Gene Variant Tied to Human Aging

Named for a figure in Greek mythology, the gene called klotho has stirred controversy since 1997, when a mouse study hinted that it has a role in aging. Now, an analysis of three human populations reveals that a certain pattern of klotho variants is more prevalent in elderly people than in newborns, suggesting that the gene influences human aging or specific age-related illnesses.

“This new study makes me take the claim that it may be important to aging more seriously,” says George M. Martin of the University of Washington in Seattle, who has been skeptical about klotho‘s role.

The gene first drew attention when Japanese scientists accidentally disabled it in a strain of mice. The animals seem normal for a few weeks after birth but then develop problems that include arteriosclerosis, infertility, emphysema, and low bone mass. They die within 8 or 9 weeks, whereas normal mice live 2 to 3 years.

Concluding that the mutant mice age prematurely, the researchers named the gene after the goddess that spins threads representing people’s lives. Martin and other investigators challenged that conclusion, however, because the conditions afflicting the mice are common in elderly people but not old rodents.

“To view [klotho] as a gene that has a fundamental impact on the process of aging has always struck me as a misinterpretation,” says Richard Miller of the University of Michigan in Ann Arbor.

The role of the protein encoded by klotho remains obscure. It exists in both secreted and membrane-bound forms, and some data indicate it’s an enzyme that modifies sugars attached to protein molecules.

To probe klotho‘s role, Dan E. Arking of the Johns Hopkins Medical Institutions in Baltimore and his colleagues compared young and old people.

“We basically asked, Are there variants of this gene that are represented at one level in infants but selected against during the aging process and [are] so underrepresented in an elderly population?” says study coauthor Harry C. Dietz. “We found that the answer was, Yes.”

The scientists initially studied 435 Bohemian Czechs older than 75 years and 611 newborns from the same population. They analyzed the two groups for the prevalence of a klotho variant that, compared with a more common version, has six changes in its DNA sequence, including two that alter the amino acids of the gene’s protein.

The percentage of people with two copies of this klotho variant was smaller among the elderly people than the

newborns, hinting that this gene combination puts an individual at a disadvantage as he or she ages. Dietz’ group did two other newborn-elderly comparisons, within African-American and white populations from the Baltimore region. The results were similar to the Czech finding. Percentage-wise, fewer elderly people than newborns had two copies of the rarer klotho, the researchers report in the Jan. 22 Proceedings of the National Academy of Sciences.

“Overall, there was a 2.6-fold increased risk of dying before age 65” for people with two copies of the variant, says Dietz.

Alan R. Shuldiner of the University of Maryland in Baltimore, who has performed similar genetic analyses of populations, cautions that such studies often produce misleading results. The klotho findings must be confirmed in more and larger groups, he says.

“Based on the data and how little we know about this particular gene, it would be very premature to dub this a longevity gene,” concludes Shuldiner.

The difference between newborns’ and elderly people’s klotho genes may arise because the rarer version doesn’t protect people from one or more age-related illnesses, such as cardiovascular disease, as well as the common form does.

That’s a view of klotho shared by Miller and Dietz.

“This [gene] is not a master controller of lifespan,” says Dietz.

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