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Abstract & Commentary
Source: Trifunovic, et al. Premature aging in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417-423.
The cause of normal aging has been widely studied, and a large number of nuclear factors have been implicated in normal aging including DNA polymerase, P53, and klotho. Some mutations result in defective repair of nuclear DNA. It has also been demonstrated that a progeroid syndrome in mice is caused by defects in A-type lamins. Mice with these defects develop a marked reduction in growth rate and death by 4 weeks of age with pathology in the bone, muscle and skin that are consistent with progeria (Mounkes, et al., Nature. 2003 423:298-301). Another major theory of aging is that mutations in mitochondrial DNA may speed up the aging process. It has long been known that mitochondrial deletions and point mutations accumulate with normal aging. This has been demonstrated in a large number of species. The mitochondria have their own genomes, which encode a few mitochondrial proteins. It has been speculated that the mutations which accumulate with age, might lead to impaired energy generation as well as increased amounts of reactive-oxygen species, resulting in cellular damage. The association between mitochondrial mutations in aging however, could be merely correlative. The numbers of mutations, which are commonly observed, are below the threshold which is observed in diseases of the mitochondrial genome. A definitive answer to this conundrum has been lacking. One argument has been that the smaller number of mutations observed may only be a tip of the iceberg phenomenon.
Larsson and colleagues put cause and effect together to address whether mitochondrial point mutations directly contribute to normal aging. Trifunovic and colleagues genetically engineered mice to carry mutations in an enzyme called DNA polymerase polg A. This enzyme is encoded by nuclear genes and then transported to mitochondria. It is involved in both copying and proofreading mitochondrial DNA, eliminating errors that it makes during replication. It is also thought to participate in DNA repair processes. Mitochondria are replaced in all cell types throughout life. New mitochondria also must be made when cells divide. This requires the replication of mitochondrial DNA. Trifunovic et al rendered the mitochondrial DNA polymerase error-prone by eliminating its proofreading activity, while maintaining its catalytic potency. The idea is that this will then lead to accumulation of mitochondrial DNA mutations.
Trifunovic et al then wanted to know whether this would accelerate normal aging. They observed that the somatic tissues of mice bearing 2 mutant copies of DNA polymerase gamma gene showed extensive mitochondrial DNA mutations largely comprising deletions and point mutations. The percentage of mitochondria bearing deletions was similar in different tissues and did not vary with age, suggesting that the deletions had occurred early in development. Point mutations were common in several enzymes. For instance, cytochrome-b had a 3-5 fold increase in single-base substitutions which were widely disbursed throughout the gene. For example, by 8 weeks, mutant animals had about 9 mutations per 10 kilobases of DNA, while normal mice had less than 1. But, it was the physiology of the animals that was most pronounced. At first they looked normal, but by about 25 weeks of age (that’s early adulthood to a mouse), they started to show signs of premature aging. The animals stopped gaining weight and became bald. Low bone mineral density curved their spines in a sign of clinical osteoporosis. Half of the animals were dead by 48 weeks and 61 weeks, respectively, much sooner than the typical lab mouse, which lives about 2 years. The mutant animals showed a decrease in the activity of enzymes involved in the respiratory chain and in the production of ATP, which may be a result of the mutations in the mitochondrial DNA encoded components of the respiratory complex. These findings strongly support the idea that mutations in mitochondrial DNA, which might be acquired during normal aging, can contribute to the aging process.
Trifunovic et al have made a very novel and important observation, which strongly links the accumulation of mitochondrial DNA mutations to normal aging. The data from their transgenic mouse model, the strongest data to date, show that the accumulation of these mutations does have functional relevance. It is likely that they contribute to the production of reactive oxygen species consistent with the oxidative damage theory of aging. This is the theory that aging is caused by an increase in levels of reactive oxygen species, which largely arise from the mitochondrial electron transport chain. Normal aging is likely to be multifactorial however, the contribution of mitochondrial impairment to it appears now to be well established based on the observations of the present authors. It is likely that this mitochondrial impairment which accompanies normal aging may contribute to the pathogenesis of age-related neurodegenerative diseases. — M. Flint Beal
Dr. Beal, Professor and Chairman, Department of Neurology, Cornell University Medical College, New York, NY, is Editor of Neurology Alert.