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Protein That Wards Off Cancer Also Affects Aging, Study Finds

Health: Chemical that protects rats in early years causes physical deterioration later, evidence shows.

January 03, 2002|From the Washington Post

WASHINGTON — A critical protein that protects animals from cancer in their early years appears, in later life, to cause much of the deterioration associated with aging, according to a provocative new study.

The results, by scientists at the Baylor College of Medicine in Houston, "raise the shocking possibility that aging may be a side effect of the natural safeguards that protect us from cancer," two commentators say in an editorial accompanying the new study, which appears in Friday's edition of the journal Nature.

The research was done in mice, and its applicability to people is uncertain. But mice and humans are close evolutionary relatives, and the new study is likely to set off a race to clarify the exact relationship between cancer biology and aging in human patients.

Arnold Levine, president of New York's Rockefeller University and co-discoverer of a vital protein involved in the body's defense against cancer, called the new study "extraordinary." Bert Vogelstein, a top cancer researcher at Johns Hopkins University, said the results are "fascinating" and "surprising." He added: "Like all good research, it raises a lot more questions than it answers."

Balancing Aging With Cancer Risk

Among the questions is whether any attempt to slow down the overall process of aging--to create an anti-aging pill--would be likely to raise cancer rates. The Nature commentary says scientists working on aging now have to take into account the prospect that "drug-related approaches to interfere with this process may come at a price--the disruption of our natural mechanisms for keeping cancer at bay."

The research also raises the possibility that younger people treated successfully for cancer with chemotherapy may be subject to premature aging later in life, a possibility that has never been rigorously examined. The Nature commentators, Gerardo Ferbeyre and Scott W. Lowe, called for immediate study of this proposition.

The new paper started with an apparent failure in the laboratory that turned into a classic tale of scientific luck and alertness.

Eight years ago, in the cancer lab of Lawrence Donehower at Baylor College of Medicine, researchers were trying to create mice with a weakened version of a protein called p53, which is a central cog in the machinery that prevents cells from growing wildly out of control and turning into tumors.

The hope was that these mice would be susceptible to tumors similar to those seen in human patients. But the techniques for manipulating genes are still crude, and instead of making mice with weakened p53, Donehower and colleagues accidentally made mice with a hyperactive version of the protein.

Exasperated, they figured the mice wouldn't do them much good in their cancer work. "We sort of set the mice off in a corner of our mouse colony and ignored them," Donehower said.

Offhand Comment 'Was Like a Lightbulb'

Even ordinary mice are fairly prone to developing tumors, and the researchers noticed as time went by that virtually none of the mutant mice were getting them. That alone was not so surprising, since p53 is such an effective tumor suppressor--up to now, in fact, that was thought to be its primary role in biology.

But as time went on, the tumor-free mice looked weirder and weirder. "I couldn't quite figure out what it was until my lab technician, Ben Cooper, said the words, 'These mice just look old,' " Donehower recalled. "That was like a lightbulb."

A young graduate student, Stuart Tyner, latched onto the project. "I felt like this was kind of a gold mine," he said. He subjected the mutant mice to a battery of tests that confirmed what was already becoming obvious to the naked eye: They were fading fast.

At an age when normal mice are still fairly vigorous, the bones of the mutant mice became brittle and porous, and they developed hunchbacks. Their hair thinned. Their muscles and other body parts shrank. They lost weight. They recovered poorly from wounds and other stresses. When a few were given a standard anesthetic at doses that don't hurt normal mice, the mutant mice keeled over, dead.

Even though virtually none of them came down with cancers, they died, on average, at 96 weeks, compared with 118 weeks for normal mice. Their enhanced cancer resistance was accompanied, in other words, by a 20% drop in life span.

"The major impact of the study is that it more tightly links tumor suppression and aging," Donehower said. "It really surprised us."

Detailed Evidence of Protein's Importance

The work confirms hints that had already been emerging in scientific literature in recent years that p53 and related proteins might play an important role in aging, but the new paper is far more detailed--and, scientists say, more compelling--than anything published to date.

By the standards of a protein, p53 was already a focus of intense study, and the new paper raises the possibility that it is a prime mechanism in not one but two of the most important aspects of human biology.

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