Study Reveals Mitochondrial Role in AgingStudy Reveals Mitochondrial Role in Aging

Experiments that caused mice to quickly develop characteristics of premature aging reveal that mutations in mitochondrial DNA may play a key role in growing old.

For years, mitochondria have been linked to aging. In the new findings, researchers demonstrated that an accumulation of genetic mutations in mitochondria sets off a cascade of signals that causes programmed cell death, or apoptosis (Kujoth et al. Science. 2005;309:481-484). The result is loss of irreplaceable cells and progression of aging.

All mitochondria have their own DNA, separate from DNA in the cell’s nucleus. Researchers have known that mutations in mitochondrial DNA accumulate over time, but how these mutations might underlie aging has not been clear. To shed light on the issue, the study’s investigators analyzed mice genetically altered to have a deficiency in a protein that “proofreads” the genetic sequence of mitochondrial DNA; these mice accumulate genetic mutations at a higher rate than normal mice. “It’s like a broken spell-checker,” said principal investigator Tomas Prolla, PhD, of the University of Wisconsin, in Madison. “By introducing a malfunction in the proofreading domain, these mutations accumulate much more rapidly,” he explained.

Due to this genetic alteration, the cells of these mice had accelerated rates of apoptosis that resulted in the loss of certain critical adult stem cells that are essential for replacing cells that die, said Prolla. This scenario led to premature hair loss, graying, and atrophied muscle and bone.

Interestingly, oxidative stress, a proposed culprit in mitochondria’s mechanism of aging, did not seem to factor into the premature aging of these animals. Some researchers have suspected that oxidative stress—cellular damage caused when mitochondria produce oxygen-derived molecules known as free radicals—is responsible for the aging process. But in this latest report, oxidative stress in some tissues actually decreased when mutations increased.

A role for DNA damage in the aging process is supported by previous findings that humans and mice with defects in DNA repair genes experience premature aging. For example, mutations in the gene WRN cause Werner syndrome, an autosomal recessive disease characterized by premature aging, large numbers of genomic alterations, and increased cancer incidence (Chang et al. Nat Genet. 2004;36:877-882).

In addition, the investigators concluded that their hypothesis that apoptosis is an important mechanism of aging is supported by studies of caloric restriction, an intervention that has been shown in some animals to retard aging, delay the accumulation of mitochondrial DNA mutations, and reduce mitochondria-mediated apoptosis.

Prolla sees clinical potential for his line of study down the road. If scientists can successfully improve mitochondrial function and reduce apoptosis in animal models, “then we can begin to think about pharmaceutical interventions to retard aging by preserving mitochondrial function,” he said.