The cancer of Dorian Gray: is growing old an inescapable cost of averting malignancy?

Science News,  Nov 4, 2006  by Ben Harder

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Dorian Gray, the everlasting dandy of Oscar Wilde's novel, halted aging. Rather than his body growing old, his portrait suffered the insults of time. In recent years, biologists have created real-life Dorian Grays: mice that don't show certain signs of age. But in both the story and the lab, there were trade-offs. By remaining young, the fictional Dorian Gray became self-destructive. In the scientific plotline, the specially bred mice develop cancer and die young.

Scientists create such mice by inserting mutations in one of two important tumor-suppressing genes that mice and people share. The result has revealed a deep link between cancer and aging. Cancer depends on over-enthusiastic cell replication, whereas replication typically dwindles during aging. In a sense, according to the new findings, growing old is the flip side offending off cancer.

"Aging itself may be part of the body's anticancer machinery," says Viktor Janzen, a hematologist-oncologist at the University of Tubingen in Germany. The trick in using that information against cancer or aging will be to uncouple one effect from the other.

In the nearer term, scientists may find new ways to minimize the side effects associated with chemotherapy and radiation exposure. In one strategy with that objective, they plan to temporarily neutralize one of the recently studied genes that controls cell replication.

The other gene in the studies may also have a near-term use. From measures of its activity, doctors might gauge a person's physiological age. That assessment of vitality might tell physicians how aggressively to test or treat a person's various ailments, says oncologist and cancer geneticist Norman Sharpless of the University of North Carolina in Chapel Hill.

A DUAL ROLE Recent experiments on one cancer-suppressing protein revealed that it's a "double-edged sword," says biologist Judith Campisi of the Lawrence Berkeley (Calif.) National Laboratory. "We thought p16 was an unequivocal good guy, but this protein can also shut down the proliferation of good cells."

Sharpless and his team created two strains of mice for use in several experiments. The strains differ in their production of the protein p16, also called [p16.sup.INK4a]. The substance suppresses replication of cancerous cells. One of Sharpless' mouse strains has a mutation that inactivates the gene for p16, while the other has an extra bit of DNA that enhances the gene's activity.

Scientists had previously noted that p16 becomes more abundant with age in some types of mammalian tissue. The new experiments, reported in three papers in the Sept. 28 Nature, establish that p16 contributes directly to the age-related process called regenerative senescence, which gradually erodes cells' capacity to replicate.

Mammals and other long-lived organisms must continually replace cells in their tissues as existing ones wear out. "Declining proliferation is a cause of mammalian aging," says Sharpless.

In one new study, he and his colleagues examined how p16 affects the proliferation of insulin-producing islet cells, which reside in the pancreas. A shortage of islet cells is a cause of diabetes.

In normal mice, old age correlates with elevated p16 concentrations and reduced islet-cell proliferation. Mice engineered to have excess p16 have little islet-cell proliferation, even during youth, the researchers found. By contrast, in the p16-deficient strain, cell proliferation remains at a youthful level of activity into maturity.

Though the p16-deficient animals excelled at islet-cell replacement, they were prone to developing cancer. Their premature deaths made it difficult for the researchers to assess whether extra cell proliferation offered any benefit to the animals. So, they exposed the protein-deficient animals, as well as some normal mice, to a drug that kills islet cells.

The toxin caused mature, genetically normal mice to develop diabetes and die. In the p16-deficient strain, mature mice were more likely to recover.

In another set of experiments, Sean Morrison of the University of Michigan in Ann Arbor and his collaborators, including Sharpless, showed that p16 can reduce regenerative capacity in the mouse brain. For example, as mice aged, those that lacked p16 had smaller declines in neuron production in the olfactory bulb, which processes odors, than normal mice did.

A third study examined p16's effects on blood-producing stem cells in bone marrow. The research team was led by David Scadden of the Harvard Stem Cell Institute and included Sharpless and Janzen.

Transplants of bone marrow cells can reinstate blood-cell production in people who have leukemia. In general, the marrow's regenerative capacity declines with the donor's age, Janzen says.

The researchers repeatedly transplanted marrow cells from one mouse to another, waiting a few weeks between transplants to see whether the cells would proliferate in their new hosts. Among aged mice, mutants that had low p16 concentrations despite their age contributed stem cells that proliferated more readily than did those in mice with a normal gene for p16. It's as if the p16-defficient mice had marrow that was still young, Janzen says.