[tt] Modulating p53 extends fly lifespans 20%, one pathway of caloric restriction

[Hughes, James J.]

http://www.eurekalert.org/pub_releases/2007-09/bu-ktl092007.php

Key to longer life (in flies) lies in just 14 brain cells

PROVIDENCE, R.I. [Brown University] -- Two years ago, Brown University
researchers discovered something startling: Decrease the activity of the
cancer-suppressing protein p53 and you can make fruit flies live
significantly longer.

Now the same team reports an intriguing follow-up finding. The p53
protein, they found, may work its lifespan-extending magic in only 14
insulin-producing cells in the fly brain.

"It's quite surprising," said Johannes Bauer, a postdoctoral research
fellow at Brown. "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."

Bauer is the lead author of the research report, published in the
Proceedings of the National Academy of Sciences. Brown biology professor
Stephen Helfand, senior scientist on the project, will discuss the
findings in his keynote address at the Gordon Research Conferences on
the Biology of Aging, to be held Sept. 23-28, 2007, in Les Diablerets,
Switzerland.

P53 is sometimes called "guardian of the genome" for defending cells
against DNA damage. Not enough of the protein can cause cancer; too
much, however, can shorten lifespan. But in 2005, Helfand and his lab
showed that a targeted 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.

But how, exactly, does p53 do its work in the brain? To find out, 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."

###