New clue into how diet and exercise enhance longevity

The traditional prescriptions for a healthy life—sensible diet, exercise and weight control—extend life by reducing signaling through a specific pathway in the brain, according to Howard Hughes Medical Institute researchers who discovered the connection while studying long-lived mice.

They said their findings underscore the importance of maintaining a healthy lifestyle and may also offer promising research directions for understanding and treating diabetes and Alzheimer’s disease.

Howard Hughes Medical Institute investigator Morris F. White and his colleagues published their findings in the July 20, 2007, issue of the journal Science. Akiko Taguchi and Lynn Wartschow in White’s laboratory in the Division of Endocrinology at Children’s Hospital Boston and Harvard Medical School were co-authors of the research article.

In their experiments, the researchers sought to understand the role of the insulin-like signaling pathway in extending lifespan. This pathway governs growth and metabolic processes in cells throughout the body. The pathway is activated when insulin and insulin-like growth factor-1 switch on proteins inside the cell called insulin receptor substrates (Irs).

Other researchers had shown that reducing the activity of the pathway in roundworms and fruitflies extends lifespan. Despite those tantalizing clues, White said, “The idea that insulin reduces lifespan is difficult to reconcile with decades of clinical practice and scientific investigation to treat diabetes.”

“In fact, based on our work on one of the insulin receptor substrates, Irs2, in liver and pancreatic beta cells, we thought more Irs2 would be good for you,” said White. “It reduces the amount of insulin needed in the body to control blood glucose, and it promotes growth, survival and insulin secretion from pancreatic beta cells.

In earlier work, the researchers had found that knocking out both copies of the Irs2 gene in mice reduces brain growth and produces diabetes due to pancreatic beta cell failure. However, in the new study, when the researchers knocked out only one copy of the gene, they found the mice lived 18 percent longer than normal mice.

Because reducing insulin-like signaling in the neurons of roundworms and fruitflies extends their lifespan, the researchers decided to examine what would happen when they knocked out one or both copies of the Irs2 gene only in the brains of mice.

Mice lacking one copy of the Irs2 gene in brain cells also showed an 18 percent longer lifespan, and the near complete deletion of brain Irs2 had a similar effect. “What’s more, the animals lived longer, even though they had characteristics that should shorten their lives—such as being overweight and having higher insulin levels in the blood,” said White.

However, both sets of Irs2 knockout mice exhibited other characteristics that marked them as healthier, said White. They were more active as they aged, and their glucose metabolism resembled that of younger mice. The researchers also found that after eating, their brains showed higher levels of superoxide dismutase, an antioxidant enzyme that protects cells from damage by highly reactive chemicals called free radicals.

“Our findings put a mechanism behind what your mother told when you were growing up—eat a good diet and exercise, and it will keep you healthy,” said White. “Diet, exercise and lower weight keep your peripheral tissues sensitive to insulin. That reduces the amount and duration of insulin secretion needed to keep your glucose under control when you eat. Therefore, the brain is exposed to less insulin. Since insulin turns on Irs2 in the brain, that means lower Irs2 activity, which we’ve linked to longer lifespan in the mouse.”

White and his colleagues are planning their next studies to better understand how healthy aging and lifespan are coordinated by Irs2 signaling pathways in the body and the brain. White speculated that the insulin-like signaling pathway in the brain might promote age-related brain diseases.

“We are beginning to appreciate that obesity, insulin resistance, and high blood insulin levels are connected to Alzheimer’s disease, Huntington’s disease, and dementias in general,” he said. “It might be that, in people who are genetically predisposed to these diseases, too much insulin overactivates Irs2 in the brain and accelerates disease progression. Thus, insulin resistance and higher insulin levels might be the environmental influences that promote these diseases,” he said.

Source: Howard Hughes Medical Institute

Related stories:

Reducing insulin signaling in the brain can prolong lifespan
One route to a long and healthy life may be establishing the right balance in insulin signaling between the brain and the rest of the body, according to new research from Children’s Hospital Boston. The study, published in the July 20 issue of Science, not only reinforces the value of exercising and eating in moderation, but also helps explain a paradox in longevity research.
Researcher develops novel method to grow human embryonic stem cells
(PhysOrg.com) -- The majority of researchers working with human embryonic stem cells (hESCs) – cells which produce any type of specialized adult cells in the human body – use animal-based materials for culturing the cells. But because these materials are animal-based, they could transmit viruses and other pathogens to the hESCs, making the cells unsuitable for medical use.
Cognitive problems associated with diabetes duration and severity
Individuals with mild cognitive impairment appear more likely to have earlier onset, longer duration and greater severity of diabetes, according to a report in the August issue of Archives of Neurology.
Exercise pill is no replacement for exercise
Recently, researchers at the Salk Institute for Biological Studies, a research organization focused on biology and its relation to health, published a study in the journal Cell on the results of a substance that increased exercise endurance without daily exertion when tested in mice. Media reports have described this substance as an "exercise pill," potentially eliminating the need for exercise.
A mechanism for the development of obesity-associated conditions
Substances known as endocannabinoids have been implicated in the development of many effects of a high-fat diet, including risk factors for type 2 diabetes. New data have now indicated that these effects of endocannabinoids occur via activation of the protein CB1 in the liver and not the brain. Therefore, targeting liver CB1 might provide an effective way to treat obesity-related medical conditions without the side effects of targeting CB1 in the brain, anxiety and depression.
Treatment corrects severe insulin imbalance in animal studies
Researchers have used a drug to achieve normal levels of blood sugar in animals genetically engineered to have abnormally high insulin levels. If this approach succeeds in humans, it could become an innovative medicine for children with congenital hyperinsulinism, a rare but potentially devastating genetic disease in which insulin levels become dangerously high.
Statins may protect against memory loss
People at high risk for dementia who took cholesterol-lowering statins are half as likely to develop dementia as those who do not take statins, a new study shows.
Marsupials and humans shared same genetic imprinting 150 million years ago
Research published in Nature Genetics by a team of international scientists including the department of zoology at the University of Melbourne, Australia, has established an identical mechanism of genetic imprinting, a process involved in marsupial and human fetal development, which evolved 150 million years ago.

News discussion:

Forget the chocolate bar in Medicine & Health news