Brain IRS2 signaling coordinates life span and nutrient homeostasis.

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.