It seems there's just no way to beat Father Time. As we age, our chromosomes fracture, and specialized proteins rush in to reverse the damage. But new research shows that in doing so, these proteins inadvertently switch on genes that can contribute to aging, allowing senescence to march ever onward.
The idea that a protein might patch up a rickety, aging chromosome is not new. About a decade ago, researchers identified a protein called Sir2 that zooms to the spot of broken DNA in yeast cells and repairs the breaks. But to do that, Sir2 has to abandon its job of inactivating a sterility gene elsewhere in the yeast genome. The result is yeast cells that have intact DNA but are sterile, a symptom of aging in the fungi. Since then, researchers have drawn more connections between Sir2 and its protein family, the sirtuins, to aging in yeast, insects, and mice (Science, 18 June 2004, p. 1731). But they didn't know if the mammalian equivalent of Sir2, a protein called SIRT1, caused the same genetic catch-22.
To find out, molecular biologist David Sinclair of Harvard Medical School in Boston and colleagues studied SIRT1 in mice. In mouse embryonic stem cells, the researchers saw that SIRT1 hangs out near strands of DNA that don't seem to produce proteins, suggesting that it plays a gene-silencing role like Sir2 plays in yeast.
Next, the researchers mimicked aging in mouse cells by exposing them to hydrogen peroxide. The chemical simulates oxidative stress, a buildup of reactive oxygen that often occurs in older cells; many researchers believe that oxidative stress damages cell structures, such as chromosomes, and causes the problems we associate with aging. After 1 hour in the peroxide solution, more than 90% of the SIRT1 proteins left their original locations on the chromosome and moved to the breaks, the researchers report today in the journal Cell.
What was the effect of SIRT1 leaving its post? Further work in the brains of aging rodents suggested that many of the genes associated with SIRT1 turn on in older mice, possibly because SIRT1 has left the scene to repair a broken chromosome. The result could be a liver gene turning on in the brain, disrupting the brain's function, says Sinclair. Such faulty gene activity contributes to a multitude of age-related problems, such as diabetes and dementia.
Overall, the findings indicate that a mammalian cell's effort to stave off old age can actually promote the symptoms of aging. "This may be a very fundamental Achilles' heel of life," says Sinclair. Still, understanding how SIRT1 contributes to the process can help researchers develop better treatments for aging-related problems, Sinclair says. For example, in further experiments, his team showed that mice fed SIRT1 lived more than 25 days longer than did control mice after exposure to genome-altering radiation.
Leonard Guarente, a molecular biologist at the Massachusetts Institute of Technology in Cambridge who conducted some of the original sirtuin studies in yeast, says the work provides greater insight into aging in mammals, including humans. It also, he notes, shows that simple organisms like yeast still have something to teach us.