Common Variation Of "Klotho" Gene Associated With Human Life Expectancy

Studying more than 2,000 anonymous samples from three ethnically distinct groups of people, the scientists found that having two copies of a less-common version of klotho is twice as prevalent in infants as in people over age 65. These results suggest that people born with the two copies die sooner than others, although the gene's exact influence on health and aging are not known, the scientists say.

"The less-common klotho variant has a clear association with life expectancy in the groups we studied," says Hal Dietz, Ph.D., a Howard Hughes Medical Institute investigator and a member of the McKusick-Nathans Institute of Genetic Medicine at Hopkins. "As with all association studies, our work must now be validated by other scientists studying other populations, and the specific role of klotho in health and disease needs to be determined."

Previously, Japanese scientists discovered klotho in mice, noticing that without klotho's protein, the mice developed atherosclerosis, osteoporosis, emphysema and other conditions common in elderly humans. Because of their interest in accelerated aging diseases, Dietz and his colleagues began studying klotho in people.

They initially examined klotho in 611 infants and 435 elderly (over age 75) Bohemian Czechs, a fairly homogenous group of Central Europeans, then expanded their investigation to include the Women's Health and Aging Study (723 Caucasians and 242 African-Americans over the age of 65 in the Baltimore area) and 646 newborns in the Baltimore-Washington Infant Study.

In these groups, the scientists discovered a variant of klotho that has six changes in the gene sequence, two of which alter the protein's sequence. Because a copy of each gene comes from each parent, people might have two regular klotho copies, one regular and one variant copy, or two variant copies.

Noting that the klotho variant appears with relative frequency in different ethnic populations, the scientists point out that many prior studies of human aging focused on genes that might be responsible for extreme longevity (greater than 100 years) in specific groups of people. Klotho, by comparison, is relevant at much earlier ages.

"What's so striking about the klotho variant is that it is relatively common and has its effect by age 65," explains Dan Arking, Ph.D., who conducted the klotho study as part of his doctoral work with Dietz. "About 3 percent of the infant population had two copies of the klotho variant, indicating they might be at increased risk for earlier death. About a quarter of the population had one variant copy, making them carriers."

The klotho variant is more common than the gene for sickle cell disease in the African-American population, for example. Nationwide, about 0.2 percent of African-Americans have two copies of the gene for sickle cell (leading to sickle cell anemia), while 10 percent of the African-American population carries one copy (which confers protection against malaria).

While having two copies of the klotho variant was associated with a shorter life expectancy in all three populations, having a single copy seemed to lead to a longer life in Bohemian Czechs, the scientists say. About 19 percent of the Bohemian Czech infants had one variant copy, as did 25 percent of the group's elderly.

"Perhaps the advantage can be seen only in the presence of a specific environmental stress," suggests Arking, now a postdoctoral fellow. "For example, having a single copy of the sickle cell gene only benefits life expectancy if malaria is a significant health problem."

Despite its association with longevity, klotho is not functionally related to genes that create accelerated aging diseases in humans, says Dietz. Instead, the klotho protein seems to belong to a family of enzymes that modifies other proteins by cutting off their attached sugars. However, even after much searching, no one has found a target for klotho, so the effects of the variant on the protein's function aren't yet known.

"Until our findings are validated and expanded, there's no advantage to learning one's klotho status," cautions Dietz. "Furthermore, if additional studies prove that klotho is important, understanding what to do with that information is essential for developing productive genetic testing and counseling. There is a lot of basic work remaining to get to that point."

Co-authors on the report are Alice Krebsova, Milan Macek Jr., and Milan Macek Sr. of Charles University, Prague, the Czech Republic; Albert Arking of Johns Hopkins University; Saira Mian of Lawrence Berkeley National Laboratory; and Linda Fried, Ada Hamosh, Srabani Day and Iain McIntosh of the Johns Hopkins School of Medicine.

The analyses were funded by the Howard Hughes Medical Institute, the U.S. National Institutes of Health, the U.S. Department of Energy and the Czech Republic.