In their efforts to conquer the aging process, researchers are zeroing in on one specific part of the cell: mitochondria, the energy-generating organelles that control our metabolism and, it seems, help regulate how long we live.
Courtesy of Nils-Goran Larsson
These mice were born on the same day, but the one on the left has a defective enzyme that causes it to develop symptoms of aging at 25 weeks. Such mice normally live three years.
Mitochondria are the only structures outside the nucleus that contain their own DNA, a distinction that might be more important than previously realized, says Nils-Goran Larsson of Sweden’s Karolinska Institute. Nuclear DNA has an extensive system of proofreading and repair enzymes to weed out mutations. Mitochondrial DNA depends largely on a single enzyme.
Larsson wanted to see what happens when that enzyme fails to catch a glitch, so he and his collaborators engineered mice with a defective, error-prone version of the enzyme. The modified mice developed muscle and hair loss, spine curvature, and loss of fertility at a greatly accelerated pace. “People have noticed a striking correlation between mitochondrial DNA damage and aging, but before it was impossible to be certain if it was causative,” Larsson says. Mutations may cause the mitochondria to operate less efficiently, producing more free radicals—reactive molecules—as a waste product. Free radicals are known to damage and weaken cells. Alternatively, flagging mitochondria might simply cause cells to run out of steam.
In parallel work, Scottish biochemists led by John Speakman at the University of Aberdeen found that mice with hyperactive mitochondria live exceptionally long. “We have this expectation that our bodies are like machines—the more we use them, the faster they will wear out,” Speakman says. “We were very surprised when we found that the mice with the fastest metabolisms outlast the others by about a third.”
He, too, suspects free radicals lie behind the aging effects: “Mice with faster metabolisms have cleaner-running mitochondria. They form fewer free radicals in the process.” The results might seem to clash with the discovery that caloric restriction, which is associated with reduced metabolism, also extends life span. Speakman theorizes that the efficiency of the mitochondria is more important than their total output: Mice on calorie-restricted diets seem to show the same mitochondria-mediated reduction in free radicals as do animals with high metabolisms.
Although mitochondria are certainly not the sole cause of aging, the findings suggest that they exert a surprisingly powerful influence. The discoveries also hint at ways to hold on to youth by altering mitochondrial activity. “If we can find a way to manipulate how they work,” Speakman says, “it could well be the new path to powerful life-prolonging drugs.”