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New Clues into the Aging Brain

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Duke Health News 919-660-1306

DURHAM, N.C. -- Researchers have discovered a potential
reason why learning and memory function declines with age:
aging brains produce lower levels of critical growth factors
that fuel the birth of new neurons in the hippocampus, the
brain's learning and memory center, according to a study in
rats.

The researchers said their findings suggest that drugs to
enhance such growth factors, or other preventive therapies,
might sustain neuronal growth and thus maintain learning and
memory in older people.

The production of new neurons in the hippocampus was known
to slow dramatically by middle age in rats -- the equivalent of
45 to 50 years in humans -- said the researchers from Duke
University Medical Center and the Durham Veterans Affairs
Medical Center (VAMC). But the molecular basis for this decline
has remained a mystery, they said.

In the Aug. 15, 2005, issue of the journal GLIA, published
early
on line
, the Duke/VAMC team reported that the levels of
three critical growth factors -- fibroblast growth factor-2
(FGF-2), insulin-like growth factor -1 (IGF-1) and vascular
endothelial growth factor (VEGF) -- decline dramatically in the
middle-aged hippocampus of rats. These growth factors are
secreted mostly by supporting cells in the brain, called
astrocytes, and they are critical for enabling stem cells to
produce new neurons.

Their results illuminate the mechanism behind the declining
production of new neurons in the dentate gyrus region of the
hippocampus, where learning and memory occur, said Dr. Ashok K.
Shetty, a Research professor of neurosurgery and lead author of
the study. Co-authors are Bharathi Hattiangady (Ph.D.) and
Geetha Shetty (M.S.).

Scientists had previously speculated that newly born cells
in the aging hippocampus were failing to reach their potential
for one of three reasons: they were differentiating into mostly
non-neuronal cells; they were not migrating to the proper brain
regions; or they were failing to survive long enough. However,
the Duke/VAMC team showed in an earlier study that newly born
cells in middle-aged and aged rats demonstrated none of these
defective behaviors. They reported these initial results in the
January 15, 2005, issue of the European Journal of
Neuroscience.

"We determined that there is no major, fundamental defect in
how newly born cells behave in the aging hippocampus," said
Shetty. "There is simply less of the growth factors that drive
stem cells to produce new neurons. This is encouraging news
because it means we can employ strategies to increase the
levels of these growth factors and see whether an increased
production of new neurons can be sustained in the aging
hippocampus."

For example, regular physical exercise and exposure to
enriching environments have both been shown to boost new neuron
production in the hippocampus, said Shetty. While these
strategies will not halt the decline, they may slow it
considerably, he said.

Young adult rat brains (equivalent to 20-35 years of age in
humans) produce approximately 2,000-3,000 new neurons per day
in the hippocampus. In contrast, by middle age (45-50 years of
age), only 500-700 new neurons are born each day. From that
point on there is little decline in neuron production, the
study showed.

However, the numbers of supporting "astrocytes" that produce
the growth factor FGF-2 continue to decline with advancing age,
the study showed. Moreover, a fraction of newly born neurons in
older brains show retarded growth of dendrites – the
tentacle-like structures that reach out to and connect with
other neurons to exchange messages. Such changes in new neuron
numbers and growth may contribute to delayed memory processes
as the brain ages, said Shetty.

Shetty said his research is the first to examine long-term
survival of newly born neurons in aging brains. Most studies
have focused on the production of new neurons at a specific age
rather than neuronal behavior over a period of time.

In their study, Shetty's team tracked new neurons in young,
middle-aged and old rats for five months as the cells divided,
matured, differentiated and migrated. They observed the
neurons' behavior and measured the levels of growth factors at
each age to determine how new neuron production and development
progressed in each age group.

Future studies will focus on developing strategies to
sustain increased neuron production in the aged brain and
examining whether increased production of new neurons in the
senescent hippocampus will improve learning and memory function
in the aged.

Their research was supported by a grant from the National
Institute for Aging of the National Institutes of Health.

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