New Findings Contradict Aging/Mitochondrial DNA Mutation Theory

Lawrence A. Loeb, MD, Ph.D.
Department of Pathology, University of Washington
NIEHS Grant U01ES011045

Point mutations in mitochondrial DNA do not cause aging in mice according to NIEHS-supported research published in the April issue of Nature Genetics. The data contradict a widely-believed theory that mitochondrial mutation drive the aging process. In the study, mice with mitochondrial mutations 500 times higher than normal levels do not show signs of premature aging.

Previous research has led to the development of the theory that accumulated mitochondrial mutations throughout life eventually cause the decline in tissue functioning associated with aging. The study authors used a new technique to measure the accumulation of mitochondrial DNA mutations. They found that mutation frequency in mouse mitochondria is more than 10 times lower than has been previously reported, suggesting the earlier work overestimated the mutation frequency. The investigators say that the new technique is much more sensitive than previous assays.

The authors used wild-type mice and "mutator" mice with abnormally high levels of mitochondrial mutations. Mice homozygous for the mutator gene have 2,500 times higher numbers of mitochondrial mutations than the wild-type mice and also have a reduced lifespan. However, heterozygotes have about 500 times the numbers of mitochondrial mutations, but show no signs of premature aging or reductions in life-span.

These data suggest that wild-type mice could never accumulate enough mutations to cause aging symptoms. However, since the researchers only counted point mutations, it is possible that large mitochondrial DNA deletions could still be an underlying cause of aging.

Citation: Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA. DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet. 2008 Apr;40(4):392-4.