By: Philip Cohen
“This doesn’t solve every mystery of ageing,” says Nils-Goran Larsson of the Karolinska Institute in Stockholm, Sweden. “But we have established a clear cause-and-effect relationship between ageing symptoms and mitochondria.”
Mitochondria are the energy-generating structures found in cells, and contain their own DNA. Biologists have long suspected they play a key role in ageing. This is because the chemical reactions that take place inside mitochondria generate dangerous by-products called free radicals that can damage biological molecules, including DNA.
While much of this damage is repaired, numerous studies in both animals and humans have shown that mutations in mitochondrial DNA accumulate as organisms age. It has long been thought that this might be one of the keys to ageing, but proving it has been difficult. Until now, researchers could not be sure whether damage to mitochondrial DNA is the fundamental cause of many age-related problems, or if it is just an effect of advancing years, like grey hair.
Larsson decided to find out by accelerating the mitochondrial mutation rate. His team created mice with a defective version of the polymerase protein that copies mitochondrial DNA. Unlike the normal polymerase, this defective protein cannot repair many mutations. The result is that the mice’s mitochondrial DNA mutates two to three times as fast as normal.
Early on in their lives, this change had little effect. The mice grew normally and seemed healthy. But dramatic changes soon became apparent. When the mice were just 25 weeks old, they began to show many signs of ageing, including baldness, spine curvature, osteoporosis, fertility loss and heart-muscle disease, which normally do not appear until mice are over a year old.
The lifespan of the animals was also slashed. Normal mice live for two to three years, but half the mutant mice had died after 48 weeks, and all of them were dead by 61 weeks (Nature, vol 429, p 417).
“It’s an elegant experiment that immediately raises some fascinating questions,” says George Martin, who researches ageing at the University of Washington, Seattle.
One issue is exactly how the mitochondria trigger ageing in different tissues. In some tissues, weakened mitochondria might simply cause a cellular energy crisis. But mitochondria also play a role in programmed cell-suicide, another possible mechanism.
It is also unclear how mitochondrial mutations interact with other known genetic factors in ageing. In mice, mutations in at least five other genes besides the one for the polymerase can trigger some symptoms of ageing.
Larsson thinks his mice will be valuable tools. For instance, he plans to make the mice better at destroying free radicals and see whether that halts some of the signs of ageing. Many drug companies are already working on drugs that soak up free radicals and the mutant mice could be an ideal way to quickly screen those compounds for biological effects.
Another approach would be to create a supercharged mitochondrial polymerase that is better at repairing errors. But Larsson says that improving on the current version will probably not be easy.
“At just 25 weeks the mice began to show signs of ageing like baldness and spine curvature”