Sci. Aging Knowl. Environ., 14 December 2005
Oxidants off the Hook?
Fast-aging mice don't suffer oxidative overload
A new study of rapidly aging mice might tarnish the idea that oxidants foster aging. The rodents deteriorate despite having normal quantities of the destructive molecules. The work implicates mitochondrial slowdown in the animals' demise. However, some researchers question the results.
Mitochondria are like coal-burning power plants. The organelles provide energy, but this process spawns pollutants. The emissions, known as reactive oxygen species (ROS), attack molecules such as DNA and proteins, and many researchers suspect that they contribute to aging (see "The Two Faces of Oxygen"). As the main source of ROS, mitochondria should absorb the worst punishment, some scientists argue. If so, a vicious circle might ensue: ROS trigger mitochondrial DNA mutations, which upset the energy-capturing machinery and boost ROS output, which in turn leads to more mutations, and so on. A "mutator" mouse that amasses mitochondrial DNA glitches allows researchers to evaluate the idea. Last year, molecular biologist Nils-G�ran Larsson of the Karolinska Institute in Stockholm, Sweden, and colleagues revealed that the rodents develop signs of premature aging and die young (see "Symphony of Errors"). Earlier this year, another team showed that the rodents' molecules didn't show larger-than-normal amounts of ROS-induced damage, but their cells were more likely to commit suicide (see "Error Prone"). Now Larsson and colleagues report that metabolism lags in the animals' cells.
The researchers first measured mitochondrial DNA mutations in embryonic and old mutator mice. The vicious-circle hypothesis predicts that the mutation count should increase exponentially as animals grow old, but the researchers found that it increased linearly. To determine whether ROS ran riot in the fast-aging animals, the team cultured connective tissue cells from embryos. Cells from mutators and controls carried similar amounts of ROS, suggesting that the destructive molecules weren't accumulating. The researchers also found that heart proteins from the genetically altered mice didn't sport increased oxidative damage, although liver proteins did show slightly more. Metabolic measurements uncovered a possible explanation for the mutators' swift senescence: Their energy-capturing pathways were sluggish. Overall, the results indicate that rapid aging in these mice doesn't require escalating ROS quantities, Larsson says. The findings contradict the hypothesis that ROS promote aging, although Larsson cautions that they don't disprove it. Earlier work suggested that the animals' speedy demise stemmed from excess cell suicide. This study implies that the cause is cellular power failures as mitochondria falter, he adds, although the researchers didn't measure cell suicide.
The study "challenges a lot of conventional thinking about the roles of ROS in aging," says molecular biologist James Sligh of Vanderbilt University School of Medicine in Nashville, Tennessee. Biochemist Simon Melov of the Buck Institute for Age Research in Novato, California, disagrees. He contends that the researchers didn't observe ROS buildup in the mutators because they checked the wrong cell types. Energy-guzzlers such as the nervous system and muscles incur the most harm from mitochondrial faults, he says, and researchers should scrutinize their cells, not connective tissue cells. The culture conditions, which exposed cells to more oxygen than usual, also muddy the results, says molecular biologist Bennett Van Houten of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. These cells are already suffering from oxidative stress, which could explain why the researchers didn't detect an ROS surge in the mutators, he says. Further work might reveal whether the results have left a mark on the oxidation hypothesis.
December 14, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150