Sci. Aging Knowl. Environ., 20 July 2005
Mitochondrial mutations might speed aging through rampant cell suicide
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/29/nf57
In the Tour de France, cycling teams can drop in the standings if individual riders lag. Similarly, mice that grow old prematurely might do so because some cells wither, according to a new study. The work suggests why one rodent line deteriorates quickly, although researchers need further evidence to nail down the cause.
Insufficient energy stores or painful lactic acid buildup can cripple a cyclist, and some researchers theorize that analogous problems contribute to aging. Mitochondria--the cell's energy generators--accumulate mutations in their DNA with age. These snags might hamper the organelles' fuel production or augment output of poisonous reactive oxygen species (ROS), and both problems potentially contribute to an organism's demise. A study published last year bolstered this idea: Mice with a defect in an enzyme that corrects typos in mitochondrial DNA age rapidly (see "Symphony of Errors"). Now, another team has looked into why such animals decline abruptly.
Kujoth and colleagues confirmed that the altered rodents showed signs of early aging. By 9 months of age, the animals' hair turned gray and fell out, and their spines bowed. The rodents lived only about half as long as did normal animals. In addition, various tissues, such as the thymus gland, bones, and testes, atrophied, and overall the mice lost weight.
Next, the researchers investigated why the animals decay quickly. DNA errors might elevate the amount of ROS in cells. But heart, liver, and muscle tissue did not show unusually large amounts of oxidative damage to proteins, lipids, or DNA, suggesting that an increase in oxidants was not to blame for speeding the rodents' deterioration. In principle, the mice might molder because their cells don't reproduce efficiently. But in culture, mutant and normal cells split the same number of times on average.
Ruptured mitochondria spur cells to commit suicide, and the heavy mutation rates in these organelles might speed cell death. To probe that idea, the team measured quantities of a particular molecule that incites cell death when mitochondria disgorge their contents. Mutant mice harbored more of the protein than did normal animals, and the quantity increased with age. In addition, more cells carried broken DNA, another indicator of cell suicide. Together, the findings suggest that accelerated cell death might speed aging in the mutant animals, perhaps by squelching tissue renewal.
"It's a big step forward" in understanding why these animals age quickly, says biochemist Thomas Kunkel of the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. The rodents' unchanged amounts of oxidative damage "don't support the favored hypothesis [that free radical damage contributes to aging]. ... That's going to surprise some people." However, biochemist Simon Melov of the Buck Institute for Age Research in Novato, California, says researchers need to perform additional experiments before he's convinced. For instance, particular cells or cell compartments might accumulate ROS even though average amounts are normal. Further studies should reveal the injuries to team members that put the body in a losing position.
July 20, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150