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A study
in rats matching the activity of 146 genes with brain aging and impaired
learning and memory produces a new picture of brain aging and cognitive
impairment. The research, by scientists at the University of Kentucky,
uses powerful new gene microarray technology in a novel way to match
gene activity with actual behavioral and cognitive performance over
time, resulting in the identification of this wide range of aging-
and cognition-related genes (ACRGs). Importantly, the changes in gene
activity had mostly begun in the mid-life of the rats, suggesting
that changes in gene activity in the brain in early adulthood might
set off cellular or biological changes that could affect how the brain
works later in life.
The
report (embargoed for release until May 7, 2003, at 5 p.m. ET) appears
in the May 1, 2003, issue of The
Journal of Neuroscience. It provides more information on genes
already linked to aging, including some involved in inflammation and
oxidative stress, and also describes additional areas in which gene
activity might play a role in brain aging. These include declines
in energy metabolism in cells and changes in the activity of neurons
(nerve cells) in the brain and their ability to make new connections
with each other. In addition, other areas in which genes appear to
play an influential role involve increases in cellular calcium levels
which could trigger cell death, cholesterol synthesis (also implicated
in Alzheimer's disease in other research), iron metabolism and the
breakdown of the insulating myelin sheaths that when intact facilitate
efficient communication among neurons.
The
study was conducted by a team led by Philip W. Landfield, Ph.D., and
colleagues Eric M. Blalock, Kuey-Chu Chen, Keith Sharrow, Thomas C.
Foster, and Nada M. Porter at the University of Kentucky, Lexington,
and James P. Herman at the University of Cincinnati, Ohio. It was
supported primarily by the National Institute on Aging (NIA). Additional
support was provided by the National Institute of Mental Health (NIMH).
Both are parts of the National Institutes of Health at the U.S. Department
of Health and Human Services.
"Gene microarrays, which can measure activity of thousands of
genes simultaneously, provide the most advanced genomics technology.
This has allowed us to do what no other study has done before - use
large numbers of microarrays to relate genes and behavior over the
lifespan of the animals on a scale that can identify most of the important
players," says Landfield. "The good news is that we have
a new, more comprehensive model of brain aging at the genetic level;
the downside is that this model shows just how very complex that process
may be."
"This
study makes it very clear that it is not a single gene or even several
genes that are responsible for brain aging. Here, we are presented
a picture of age-related changes in multiple cellular pathways and
systems which interact with one another to change the brain's structure
and how it functions," notes Brad Wise, Ph.D., Program Director,
Fundamental Neuroscience, NIA.
In the
study, young, middle-aged, and aged rats were trained on two memory
tasks, learning to navigate a water maze and remembering familiar
objects in their cages. After training, the scientists examined the
brain tissue of the rats, specifically the hippocampus, an area associated
with memory and cognition. RNA (ribonucleic acid, which carries out
the DNA's instructions for making proteins) was isolated from each
rat and selectively bound to a separate chip containing over 8,700
fragments of genes to generate gene expression, or activity, profiles.
One important step was further refining of the analyses to reduce
false positives and false negatives while statistically assessing
changes in gene activity. The researchers then homed in on genes that
changed with aging and, finally, on genes involved in age-related
changes in the performance of the rats on the two memory tests. Ultimately,
they zeroed in on 146 ACRGs (aging- and cognition-related genes),
which were then assigned to functional categories representing different
cellular processes in the brain. A complete listing of the genes and
what they do appears in the original journal article.
Offering
one model of brain aging, the researchers suggest that loss of neuronal
processes and the compromise of their insulating myelin sheaths may
trigger brain inflammation, eventually leading to loss of the cells'
function. The changes in gene expression for the most part were seen
in mid-life, before cognition was impaired, suggesting that changes
in gene activity in the brain in early adulthood might initiate cellular
or biological changes that could lead to functional changes later
in life.
The
NIA leads the Federal effort to support and conduct basic, clinical,
and social and behavioral studies on aging and on age-related memory
change and dementia. It supports the Alzheimer's Disease Education
and Referral (ADEAR) Center, which provides information on research
on age-related memory change and Alzheimer's disease. ADEAR's website
can be viewed at www.alzheimers.org. ADEAR may also be contacted at
1-800-438-4380. Press releases, fact sheets, and other materials about
aging and aging research can be viewed at the NIA's general information
website www.nia.nih.gov.
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