Brain benefits: Severe Calorie Restriction Has Some Positives
By Gila Z. Reckess - Washington University Record, Washington

November 5, 2004

Severe calorie restriction prevents certain aging-related changes in
the brain, including the accumulation of free radicals and
impairments in coordination and strength, according to a mouse study
at the School of Medicine.
However, the dietary changes did not seem to prevent mice from
developing some cognitive deficits associated with age, such as
declines in memory.

The study was presented Oct. 24 at "Neuroscience 2004," the Society
for Neuroscience's 34th annual meeting in San Diego.

"Our findings help us understand the processes underlying both normal
aging and calorie-restriction benefits," said principal investigator
Laura L. Dugan, M.D., associate professor of neurology, of medicine
and of anatomy and neurobiology. "If some aspects of aging are
influenced by free-radical damage, we may be able to prevent or
reverse these impairments."

Though numerous studies have shown severe calorie restriction helps
animals live longer and resist some effects of aging, scientists
still do not know why. One theory suggests a restrictive diet
decreases the effect of free-radical damage.

Free radicals are chemically reactive molecules produced either as
byproducts of the body's natural processes or as a result of stress
from the environment, like smog or sunlight.

It's normal to have some free radicals, but scientists think
accumulating too many may cause cell damage and contribute to a
variety of diseases ranging from stroke to cancer. Antioxidants like
vitamins C and E help prevent free radicals from wreaking too much
havoc.

Because there is evidence that both antioxidants and calorie
restriction increase lifespan and reduce aging-related diseases,
Dugan and her colleagues hypothesized that calorie restriction, like
antioxidants, helps protect the brain against free-radical damage.

To test its theory, the team compared young and old mice fed normal
diets with old mice fed 35 percent fewer calories starting at about 1
year old. One year for mice is roughly the physiological equivalent
of 40 years for humans.

The animals were injected with a fluorescent dye that changes color
when it interacts with a free radical called superoxide. The
researchers studied brain slices from the three groups to measure
levels of superoxide in specific areas of the brain.

Old mice fed normal diets had significantly more superoxide in
several regions of the brain than their young counterparts,
particularly in the substantia nigra, a region implicated in
Parkinson's disease. But calorie-restricted old mice did not.

"For the last 20 years, there have been studies that suggest free
radicals, particularly superoxide, are involved in cumulative damage
with aging and that the nervous system may be one of the most
vulnerable targets," Dugan said. "Most of that evidence has been
indirect, though.

"By using sensitive, state-of-the-art methods, we were actually able
to see which cells are producing excess levels of free radicals."

Dugan and her colleagues then evaluated animals that retained low
levels of superoxide to see if they maintained their ability to do a
range of behavioral tasks. They found that old, calorie-restricted
animals were just as good as young animals at tests of grip strength,
coordination and flexibility, such as quickly climbing down a pole
and hanging upside down from a screen.

Old animals fed normal diets were significantly worse at these tasks.


But calorie restriction had almost no effect on several drills used
to measure pure cognitive performance. In one test of spatial
learning and memory called the "Morris water maze," mice are placed
in a pool of opaque water and have to learn to find a submerged
platform in order to climb out of the pool.

Old mice, regardless of their diet, performed much worse than young
mice on this task when they were required to learn different
consecutive platform locations.

Calorie restriction also did not result in improved performance on a
fear-conditioning task. When a tone is matched with an electric
shock, young mice eventually learn to freeze when they hear the tone.


Old mice, regardless of diet, were much worse at this. The
researchers noticed a trend that suggests mice on calorie-restriction
diets were even worse than old mice on normal diets.

The researchers are not sure whether this poor performance is a sign
of learning deficits or of hearing problems that often develop in
older mice.

"It's interesting to me that calorie restriction does not seem to
reverse age-related cognitive impairments," said David F. Wozniak,
Ph.D., research associate professor of psychiatry, who supervised the
behavioral studies. "We need to do bigger, more extensive studies to
fully understand these findings, but the bottom line is that you
don't get uniformly positive results from calorie restriction.

"I don't think anyone has really stressed this point before,
particularly with regard to the lack of effects on cognition."

In addition to validating these findings in larger groups of mice,
the team is also exploring the possibility that adjusting other
dietary factors may enhance and add to the calorie-restriction diet's
benefits. The researchers have also begun testing the protective
effects of potent antioxidants on aging mice fed normal diets to see
whether they too can prevent or reverse some of the effects of aging.


"We believe sensitive signaling pathways that are particularly
important in the brain are disrupted by high levels of free radicals
and that these disruptions may explain why, under normal
circumstances, brain function declines over time," Dugan said.
"Fortunately, it would be much easier to reverse a misregulation in
signaling than it would to reverse cell damage."

SOURCE: Washington University Record, Washington
http://record.wustl.edu/news/page/normal/4183.html

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