Mutations That Dim the Fire of Life?

Mutations in our cells' internal power plants, called mitochondria, may contribute to the aging process, according to a paper in today's issue of Science (p. 774). The study shows that such mutations accumulate in older people in a particularly important region that controls replication of the mitochondria's small genome. This could lead to a decline in the number of mitochondria, which would deprive cells of energy.

Other researchers had previously found low frequencies of mutations in mitochondrial DNA as people age, but given that cells have hundreds of mitochondria, each with multiple genome copies, skeptics argued that the changes were not extensive enough to really hamper a cell's activity. But a team led by Giuseppe Attardi, a human geneticist at the California Institute of Technology (Caltech) in Pasadena, has found that the accumulating damage can be extensive indeed.

The Caltech team sampled connective tissue cells, called fibroblasts, from 18 randomly picked healthy individuals ranging in age from less than a year to 101. The researchers also obtained two sets of stored cells, taken 9 to 19 years apart, from each of nine other individuals. They used DNA probes to pull out the approximately 1000-base-pair control regions from each of the cell samples as seven separate segments, which they cloned and sequenced.

They found that in one segment, mutations were not present in any of the clones from younger individuals, but they were in 5% to 50% of the clones from the older individuals, eight of whom had exactly the same mutation. They also found three people who had at least one of these mutations in the older cells but not in the younger cells. Thus, their data indicate that specific mutations in the mitochondrial replication control region accumulate with age in some people, sometimes in high numbers.

Researchers say that much more work is needed to clarify how aging is related to mitochondrial mutations. For instance, the Caltech team has not yet demonstrated that these changes alter mitochondrial--or cell--survival or activity. Still, the work "really shows that aging does something to the mitochondrial genome," says Manuel Graeber, a neuropathologist at the Max Planck Institute for Neurobiology in Martinsried, Germany. "The mitochondria have been compared to the fire of life," he explains. Perhaps "that fire is slowly extinguished as we grow old."