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

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Scientists Link Longevity With Reduced Insulin-Like Signaling in the

Brain

Medscape Medical News 2007. © 2007 Medscape

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 White, PhD, a

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.