Critical role of p53 gene

Nov 21 2005

Fruit flies can live significantly longer, and remain healthy, when activity of the fly version of the tumor-suppressing protein p53 is reduced in nerve cells.

Published in Current Biology, the results shed important new light on the role this "protector of the genome" plays in aging and point to p53 as a viable target for anti-aging drugs.

The p53 gene plays a critical role in the body. It protects human cells by producing a protein that triggers apoptosis, or cell suicide, when DNA is badly damaged. This prevents the spread of genetic mutations and the formation of cancer. When the p53 gene is damaged or missing, cancer may result. In fact, more than 50 percent of human cancers carry p53 mutations.

There is, however, a flip side to this guardian gene. When p53 is hyperactive - pumping out higher-than-normal levels of tumor-suppressing protein - it accelerates aging and shortens life span in mice.

"What this new work shows is that there is a 'golden mean' with p53," said Stephen Helfand, a Brown University biologist who served as senior scientist for the study. "By targeting a decrease in p53 protein, specifically in neurons, we can extend healthy life span in fruit flies. This is an important conceptual shift. Decreasing the activity of p53 can have positive effects on aging."

Helfand, now a professor in Brown's Department of Molecular Biology, Cell Biology and Bio-chemistry, oversaw the project while at the University of Connecticut Health Center. To test speculation that tinkering with p53 could produce life-extending results, Helfand and colleagues designed an experiment using fruit flies - which share thousands of genes with humans and also express a version of the p53 gene.

The team engineered a line of flies that carried a mutant version of p53. When flies had the altered gene switched on, they produced a mutant form of the p53 protein that deactivated normal p53 protein. But the affect was targeted to occur only in neurons. Why single out neurons? Because adult nerve cells don't divide - making them much less prone to cancer.

Results showed that adult mutant flies lived up to 58 percent longer - an average of 60 days, up from the average of 38 days. At the same time, the flies appeared healthy, continuing to feed, move and reproduce normally.

The experiment does not explain why targeted, decreased p53 activity extends healthy life span. But it suggests a mechanism - caloric restriction, a biochemical cascade proven to slow aging. To test the hypothesis, the specially engineered flies were fed a calorie-diluted diet. But the flies didn't live any longer, suggesting that this pathway was, indeed, already in play.

"We believe that p53 is part of the caloric restriction life span extension pathway," Helfand said. "It's not the entire explanation, but it appears to play a major role."