Shields Down: A cancer-fighting gene declines in old age

As people age, their risk of cancer increases, primarily because cancer-causing damage to DNA accumulates over time. A new study suggests another possible reason for the increased risk. Experiments in mice show that a key tumor-suppressing gene is less active in old age.

The gene, called p53, is one of the most important and thoroughly studied anticancer genes. When a cell’s DNA becomes damaged, p53 orchestrates a response that either repairs the cell or causes it to self-destruct, thus preventing the cell from growing into a tumor. More than half of all tumors in people are estimated to have mutations in p53.

Researchers led by Arnold J. Levine of the Cancer Institute of New Jersey in New Brunswick subjected mice of various ages to strong doses of gamma radiation, which triggered the gene’s damage-control response. Six hours later, the activity of p53 in the youngest mice had ramped up by a factor of 7 to 8. In mice approaching the species’ 3-year maximum life span, however, the gene’s activity increased only twofold to threefold. The damage-control genes regulated by p53 showed about half as much activity in the older mice as they did in the youthful mice.

“This work provides a second reason why cancers arise late in life,” the researchers say online and in an upcoming Proceedings of the National Academy of Sciences.

The slowdown in p53 activity occurred earlier in females than in males. At 20 months of age, females were already showing decreased responses of the gene, while males of the same age still had youthful responses. The researchers suggest that this ties the change in p53 activity to life span, not just chronological age, because the natural life span of female mice is about 2 to 3 months shorter than that of males.

The gene-response difference between the sexes also suggests that hormones might play a role in regulating the gene, the scientists say.

The effect appears to go beyond the overall decline in bodily functions with age. Other genes related to tumor formation and longevity maintain youthful activity even after p53 declines, Levine’s team notes. And the scientists accounted for the animals’ decline in metabolism by making their measurements relative to the activity of a muscle protein called actin.

“It’s really an amazing result,” comments Norman E. Sharpless, a cancer geneticist at the University of North Carolina at Chapel Hill. “The data look very convincing.”

Levine’s team confirmed the results in cells from nine internal organs of mice and by using five different ways to damage the cells, in addition to gamma radiation. The scientists say that further research is needed to determine whether the effect occurs in people.

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