.:: Gene Found to Switch Off Stem Cells During Aging ::.

[Tomahawk]

New York Times Article Source

Biologists have uncovered a deep link between lifespan and cancer in the form of a gene that switches off stem cells as a person ages.

The critical gene, already 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 Wednesday 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 indicates that many of the degenerative diseases of aging are caused by an active shutting down of the stem cells that renew the bodyΆs various tissues, and are not just a passive disintegration of tissues under lifeΆs daily wear and tear, as is often assumed.

“I donΆt think aging is a random process – itΆs a program, an anti-cancer program,” said Dr. Norman E. Sharpless of the University of North Carolina, senior author of one of the three reports. The two other senior authors are Dr. Sean J. Morrison of the University of Michigan and Dr. David T. Scadden of the Harvard Medical School.

The findingΆs implications for cell therapy based on using a patientΆs own adult stem cells are not yet clear, but news that the cells get switched off with age does not seem particularly encouraging. The result may undercut opponents of research with human embryonic stem cells who argue that adult stem cells are sufficient for cell therapy. Dr. Sharpless said his finding emphasized the need to pursue both types of research.

The gene involved in the new finding has the unmemorable name of p16-Ink4a but plays a central role in the bodyΆs defenses against cancer. 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 these proteins had also been noted to increase substantially with age. The cells of a 70-year-old person produce 10 times as much of the Ink-4 protein as do those of a 20 year-old, Dr. Sharpless said. To help understand why this was so, Dr. Sharpless genetically engineered a strain of mouse in which the gene was knocked out.

He set out to see if loss of the gene would have any effect on the miceΆs blood-making stem cells. Learning that Dr. Morrison was interested in the same question with brain cells, and Dr. Scadden with the insulin-making cells of the pancreas, he shared his mice with them and the three teams agreed to publish their findings together, a departure from the usual competitiveness between researchers.

All three teams report essentially the same result, that in each type of tissue the cells have extra ability to proliferate when the Ink-4 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 one year of age.

The researchers assume, but have not yet proved, that the increasing amounts of Ink-4 made as a person ages will thrust the stem cells into senescence, meaning 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 hoping to increase longevity must tackle a system that may be hard to cheat. Any intervention that reduces production of the Ink-4 protein in order to prevent the age-related decline of stem cells will also increase the risk of cancer.

“There is no free lunch — we are all doomed,” Dr. Sharpless said. But he quickly modified his comment by noting that a calorically restricted diet is one intervention that is known to increase lifespan and reduce cancer, at least in laboratory mice. The reason, he said, is probably because these 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 there would turn out to be some sloppiness in the Ink-4 geneΆs 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, thatΆs the challenge,” he said.

Some proposals for stem cell therapy with adult stem cells envisage taking a patientΆs 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. Morrison said it had long been known that older patients donΆt do as well in bone marrow transplants as younger ones, and the new finding might explain why. “I donΆt think any of these findings dims the promise of stem cell research at all,” he said, because the greater robustness of younger peopleΆs cells was already well known.

The researchers say they do not yet know what stimulus makes cells increase their production of the Ink-4 protein as a person grows older. Their suspicion is that the usual factors implicated in aging, such as mutation and oxidative damage to tissues, would turn out to play a role in making cells produce more Ink-4.

Dr. Ronald A. DePinho, an expert on cellular aging and a co-author of Dr. ScaddenΆs 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. Scott Lowe, a cancer gene expert at the Cold Spring Harbor Laboratory who was not involved in the three papers, said the new results were very interesting because they linked to aging a gene of central importance in cancer.