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Science 317 (5836): 369-372

Copyright © 2007 by the American Association for the Advancement of Science

Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis

Akiko Taguchi, Lynn M. Wartschow, Morris F. White*

Abstract: Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila. Here, we show that, in mice, less insulin receptor substrate–2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase–2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.

Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: morris.white{at}childrens.harvard.edu

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