~ Life-Lengthening Hormone Found in Mouse Research

washingtonpost.com, 08-26-05

Scientists have identified a hormone that significantly extends the life span of mice, a discovery that could mark a crucial step toward developing drugs that boost longevity in people.

The hormone is the first substance identified that is produced naturally in mammals, including humans, and can extend life span -- a long-sought goal in the intense effort to help people live longer.

Much more work is needed to study the substance, and investigate whether the hormone or a similar compound would be effective and safe in people, experts cautioned. But the discovery opens highly promising avenues for research and provides tantalizing new clues toward deciphering the basic biology of aging.

"This is a significant discovery. It's an exciting paper," said Anna McCormick of the National Institute on Aging, which helped fund the new research, published online yesterday by the journal Science. "It's definitely the way you would go about designing molecules that would promote healthy aging and longevity in people."

Makoto Kuro-o of the University of Texas's Southwestern Medical Center at Dallas, who led the research, said, "This could provide a key to understanding the molecular mechanisms of aging and opens up new areas to the potential therapy for multiple age-related diseases in humans."

The discovery was triggered by a study Kuro-o and his colleagues published in 1997. That study identified a gene in mice that, when damaged, caused the animals to experience all the hallmarks of aging in humans -- hardening of the arteries, thinning bones, withered skin, weak lungs -- and to die prematurely. They dubbed the gene Klotho, for the Greek goddess who spins the thread of life.

Suspecting the gene may play a role in regulating life span, Kuro-o and his colleagues genetically engineered mice with overactive Klotho genes. In the latest experiments, they found that these animals lived an average of 20 to 30 percent longer than normal -- 2.4 to 2.6 years vs. a normal life span of about two years -- without any signs of ill effects, according to the new report.

"The extension of life span is widely accepted as a reliable marker for the suppression of aging," Kuro-o said. "This shows the Klotho gene regulates aging."

The researchers then identified a small protein component, called a peptide, that the gene produces and found it circulating in the animals' blood at double the normal level.

After isolating and purifying the substance and reproducing it through genetic engineering techniques, the researchers injected the substance into normal mice. Tests on those animals, combined with experiments involving cells in the laboratory, indicate that the substance modulates a crucial biological pathway involved in an array of basic metabolic functions that has become the focus of aging research in recent years.

"It's a pathway that has been conserved by evolution that has been found to play a key role in regulating life span for flies, worms, mice and probably humans," Kuro-o said.

Studies, for example, suggest that damping down this pathway -- known as the insulin/insulin-like growth factor-1 signaling pathway -- may be the mechanism that extends longevity in animals that are fed an ultra-low-calorie diet.

The Klotho hormone appears to have a similar effect, Kuro-o said.

"Our work shows that the Klotho gene is an aging-suppressor gene," he said.

Other researchers said the findings were remarkable because no one had previously found a naturally occurring hormone capable of extending the life span of a mammal.

"You have lots of ways to shorten the life of an animal, but it's hard to get an animal to live longer," said George M. Martin of the University of Washington, who is scientific director of the American Federation for Aging Research. "You can kick a radio to make it not work so well, but it's hard to make it work better. It's quite a wonderful discovery."

Kuro-o and his colleagues plan to inject the substance into normal mice to see whether it extends their life spans and to measure the substance in humans to determine whether levels of the protein are correlated with longevity. Previous research has shown that humans have the protein in their blood, and that people with a certain variation of the gene are prone to age-related diseases such as heart attacks, strokes and osteoporosis.

Scientists will have to determine whether the protein can be produced in sufficient quantities to use it as a drug. It may turn out that other substances that mimic the protein's effects would also work or be safer, Kuro-o said. "That might be more practical," he said.

Kuro-o and others cautioned, however, that agents that appear effective and safe in mice often produce complications in humans. The hormone, for example, appears to decrease the effectiveness of insulin, which could limit its usefulness.

"It appears to play a role in the same pathway in people, but that doesn't necessarily mean it's going to be as straightforward to extend life span in people as it is in mice," said Valter Longo of the University of Southern California. "But this adds a new component to our picture and perhaps a component that could extend life span with few ill effects."

Beyond the possible clinical applications, other researchers said the finding underscores the growing understanding of the basic biology of aging.

"Papers like this are filling in the pieces of the puzzle that will explain the evolutionary biology of aging," said L. Stephen Coles of the UCLA School of Medicine.

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