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02/12/2003 08:00:00

Caltech, Italian Scientists Find Human Longevity Marker

"A very short one." Oldest known living person in 1995, Jeanne Calment, of France, then 120, when asked what sort of future she anticipated having. Quoted in Newsweek magazine, March 6, 1995.

PASADENA, Calif. – Even though Jeanne Louise Calment died in 1997 at the age of 122, we envy her longevity. Better, perhaps, to envy her mother's lineage, suggest scientists at the California Institute of Technology.

In a study of nonrelated people who have lived for a century or more, the researchers found that the centenarians had something in common: each was five times more likely than the general population to have the same mutation in their mitochondrial DNA (mtDNA).

That mutation, the researchers suggest, may provide a survival advantage by speeding mtDNA replication, thereby increasing its amount or replacing that portion of mtDNA which has been battered by the ravages of aging

The study was conducted by Jin Zhang, Jordi Asin Cayuela, and Yuichi Michikawa, postdoctoral scholars; Jennifer Fish, a research scientist; and Giuseppe Attardi, the Grace C. Steele Professor of Molecular Biology, all at Caltech, along with colleagues from the Universities of Bologna and Calabria in Italy, and the Italian National Research Center on Aging. It appears in the February 4 issue of the Proceedings of the National Academy of Sciences, and online at the PNAS website (http://www.pnas.org/).

Mitochondrial DNA is the portion of the cell DNA that is located in mitochondria, the organelles which are the "powerhouses" of the cell. These organelles capture the energy released from the oxidation of metabolites and convert it into ATP, the energy currency of the cell. Mitochondrial DNA passes only from mother to offspring. Every human cell contains hundreds, or, more often, thousands of mtDNA molecules.

It's known that mtDNA has a high mutation rate. Such mutations can be harmful, beneficial, or neutral. In 1999, Attardi and other colleagues found what Attardi described as a "clear trend" in mtDNA mutations in individuals over the age of 65. In fact, in the skin cells the researchers examined, they found that up to 50 percent of the mtDNA molecules had been mutated.

Then, in another study two years ago, Attardi and colleagues found four centenarians who shared a genetic change in the so-called main control region of mtDNA. Because this region controls DNA replication, that observation raised the possibility that some mutations may extend life.

Now, by analyzing mtDNA isolated from a group of Italian centenarians, the researchers have found a common mutation in the same main control region. Looking at mtDNA in white blood cells of a group of 52 Italians between the ages of 99 and 106, they found that 17 percent had a specific mutation called the C150T transition. That frequency compares to only 3.4 percent of 117 people under the age of 99 who shared the same C150T mutation.

To probe whether the mutation is inherited, the team studied skin cells collected from the same individuals between 9 and 19 years apart. In some, both samples showed that the mutation already existed, while in others, it either appeared or became more abundant during the intervening years. These results suggest that some people inherit the mutation from their mother, while others acquire it during their lifetime.

Confirmation that the C150T mutation can be inherited was obtained by looking at mtDNA samples from 20 monozygotic (that is, derived from a single egg) twins and 18 dizygotic (from separate eggs) twins between 60 and 75 years of age. To their surprise, the investigators found that 30 percent of the monozygotic twins and 22 percent of the dizygotic twins shared the C150T mutation.

"The selection of the C150T mutation in centenarians suggests that it may promote survival," says Attardi. "Similarly, it may protect twins early in life from the effects of fetal growth restriction and the increased mortality associated with twin births.

"We found the mutation shifts the site at which mtDNA starts to replicate, and perhaps that may accelerate its replication, possibly, allowing the lucky individual to replace damaged molecules faster." Attardi says the study is the first to show a robust difference in an identified genetic marker between centenarians and younger folks. Their next goal, he says, is to find the exact physiological effect of this particular mutation.

The researchers who contributed to the paper in Italy were Massimiliano Bonafe, Fabiola Olivieri, Giuseppe Passarino, Giovanna De Benedictis, and Claudio Franceschi.

Contact: Mark Wheeler (626) 395-8733 wheel@caltech.edu

Visit the Caltech Media Relations Website at http://pr.caltech.edu/media

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Written by Marcus Woo