One route to a long and healthy life may be establishing the right balance in insulin signaling in the body and brain, as per new research from Children's Hospital Boston. The study, reported in the July 20 issue of Science, not only reinforces the value of exercising and eating in moderation, but also helps explain a paradox in longevity research.

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, scientists 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 believe 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. Eventhough 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 treatment 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 therapys for diabetes, he suggests, would concentrate on sensitizing the body's cells to low amounts of insulin.


Posted by: Ken    Source

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