Gene link found between life span and cancer

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Biologists have uncovered a deep link between life span and cancer in

the form of a gene that switches off stem cells as a person ages.

The critical gene, well known for its role in suppressing tumors,

seems to mediate a profound balance between life and death. It weighs

the generation of new replacement cells, required for continued life,

against the risk of death from cancer, which is the inevitable outcome

of letting cells divide.

To offset the increasing risk of cancer as a person ages, the gene

gradually reduces the ability of stem cells to proliferate.

The new finding, reported by three groups of researchers online

yesterday in Nature, was made in a special breed of mice that lack the

pivotal gene, but is thought likely to apply to people, as well.

The finding suggests that many degenerative diseases of aging are

caused by an active shutting down of the stem cells that renew the

body's various tissues and are not just a passive disintegration of

tissues under daily wear and tear. " I don't think aging is a random

process — it's a program, an anticancer program, " said Dr. Norman E.

Sharpless of the University of North Carolina, senior author of one of

the three reports.

The other senior authors are Drs. J. on of the University

of Michigan and T. Scadden of the Harvard Medical School.

The full implications are far from clear, but the finding that the

cells are switched off with age does not seem too encouraging for

researchers who hope to use a patient's own adult stem cells to treat

disease. That result may undercut opponents of research on human

embryonic stem cells who argue that adult stem cells are enough to

build new tissue.

Dr. Sharpless said his finding showed the need to pursue both types of

research. The gene in the finding has the unmemorable name of

p16-Ink4a. It plays a central role in the body's defenses against

cancer, and it produces two quite different proteins that interact

with the two principal systems for deciding whether a cell will be

allowed to divide.

One of the proteins had also been noted to increase substantially with

age. The cells of a 70-year-old produce 10 times as much of the Ink4

protein as those of a 20-year-old, Dr. Sharpless said.

To help understand that Dr. Sharpless genetically engineered a mouse

strain with the gene knocked out. He set out to see whether losing the

gene would affect the blood-making stem cells. Learning that Dr.

on was interested in that with brain cells and Dr. Scadden with

the insulin-making cells of the pancreas, he shared his mice with them.

The teams agreed to publish their findings together, a departure from

usual researchers' competitiveness.

All three teams report essentially the same results, that in each type

of tissue the cells have extra ability to proliferate when the Ink4

protein can no longer be made.

At the same time, the Ink-less mice are highly prone to cancer, which

they start to develop as early as 1 year of age.

The researchers assume, but have not yet proved, that the increasing

amounts of Ink4 as a person ages will thrust the stem cells into

senescence, meaning that they can never divide again. The evolutionary

purpose is evidently to avert the risk that a damaged stem cell might

evade controls and proliferate into a tumor.

One implication is that therapists who hope to increase longevity have

to tackle a system that may be hard to cheat. An intervention that

reduces Ink4 production to prevent the age-related decline of stem

cells will also increase the risk of cancer.

" There is no free lunch,'' Dr. Sharpless said. " We are all doomed. "

He quickly modified that by noting that a calorically restricted diet

is one intervention that is known to increase life span and reduce

cancer, at least in laboratory mice. The reason, he said, is probably

because such diets reduce cell division, the prime source of cancer risk.

For cell therapists, the dual activity of Ink4 may be " a hard box to

get out of, " he said, unless they use cells that are somehow much

younger than the patient.

Dr. Scadden, however, said he hoped that there would turn out to be

some sloppiness in the Ink4 gene's balancing trick, allowing it to be

switched off temporarily with yet-to-be invented drugs in a way that

would promote stem cell proliferation without greatly increasing the

risk of cancer. " There is clearly a dark side to the finding, but

whether or not we can exploit it, that's the challenge, " he said.

Some proposals for stem cell therapy with adult stem cells envisage

taking a patient's stem cells, making them divide in the laboratory

and putting them back in the patient to build new tissue.

" The notion that adult stem cells are infinite in proliferative

capacity is seriously undermined by this work, " Dr. Sharpless said.

Dr. on said it had long been known that older patients did not

do as well in bone marrow transplants as younger ones, and the new

finding might explain why.

" I don't think any of these findings dims the promise of stem cell

research at all, " he said, because the greater robustness of younger

people's cells was already well known.

The researchers said they did not yet know what stimulus makes cells

increase their production of the Ink4 protein as a person grows older.

Their suspicion is that the usual factors implicated in aging like

mutation and oxidative damage to tissues would turn out to have a role

in making cells produce more Ink4.

Dr. A. DePinho, an expert on cellular aging and a co-author of

Dr. Scadden's report, said the new finding, in showing how the renewal

capacity of stem cells was governed, might enable drugs to be made

that would improve cell transplants.

Dr. Lowe, a cancer gene expert at the Cold Spring Harbor

Laboratory on Long Island who was not involved in the three papers,

said the results were interesting because they linked to aging a gene

of central importance in cancer.