A
Grim Choice: The Ravages of Age, or of Cancer?
By: Justin Gillis
International Herald Tribune, January 3, 2002
Scientists See a No-Win Link Between Two
Human Scourges.
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 were "fascinating" and "surprising." He
added: "Like all good research, it raises a lot more questions than
it answers."
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
Lowe, called for immediate study of this proposition.
The new paper started with an apparent failure in the
laboratory, then 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, Mr. Donehower and his colleagues accidentally made mice with
a hyperactive version of the protein.
Exasperated, they figured that 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," Mr. Donehower said.
Even ordinary mice are fairly prone to develop
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 more
and more strange. "I couldn't quite figure out what it was until my
lab technician, Ben Cooper, said the words, "These mice just look
old," Mr. Donehower recalled. "That was like a light bulb."
A young graduate student, Stuart Tyner, grabbed hold
of 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 a
population of normal mice. Their enhanced cancer resistance was
accompanied, in other words, by a 20 percent drop in life span.
"The major impact of the study is that it more
tightly links tumor suppression and aging," Mr. Donehower said.
"It really surprised us."
The work confirms hints that had already been
emerging in the 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 previously.
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.
"I think the Donehower paper makes an enormous
contribution," said Mr. Levine, the Rockefeller president. "It's
not that everyone knows it's right yet, or that there aren't other lines
of evidence that are important. But it's conceptually extraordinary."
The paper adds weight to the developing hypothesis
that the body has to walk a line between cancer protection and aging, that
they are, in effect, two sides of a coin. "You have a fine
balance," Mr. Donehower said. "Too much p53 and you get this
aging effect. Too little and you get cancer. My guess is that evolution
has evolved just the right level".
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