Life

Insulin sends a vital signal in the body, telling cells to use sugar from the blood. When cells become less sensitive to insulin, which often happens as we age and gain weight, the body makes more insulin to compensate. For a long time, researchers thought that "more insulin signaling was good," says Morris White, PhD, a Howard Hughes Medical Institute investigator in Children's Division of Endocrinology, who led the new study. "But this insulin is also hammering the brain, and we now think that's probably a bad thing."

Recent studies in the worm C. elegans and in fruit flies have shown that reducing insulin signaling lengthens lifespan. But in mammals, reducing insulin signaling can lead to fatal diabetes. White suspected that the key to explaining this paradox -- and to maximizing both health and longevity -- is to reduce insulin signaling only in the brain.

To test this hypothesis, White's team measured longevity and other characteristics in three types of mice. One group had normal insulin signaling in their brains. The other two groups were genetically engineered to have reduced brain insulin signaling, having less of a protein called Irs2 that carries insulin's message inside cells.

As the mice aged and gained weight, their sensitivity to insulin decreased, and higher insulin levels began to bombard their brains. The mice with reduced brain insulin signaling lived 18 percent longer than the normal mice. They were more active in old age, retained youthful metabolic cycles (burning sugar by day and fat by night) and retained protective levels of anti-oxidant enzymes such as superoxide dismutase, which protect against oxidative stress, or "biological rusting," in the brain and body.

In contrast, the mice with normal insulin signaling had become more sedentary, had lost the metabolic rhythms of youth and had reduced anti-oxidant enzymes, leaving them vulnerable to cellular damage. Such damage correlates with a host of age-related diseases such as atherosclerosis, Alzheimer's disease and cancer, notes White.

White believes his findings suggest a new approach to preventing diseases that shorten lifespan. "If we could hit cancer and cardiovascular disease by attenuating how much insulin that gets to the brain, or the amount of insulin signaling that happens deep within the brain," he says, "that's going to be much easier than trying to cut every cancer out."

Drugs that regulate Irs2 signaling in the brain (but not elsewhere in the body) are one possible strategy, but no such drug has yet been found.

The easiest method, White says, is old-fashioned diet and exercise. Although obesity and sedentary lifestyles tune down the body's sensitivity to insulin, exercise tunes it back up. Furthermore, eating smaller meals keeps insulin low in the bloodstream, ensuring that less reaches the brain.

"This study gives a molecular explanation of why it's good to exercise and not eat too much," says White. "If we can put a sound scientific basis behind the idea that diet and exercise are good, maybe we'll convince some more people to do it."

The study also calls into question the long-term effects of insulin therapy for diabetes, White adds. "Too much insulin might be fine to keep glucose levels under control. But it's probably damaging your brain in the long run," he says. Better treatments for diabetes, he suggests, would concentrate on sensitizing the body's cells to low amounts of insulin.

The work was supported by the Howard Hughes Medical Institute, the National Institutes of Health, the Japan Society for the Promotion of Science, and the Yamada Science Foundation.