An international team of researchers reports that although the p53 protein is critical to controlling cancer, having too much of the protein may lead to premature aging. It's a discovery another p53 expert calls both shocking and provocative.
The p53 gene and the similarly named protein it produces are two of the body's most important weapons against cancer. The protein responds to DNA damage that could turn a cell cancerous by repairing the damage, stopping the cell from dividing, or killing the cell.In the January 3 issue of the journal Nature, researchers report that a strain of mice bred with a mutation that causes hyperactivation of the p53 gene had a life span that's roughly 20 percent shorter than normal. That, despite the fact the mice strain has a much lower risk of cancer because of the mutated gene.
The discovery was part ingenuity and part luck, says senior investigator Lawrence Donehower, a professor of molecular biology at the Baylor College of Medicine in Houston.
About eight years ago, Donehower was trying to breed mice with a particular p53 gene mutation; he removed a large portion of one end of the gene. He then assumed the abundance of p53 protein that resulted was simply a mistake and put the mice aside. But his interest was peaked when he noticed the mice were aging faster and dying earlier than expected.
Compared to normal mice, the mutants had a significantly greater resistance to spontaneous cancers. But it came at a price. The mice lived for an average of only 96 weeks, compared to a normal life span of 118 weeks.
"A number of aspects of these mice did resemble aging," Donehower says. "They showed osteoporosis, thinner skin [and] delayed wound healing. They just looked scruffier their hair didn't grow as well. All of these things were suggestive of accelerated aging syndrome."
"Maybe if you have too little p53, you have a situation in which you are susceptible to tumors," Donehower says. "If you have too much, maybe you're more resistant to tumors, but at the same time you pay for that benefit by aging more quickly."
"It's almost like an evolutionary bargain," he adds.
Scott Lowe, a professor at the Cancer Center at Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y., has been studying p53 and cancer for a decade.
"What's so interesting or shocking about this study is that it raises the possibility that the molecule has broader roles, and can be involved in aging," he says.
Donehower says little is known about the balance between p53's ability to fight cancer and its effect on aging. But in an accompanying commentary in Nature, Lowe says the findings offer clues to the role of p53 in normal aging.
In the course of our lives, p53 responds to stresses that might trigger cancer, Lowe says. "The accumulation of all this response to damage could lead to side effects," he adds, and that aging may itself be a side effect of the cellular reactions that prevent cancer.
His commentary raises the theoretical possibility that as much as people might crave anti-aging treatments, such therapies might interfere with the body's built-in cancer-fighting mechanism. And vice-versa: Anti-cancer therapies could have the unwanted side effect of speeding aging.
But Donehower says conventional cancer therapies that involve activating p53, such as radiation, are unlikely to have negative long-term effects on aging.
"These are very transient, very short-lived interventions," he says.
Donehower says that future studies will try to determine what controls the fine p53 balance between tumor suppression and premature aging.