Scientists Link Longevity With Reduced Insulin-Like Signaling in the Brain

July 23, 2007 — Reducing insulin-like signaling in the brains of mice causes them to develop classic risk factors for diabetes type 2 and still allows them live significantly longer than their normal counterparts, according to a recent report published in the July 20 issue of Science.
Previous studies have shown that a reduction in insulin-like signaling in the neurons extends the lifespan in the worm, Caenorhabditis elegans, and the fruit fly, Drosophila melanogaster. To test the effect of reduced insulin-like signaling in mammals, investigators at the Children's Hospital Boston, in Massachusetts, compared the lifespan and metabolism of mice with a genetically engineered reduction of insulin sensitivity to that of normal, wild-type mice.
To reduce the signaling in mice, the researchers targeted insulin receptor substrate 2 (Irs2), a protein that carries the insulin signal inside of cells and is expressed throughout the body as well as in many regions of the brain.
Analysis showed that compared to normal mice, mice with an overall reduction in insulin-like signaling (Irs2+/−) had a median lifespan that was 17% longer (P = .01). Interestingly, results showed that this increase in longevity extended to mice in which Irs2 expression was reduced only in the brain. Mice genetically engineered to have insulin-like signaling in the brain reduced by half (bIrs2+/−) or removed altogether (bIrs2−/−) were found by parametric regression to live 18% and 14% longer, respectively, than normal controls.
These increases in longevity occurred despite the fact that the bIrs2+/− and bIrs2−/− mice, maintained on a high-energy diet identical to the normal controls, were insulin resistant, hyperinsulinemic, and glucose intolerant. However, diabetes in these mice reportedly did not develop because insulin concentration increased to compensate for peripheral resistance.
Furthermore, the genetically engineered mice were more active, displayed greater glucose oxidation, and during meals had higher concentrations in the hypothalamus of the antioxidative enzyme, superoxide dismutase-2, compared with controls.
These results, the investigators write, "point to the brain as the site where reduced insulin-like signaling can have a consistent effect to extend mammalian lifespan — as it does in C. elegans and D. melanogaster."
The investigators postulate that by attenuating Irs2 signaling, the brain is protected from the negative effects of hyperinsulinemia, which normally develops with increasing weight and age to maintain glucose homeostasis and prevent progression toward diabetes. They also conclude that the findings support the idea that the reduction of circulating insulin through moderate daily exercise, calorie restriction, and weight loss may also increase lifespan by keeping insulin signaling in the brain low.
"This study provides a new explanation of why it's good to exercise and not eat too much," lead investigator Morris White, PhD, a Howard Hughes Medical Institute investigator in Children's Division of Endocrinology at Children's Hospital, says in news release. "It has less to do with how we look, and more to do with a healthy brain, especially in old age."
The effect might also be achieved with other strategies for improving peripheral insulin sensitivity, such as reduced growth hormone signaling, according to the researchers, who noted that human centenarians display increased peripheral insulin sensitivity and reduced circulating insulin concentrations.
Science. 2007;317:369–372.