The cancer suppressing P53 is sometimes called "guardian of the genome" for it defends cells against DNA damage. Not enough of the protein can cause cancer, but too much can shorten lifespan.
But in 2005, Brown University biology professor Stephen Helfand, senior author and his lab showed that a targetted decrease of p53 in fruit flies - a decrease specifically in their brain cells - allowed flies to live healthy lives that were as much as 58 percent longer.
"It's quite surprising, in the fruit fly brain, there are tens of thousands of cells. But we found that it takes a reduction of p53 activity in only 14 of those brain cells to extend lifespan. It was like finding a needle in the haystack - a very small needle at that," said Johannes Bauer, a postdoctoral research fellow at Brown.
To find out how exactly the protein works in the brain, Bauer spent a year conducting painstaking experiments. He'd take a batch of young flies, each genetically altered to reduce p53 activity in a small portion of their nervous systems, and watch the flies age. Time and again, the flies lived for about two months - the average lifespan for these insects.
But when Bauer manipulated a cluster of 14 insulin-producing cells in their brains, the flies lived about 15 to 20 percent longer. Bauer ran the experiment again and again - and got the same result.
Bauer and Helfand then wanted to know if this was caloric restriction at work. Studies have shown that low-calorie diets can significantly increase the lifespan of flies, worms, mice and rats. The phenomenon is of intense interest to researchers who study aging. They want to know if caloric restriction works in people and if drugs could be made to mimic its effects.
So researchers restricted the diets of the flies and ran the same experiments. The calorie-restricted flies didn't live any longer when p53 was reduced in the insulin-producing cells. This evidence supports the notion that p53 reduction is one of the direct effects of caloric restriction.
Even more intriguing, Helfand said, is the fact that the 14 insulin-producing cells that seem to be critical for lifespan extension are the equivalent of beta cells in the human pancreas. Beta cells make and release insulin, the hormone that controls the level of glucose in the blood. The research team found that when p53 activity drops, so does insulin-responsive activity in the fat body, the major metabolic organ in the fruit fly.
"Our findings suggest that lifespan regulation is linked to metabolic regulation," said Helfand, a professor in Brown's Department of Molecular Biology, Cell Biology and Biochemistry.
"The findings also suggest a tight connection between aging and diabetes. And we may have a new laboratory model for studying diabetes and other metabolic diseases," Helfand added.
The study is published in the proceedings of the National Academy of Sciences.