Brain's genes begin to deteriorate at 40!

From the WSJ:

HEALTH
As Early as Age 40, Genes in the Brain Begin to Deteriorate
By LAURA JOHANNES, Staff Reporter of THE WALL STREET JOURNAL
June 10, 2004; Page D1

Harvard University researchers found that 20 genes critical for
learning and memory begin to decline in function as early as age 40,
pointing the way for further research aimed at tackling the mental
infirmities that come with growing old.

The Harvard work, released yesterday in the online edition of Nature,
is the first major study to use a “genetic signature” to study
brain-function decline in normal aging.

A genetic signature is a recent scientific innovation that measures the
activity level of thousands of genes — determining which are working
hard, which are minimally active, and which are idle in controlling the
production of proteins, which are the main actors in all microscopic
bodily functions, including work performed by the brain.

The researchers studied well-preserved brain tissue from 30 people,
aged 26 to 106 at the time of death. The changes they found occurred in
a wide variety of genes, with functions that range from regulating
sleep to metabolizing fat. But most interesting was a marked decline in
function among 20 genes involved in learning, memory and the
plasticity, or flexibility, of brain function. As the subjects aged,
these genes became damaged, reducing their effectiveness. “Some genes
begin to decline much earlier than expected, as early as the early
40s,” says senior author Bruce Yanker, a professor of neurology and
neuroscience at Harvard Medical School and Children’s Hospital in
Boston.

The Harvard researchers believe the damage is caused by exposure to
toxins, including unstable molecules called free radicals. Free
radicals are created both by the body’s own energy-producing processes
and by exposure to environmental hazards. Antioxidants such as vitamins
C and E are believed to protect the body against the ravages of free
radicals. Antioxidants could, in theory, help the brain protect itself
from age-related damage, Dr. Yanker says, but there’s still no proof
that it would work.

In the older brain samples, the researchers found that genes whose job
is to protect and repair neurons from damage had been working overtime.
That compensatory activity may delay the effects of the damage, and
could explain why damage to cognitive function often doesn’t show up
until later in life, and why some individuals retain their intellectual
acumen longer than others. The effectiveness of the compensatory
activity “may be a function of genetics, and lifestyle, probably a
combination of both,” Dr. Yanker says.

Their search was limited to 11,000 of the body’s 30,000 genes because
those were the only genes available on the microchip used to perform
the computerized search — the best available at the time the work
began two years ago. The researchers found that 4% of the 11,000 genes
changed in activity with age. Some became less active, and others
stepped up their activity. The changes began in the early 40s and
varied widely from person to person until age 71. Over that age, the
gene activity pattern was largely the same from one person to the next.

No Immediate Cures

The findings don’t in themselves offer immediate cures to age-related
mental decline, Dr. Yanker says, but are a “treasure trove” of
information that will help researchers find the most promising avenues
of study.

The research “adds to our understanding of the genetic factors that
might contribute to memory loss,” says Gary Small, director of the
Center on Aging at the University of California, Los Angeles. He adds
that the fact that the genetic changes start early “emphasizes how
important it is to begin lifestyle changes early.” Dr. Small is
researching the effect of lifestyle changes, such as a healthy diet and
exercise, on age-related declines in cognitive functions.

In his work, Dr. Small found that as little as two weeks on a program
that includes exercise, stress reduction, and a healthy diet with
antioxidants such as Japanese green tea, appears helpful for brain
function. He found that subjects required less cerebral effort — as
measured by brain scans of neuronal activity — to complete the same
mental tasks than they did before they began the healthy program.
Healthy diets are already widely believed to reduce fat buildup, which
can increase the risk of strokes, Dr. Small says. But good nutrition
also may have other, not yet understood effects on gene function.

Studying Enzymes

Another possible approach is to try to mitigate the gene damage through
medications. The Harvard researchers found that a very promising area
of study is an enzyme used by the body to repair DNA damage, called
oxoguanine DNA glycosylase. The enzyme was already known to the
scientific community, but the Harvard researchers found that it was
very effective in repairing genetic damages in brain neurons placed in
a petri dish.

“If one had, for example, a drug to stimulate the activity of this
enzyme, one might be able to repair the DNA” and slow the mental
decline that happens with age, Dr. Yanker says.

The research, funded by the National Institutes of Health and anonymous
philanthropic donations, was done using a gene chip from Affymetrix
Inc., of Santa Clara, Calif. The Harvard researchers are repeating the
study with all 30,000 human genes on a newer chip from Affymetrix. The
scientists also plan to study gene changes in people with Alzheimer’s
disease, and compare them to the changes found in normal aging.

Write to Laura Johannes at laura.johannes@wsj.com

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