In today’s Science, an international team of collaborators, led by Thomas Prolla at the University of Wisconsin, reports that accumulation of mutations in the mitochondrial genome may play a significant role in the aging process. This may come as no surprise, given previous reports supporting this old theory, but what might be unexpected is the finding that premature aging brought on by these mutations is not associated with an increase in oxidative stress, but rather a defect in programmed cell death, or apoptosis.

Evidence has steadily mounted for the role of accumulating mutations in normal aging. Last year, findings from Bruce Yankner’s lab at Harvard suggested that, in humans, sufficient mutations in nuclear DNA accumulated after age 40 to reduce gene expression (see ARF related news story). Around the same time, Nils-Goran Larsson and colleagues at the Karolinska Institute in Stockholm reported that aging is accelerated in mice that are compromised in mitochondrial DNA repair (see ARF related news story), suggesting that organelle DNA might also be a piece of the aging puzzle. The Swedish group had generated animals lacking a fully functional mitochondrial DNA polymerase. With poor proofreading capability, this enzyme replicated mitochondrial DNA while allowing mutations to accumulate. Now, Prolla and colleagues report a similar strategy to study aging in mice, generating animals with a single point mutation (D257A) that turns a normally diligent mitochondrial DNA polymerase G into a sloppy proofreader.

First author Gregory Kujoth and colleagues found that their mice aged very similarly to the ones generated by Larsson's group. The D257A homozygous animals lived to a maximum of about 460 days, a time when most mice, which generally live to about 900 days, are in their prime. The mutant animals looked no different from wild-type littermates when young (2 months), but by 9 months old they were graying, losing hair, and suffering from kyphosis, or curvature of the spine. Hearing loss and muscle weakness were apparent at about the same time, much earlier than would be found in normal animals.

Kujoth and colleagues confirmed that these animals harbored more mitochondrial mutations than did their wild-type littermates. When the researchers sequenced a 500-base-pair region that spans the control region—that key regulatory section of the circular mitochondrial genome—they found that mutations there were about three- to eightfold higher than normal. This may be particularly relevant to neurodegenerative diseases, because Pinar Coskun and colleagues reported this time last year that control region mutations are much higher in brain samples taken from Alzheimer disease patients than from controls (see ARF related news story).

The real surprise, however, was when Kujoth and colleagues looked for evidence of increased oxidative stress. It has been postulated that mitochondrial mutations might lead to increased levels of reactive oxygen species (ROS), which are produced overwhelmingly in the mitochondria, and that increased ROS would in turn lead to more DNA damage, and even more ROS, and so on until a vicious cycle was set in motion. But when the authors measured several ROS indicators, they found that they were no different than in control mice. In 9-month-old D257A animals, levels of hydrogen peroxide, protein carbonyls, isoprostanes, and oxidized DNA and RNA, all products of ROS chemistry, were similar to age-matched wild-type animals.

So why are these animals aging rapidly? Since the mitochondria also play a key role in apoptosis, or programmed cell death, the authors examined levels of cleaved caspase 3, an indication of active apoptosis. They found that the D257A animals did indeed have significantly higher levels of the protein than did control mice. In the polymerase-compromised mice, cleaved caspase 3 had reached twice the normal level in a variety of tissues, including liver, muscle, and duodenum, by 3 months of age. Oddly enough, however, even at 9 months of age, levels of the apoptotic marker were normal in the brains of the rapidly aging animals. This “suggests that postmitotic tissues may be more resistant to the induction of apoptosis mediated by mtDNA mutations,” write the authors, who conclude that “apoptosis and subsequent loss of irreplaceable cells may be an important mechanism of aging in mammals.”—Tom Fagan

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References

News Citations

  1. After 40, DNA Damage Accrues in Genes, Hampering Expression
  2. Poor Proofreading May Shorten Your Lifespan
  3. Promoter Bashing—Mitochondrial Ones Damaged in AD Brain

Further Reading

Primary Papers

  1. . Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005 Jul 15;309(5733):481-4. PubMed.