Reducing insulin signaling in the brain can prolong lifespan

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Diet and Insulin

One route to a long and healthy life may be establishing the right balance in insulin signaling between the brain and the rest of the body, according to new research from Children's Hospital Boston. The study, published 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 throughout the body telling cells to use sugar from the blood. But when cells become less sensitive to insulin, which often happens as we age and gain weight, the body must make more insulin to keep sugar under control and avoid type 2 diabetes. For a long time, clinicians and scientists thought that "more insulin was a good thing," says Morris White, PhD, a Howard Hughes Medical Institute investigator in Children's Division of Endocrinology, who led the new study. "But the increased insulin also gets into the brain, where it can be detrimental."

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Studies in the worm C. elegans and in fruit flies show that reducing insulin signaling lengthens lifespan. But in humans and rodents, reducing insulin signaling often causes diabetes. The view that insulin could reduce lifespan is difficult to reconcile with decades of clinical practice and scientific investigation to treat 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 idea, White's team measured longevity and other characteristics in several groups of mice. In one group, they used a genetic trick to cut in half the amount of Irs2, a protein that carries the insulin signal inside the cell, in every cell of the body. Two other groups of mice were genetically engineered to have half, or nearly all, Irs2 removed only from the brain cells. Another group of normal mice served as controls.

"To our surprise, all of the engineered mice lived longer," says Akiko Taguchi, PhD, first author of the study. Even more surprising, the mice lacking Irs2 only in the brain lived almost half a year longer than the normal mice

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