10/21/1999 07:00:00

Mutations in the mitochondrial DNA of cells dramatically increase with aging, Caltech study shows

PASADENA-Certain effects of aging could be caused by mutations in the DNA molecules of the energy-producing engines of cells known as mitochondria, according to new research from the California Institute of Technology and the University of Milan.

The study, published in the October 22 issue of the journal "Science", describes the results of skin-cell biopsies of about 30 individuals in a variety of age groups. The study concludes that damage to mitochondrial DNA dramatically increases around the age of 65.

"It's not a magic number, but we see a clear trend," says Giuseppe Attardi, who is Grace C. Steele Professor of Molecular Biology at Caltech and leader of the team authoring the paper.

Attardi and his colleagues focused their efforts on the small structures in cells known as mitochondria. Every cell can have tens to hundreds of these structures, which play an important metabolic role in the energy production that allows the cell to do its work.

Each of the mitochondria has about 10 to 20 molecules of DNA, which means that a single cell can have hundreds or thousands of mitochondrial DNA molecules.

But mitochondrial DNA is known to be susceptible to mutations over the course of a lifetime. These mutations can be due to oxidative damage, some enzyme malfunction, or even the cell's own efforts to repair itself. But prior to the new study, molecular biologists had difficulty in detecting aging-related mutations.

Over a period of about five years, Attardi and his colleagues developed a technique for detecting aging-related mutations in the main control region of mitochondrial DNA. This provided a very reliable method for determining the percentage of mitochondrial DNA molecules in a cell that had actually undergone mutations.

With this technique, they then studied tissue samples provided by the National Institutes of Health (NIH) and the University of Milan from skin biopsies. These biopsies came from individuals ranging from a 20-week-old fetus to a 101-year-old subject, which allowed the researchers to determine the prevalence of mutations in different age groups.

The results showed virtually no aging-related mutations for any of the subjects under the age of 65. But a dozen or so individuals above the age of 65 showed a dramatic increase in mutations. And not only did the rate of mutations sharply increase with age, but individuals also showed a sharp increase in mutations if they passed the age of 65 between biopsies.

Overall, the researchers found that up to 50 percent of the mitochondrial DNA molecules had been mutated in subjects 65 or over.

Attardi says future study will be needed to ascertain the precise effects of the mutations and the relationship to the known characteristics of aging. In addition, the researchers would like to know how the original mutation "amplifies," or is established in thousands of other molecules.

Also, the precise mechanism of the mutations is not known at this time. And finally, the study was done only on skin cells, although Attardi says the effect may possibly be seen in other cells of the human body.

In addition to Attardi, the other authors are Yuichi Michikawa, a senior research fellow in biology at Caltech; and Franca Mazzucchelli, Nereo Bresolin, and Guglielmo Scarlato, all of the University of Milan.

Written by Robert Tindol