Long life: it’s all in the mitochondria

“A very short one.”
—Jeanne Calment of France, age 120, when asked what sort of future she anticipated, in Newsweek, March 6, 1995.

We might well envy the longevity of Calment, who died in 1997 at 122. Better, perhaps, to envy her mother’s lineage, Caltech and Italian scientists now suggest.

In a study of nonrelated people who have lived for a century or more, the researchers found 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 replication of mtDNA, thus increasing its amount or replacing portions ravaged by aging.

Published February 4 in the Proceedings of the National Academy of Sciences, the study was conducted by postdoctoral scholars Jin Zhang, Jordi Asin Cayuela, and Yuichi Michikawa; research scientist Jennifer Fish; and Steele Professor of Molecular Biology Giuseppe Attardi, all of Caltech, along with colleagues at the Universities of Bologna and Calabria in Italy and the Italian National Research Center on Aging.

Mitochondrial DNA (mtDNA) is the portion of cell DNA located in mitochondria—organelles that are the cell’s “powerhouses,” capturing energy released from metabolite oxidation and converting it into ATP, the cell’s energy currency. Passing only from mother to offspring, mtDNA molecules are found by the hundreds or thousands in every human cell.

It’s known that mtDNA has a high rate of mutation. Such mutations can be harmful, beneficial, or neutral. In 1999, Attardi and others found what he described as a “clear trend” in mtDNA mutation in people over age 65. In fact, in examining skin cells, the researchers found up to 50 percent of the mtDNA molecules had 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, the observation raised the possibility that some mutations may extend life.

Now, by analyzing mtDNA from a group of 52 Italians, aged 99 to 106, the researchers have found a common mutation in the same main control region. Looking at mtDNA in the centenarians’ white blood cells, they found that 17 percent had a specific mutation called the C150T transition, compared to only 3.4 percent in a group of 117 people under age 99.

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

The mutation’s inheritability was confirmed by examining mtDNA samples from two sets of elderly twins, some monozygotic (from a single egg) and some dizygotic (from separate eggs). To their surprise, the researchers found that 30 percent of the monozygotic and 22 percent of the dizygotic twins shared the 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 asso-ciated 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.”

According to Attardi, the study is the first to show a robust difference in an identified genetic marker between centenarians and younger folks. The next goal is to find the mutation’s exact physiological effect.

Massimiliano Bonafe, Fabiola Olivieri, Giuseppe Passarino, Giovanna De Benedictis, and Claudio Franceschi also contributed to the paper, which can be found at www.pnas.org.
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