August 26, 2005|
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August 26, 2005 |
Physiology: Boosting Gene Extends Mouse Life Span By Jennifer Couzin "I'm not a dreamer; I don't think we're going to find a master control gene for aging," says Harry Dietz, a geneticist at Johns Hopkins University in Baltimore, Maryland, who studies Klotho's counterpart in humans. But, he says, "this is the next best thing. We have found something that perhaps has the ability to make old age richer." But Kuro-o, who discovered the gene that encodes Klotho, worries that "too much Klotho might not be very good." The mice he created with extra Klotho look like animals at risk of diabetes. There's also disagreement over how Klotho works. Mice lacking Klotho die young, after developing arteriosclerosis and other age-related conditions much earlier than normal (Science, 7 November 1997, p. 1013). Still, many doubted that extra Klotho would lengthen life span. With a short-lived mutant, "you always have to worry that it's just sick," says Cynthia Kenyon, who studies aging at the University of California, San Francisco. So, Kuro-o, his postdoctoral fellows Hiroshi Kurosu and Masaya Yamamoto, and colleagues at universities in the U.S. and Japan created mice overexpressing the gene for Klotho. While Klotho is produced only in the kidney and brain, a fragment of it slips into the blood and may act like a hormone. Males making extra Klotho lived up to 30% longer than normal males, and the mutant females survived 20% longer than normal counterparts. As with lab animals coaxed to have lengthy life spans, the altered rodents had fertility problems. They produced about half the expected number of offspring. Males appeared more affected by Klotho than females did. Their blood, unlike that of females, contained more insulin than normal mice. This suggested that the male mutants were somewhat resistant to insulin--a symptom, in extreme forms, of diabetes. The Klotho-boosted males and females had normal glucose levels, a surprise because untreated diabetes causes high glucose. These features don't appear in other long-lived mice, which are usually insulin-sensitive and have low glucose. Klotho's effects on insulin could connect the protein to a hot story in aging research. Suppression of signaling by insulin and the related hormone insulin-like growth factor-1 (IGF-1) is one of the most consistently successful ways to extend life span in many species. Long-lived mice that are sensitive to insulin also usually have dampened insulin and IGF-1 signaling. In rat cells, Klotho inhibited insulin signaling, making it tough for the hormone to do its job. Kuro-o's group also showed that some mice lacking Klotho survived somewhat longer and suffered fewer diseases when the team coaxed insulin and IGF-1 signaling back to normal. Klotho "ties in beautifully" with the IGF-1 story, says George Martin, a gerontologist at the University of Washington in Seattle. Others are less sure. The link is "tenuous," says Luciano Rossetti, director of the diabetes research center at Albert Einstein College of Medicine in New York City. He points out that female mice with extra Klotho have normal insulin action but live substantially longer. Kenyon says the new work raises the possibility that life span can be extended alongside mild insulin resistance, a trait considered deleterious to longevity. Researchers would now like to know if Klotho levels in humans correlate with life span--for example, if the blood of centenarians is swimming with it.
Volume 309, Number 5739, Issue of 26 Aug 2005, pp. 1310-1311.
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