Old Mice Reveal Tale of Insulin-like Signaling in Longevity

BOSTON, July 19 -- Simply by reducing insulin-like signaling within the brains of mice, the creatures developed risk factors for diabetes but became long-lived, investigators here reported.

Mice genetically engineered to be lacking insulin receptor substrates in their brains grew fat, secreted excessive insulin levels, and were glucose intolerant. Nevertheless, they lived 18% longer than controls, reported Morris White, Ph.D., of Children's Hospital Boston and Harvard, and colleagues.

The increases in longevity came despite the fact that at 22 months, the genetically engineered mice, kept on an identical diet to that of controls, had developed all the classic risk factors for type 2 diabetes--overweight, hyperinsulinemia, and glucose intolerance.

Yet despite having the metabolic deck seemingly stacked against them, the mice were more active and displayed greater glucose oxidation than controls, and during meals had higher concentrations in the hypothalamus of the anti-oxidative enzyme superoxide dismutase-2, the authors reported in the July 20 issue of Science.

Thus, the authors wrote, less insulin-like "signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice."

The findings, the investigators concluded, support the idea that diet and exercise can stave off type 2 diabetes complications by keeping insulin signaling in the brain low.

"The engineered mice live longer because the diseases that kill them - cancer, cardiovascular disease and others - are being postponed by reducing insulin-like signaling in the brain, regardless of how much insulin there is in the rest of the body," said Dr. White.

Previous studies have shown that reducing insulin signaling by selectively knocking out insulin receptor substrate genes can result in superannuated roundworms and fruit flies, but similar studies in mammals have yielded surprisingly different results, the authors noted.

In earlier studies, when both alleles of the gene for insulin receptor substrate 2 (Irs2) were bred out of a strain of mice, the animals did not become long-lived, but instead died of diabetes at three months due to the failure of insulin-secreting pancreatic beta cells.

Yet when only one of the alleles was knocked out, the young mice had a normal metabolic phenotype at two months, and at 22.5 months (a somewhat advanced age for mice) the knockouts were only slightly heavier than wild-type controls, despite consuming the same amount of food.

What's more, the knockout mice had greater insulin sensitivity than wild-type mice because the former had lower fasting insulin and glucose concentrations.

"Irs2 is expressed throughout the body and many regions of the brain, including the cerebrum, the cerebellum, and the arcuate and paraventricular nuclei of the hypothalamus," the investigators wrote. "Reduced insulin-like signaling in neurons increases the life span of C. elegans and Drosophila, so it is possible that reduced neuronal Irs2 could extend mouse life span."

To test this hypothesis, the authors studied a group of mice with one Irs2 allele knocked out systemically, and two other batches bred for brain-only deletion of either one or both alleles, and compared the effects on metabolism and longevity, using wild-type mice as controls.

"To our surprise, all of the engineered mice lived longer," said Akiko Taguchi, Ph.D., a co-author.

The mice with one brain-specific allele had a median lifespan that was 18% longer (nearly six months longer) than that of controls, and the animals with both alleles missing lived 14% longer.

The findings suggest that insulin supplementation in people with type 2 diabetes may have harmful long-term effects, Dr. White commented.

"High insulin should be the short term solution to insulin resistance, because it might damage the brain in the long run," he said, adding that insulin-sensitizing therapies may be a more effective strategy.

The authors noted that "other strategies for improving peripheral insulin sensitivity, such as reduced growth hormone signaling, could have the same effect. Indeed, human centenarians display increased peripheral insulin sensitivity and reduced circulating insulin concentrations."