X-Message-Number: 27395
Date: Sat, 26 Nov 2005 20:23:02 -0800 (PST)
From: Doug Skrecky <>
Subject: P53 accelerates fly aging as well

Decrease Cancer-suppressing Protein Activity, Increase Life Span

  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
  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
  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
  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."

Curr Biol 2005 Nov 22;15(22):2063-8
Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila
melanogaster Extends Life Span.
  Hyperactivation of p53 leads to a reduction in tumor formation and an
unexpected shortening of life span in two different model systems . The
decreased life span occurs with signs of accelerated aging, such as
osteoporosis, reduction in body weight, atrophy of organs, decreased
stress resistance, and depletion of hematopoietic stem cells. These
observations suggest a role for p53 in the determination of life span and
the speculation that decreasing p53 activity may result in positive
effects on some aging phenotypes . In this report, we show that
expression of dominant-negative versions of Drosophila melanogaster p53 in
adult neurons extends life span and increases genotoxic stress resistance
in the fly. Consistent with this, a naturally occurring allele with
decreased p53 activity has been associated with extended survival in
humans . Expression of the dominant-negative Drosophila
melanogaster p53 constructs does not further increase the extended life
span of flies that are calorie restricted, suggesting that a decrease in
p53 activity may mediate a component of the calorie-restriction life
span-extending pathway in flies.

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