Cancer fighter reveals a dark side

Too much of a good thing can be bad, even when it comes to a tumor-suppressing gene. Researchers report that mice with an overactive gene for a protein called p53, which checks inappropriate cell division and helps prevent cancer, prematurely suffer age-related conditions such as osteoporosis and die earlier than normal. This raises the prospect that there’s a trade-off between tumor suppression and a long lifespan.

Lawrence A. Donehower of the Baylor College of Medicine in Houston and his colleagues were trying to produce mice with a disabled p53 gene when they accidentally created a mouse strain in which the gene is overactive. Mice lacking the p53 gene are cancer-prone, so it isn’t surprising that the new mutant strain is much less likely than normal to develop tumors.

Despite the enhanced cancer protection, the mutant mice die earlier than normal. The median lifespan of the mutant mice is 96 weeks, whereas normal mice have a median lifespan of 118 weeks, Donehower’s team reports in the Jan. 3 Nature.

The researchers couldn’t find any common cause of death in the mutant mice, so they wondered whether the animals suffer from accelerated aging. Further investigation proved that hunch to be right, revealing that these mice develop osteoporosis, impaired wound healing, muscle weakening, organ atrophy, and other age-related conditions much earlier in their lives than rodents normally do.

The mutant mice didn’t age faster in all ways, however. For example, cataracts, joint diseases, and hair loss were not more common in the mutant mice than in normal mice of the same age. Donehower and his colleagues speculate that the conditions seen in the mutant mice result from a p53-mediated reduction in the ability of unspecialized cells to proliferate and keep tissues healthy.

The results “raise the shocking possibility that aging may be a side effect of the natural safeguards that protect us from cancer,” Gerardo Ferbeyre of the University of Montreal and Scott W. Lowe of Cold Spring Harbor (N.Y.) Laboratory in a commentary accompanying the research report.

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