You’re Not Getting Older, Just Your DNA

Illustration by Christoph Niemann

The Paper: Premature Aging in Mice Deficient in DNA Repair and Transcription

The Journal: Science, May 17, 2002

The Authors: Jan de Boer, Jaan Olle Andressoo, Jan de Wit, et al.

The Gist: Want to live longer? Be kind to your DNA.

Before Translation: “TTD mice carrying an additional mutation in XPA, which enhances the DNA repair defect, showed a greatly accelerated aging phenotype which correlated with an increased cellular sensitivity to oxidative DNA damage. We hypothesize that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.”

Everything conks out eventually-our TV sets, our cars, even our bodies. It’s obvious why appliances wear out, but not people. Bodies have a tremendous ability to repair themselves. So why then do we age?

According to one theory, it’s all genetic: Just as our cells are programmed to make us grow, at a certain point they are programmed to make us die. But another theory is becoming much more popular: It holds that our DNA is constantly being assaulted and damaged by reactive oxygen species-chemicals that are generated when we break down food. As we age, this damage reaches critical mass and our spoiled cells essentially commit suicide, taking us with them.

This theory has received a boost from a group of Dutch researchers led by Jan de Boer of Erasmus University in Rotterdam. De Boer’s team began by creating mutant mice that aged prematurely because of accumulated damage to their DNA. In particular, the mice had a defect in an enzyme called a helicase that unwinds DNA so cellular machinery can fix it. At birth, the mice looked just like their normal littermates. But after about 3 months, the mutants’ fur began to turn gray, and they became shrunken and, in many cases, infertile. By 14 months (normal mice live an average of 2 years), the surviving mutants had osteoporosis and their faces became tiny and bird-like.

Among scientists who believe that DNA damage causes aging, there are some who suggest we age because our repair mechanisms break down, and others who say it’s because we accumulate so much damage as we get older that the repair machinery can’t keep up. De Boer’s study suggests that it could be a combination. The group demonstrated this by creating mice that lacked not only the helicase enzyme but also some ability to repair DNA. These mice aged so fast that all died before they were three weeks old. What’s more, when cells from the double mutants were exposed to X rays and paraquat (a common herbicide known to damage DNA at high doses) they died much sooner than cells taken from the single mutants.

De Boer’s study is consistent with others showing that consuming fewer calories can extend lifespan. Monkeys fed a third fewer calories than in a typical monkey’s diet are outliving their plumper kin, strongly suggesting the same would be true of humans. How near-starvation diets prolong life is unproven, but evidence points to less DNA damage. The less one eats, the less the body has to metabolize-which means there are fewer reactive oxygen species to bump into one’s DNA.

But whether damage to our DNA actually causes the outward signs of aging is still controversial. There’s no question that DNA gets beaten up over time and that this causes the body to wither somewhat. But a few scientists argue that physical aging is actually the result of our cells’ fight to fend off the trauma. Whether they’re right remains one of the great mysteries of medicine.

-Gunjan Sinha