Rare milestone. Mice overexpressing the Klotho gene are pictured here on their third birthday.

Methuselah Mice

A protein named after the Greek goddess who spins life's thread has joined the short list of ways to extend a mouse's natural life span. While lab mice can live about 2 years, many of the mice engineered to overproduce this protein, called Klotho, have celebrated third birthdays. The mutant rodents represent a rare case of a single gene substantially influencing life span in mammals.

The work, performed by Makoto Kuro-o of the University of Texas Southwestern Medical Center in Dallas and his colleagues, builds on research he published 8 years ago. Then, he found that mice lacking Klotho died 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.

In the new study, Kuro-o and collaborators created mice overexpressing the gene for Klotho. Males making the most extra Klotho lived, on average, 30% longer than did normal males, and the mutant females survived 20% longer than normal counterparts, the team reports 25 August in Science. As with other lab animals coaxed to have lengthy life spans, the altered rodents had fertility problems. They produced about half the expected number of offspring. In addition, male Klotho mutants looked like animals at risk for diabetes. Their blood contained more insulin than that of normal mice. This suggested that the male mutants were somewhat resistant to insulin--a symptom, in extreme forms, of diabetes. 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) extends life span in many species.

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.

Whatever Klotho's ultimate mechanism, the work raises the intriguing possibility that life span can be extended despite or perhaps via mild insulin resistance, a trait long 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.

Related sites
National Institute on Aging
Article on Klotho in humans