UK Study Finds Decreasing Food Intake Could Shield Against Brain Disorders

January 04, 1999

LEXINGTON, KY (Jan. 4, 1999) - Decreasing daily food intake could help ward off several age-related brain disorders such as Alzheimer's disease and Parkinson's disease, according to findings of a University of Kentucky Sanders-Brown Center on Aging research team led by Mark Mattson, Ph.D., UK professor of anatomy and neurobiology.

Reported in the January issue of the Annals of Neurology, the findings show that eating less made nerve cells in the brain more resistant to deterioriation and death in animal models of neurodegenerative disorders.

"Previous studies have shown that high levels of food intake are associated with increased risk for cardiovascular disease, diabetes and cancer, but these findings are the first to suggest that reduced calorie intake also may help shield the brain," Mattson said.

In the study, one group of rats was fed every other day, consuming 30 percent fewer calories than a second group of rats, which ate a normal amount of food.

Then two different brain toxins were administered: kainic acid, which destroys nerve cells in the hippocampus, a brain region involved in learning and memory; and 3-nitropropionic acid, which destroys nerve cells in the striatum, a brain region associated with control of body movements. Nerve cells in the hippocampus are destroyed in people with Alzheimer's disease and in many stroke patients, and nerve cell circuits in the striatum are damaged in people with Huntington's disease and Parkinson's disease.

In the rats whose diet was restricted, the kainic acid caused much less damage to hippocampal nerve cells than in those whose diet was not restricted. Also, the kainic acid caused severe learning and memory deficits in the control group, but little or no learning and memory deficits in the dietary-restricted rats.

The results were even more obvious in the model of Parkinson's disease and Huntington's disease. The toxin caused severe motor problems in the normally fed rats, but had essentially no effect on the rats that had been on the reduced calorie diet.

"The beneficial effects of the dietary restriction were striking," Mattson said. "The importance of these studies is that they demonstrate that food restriction can reduce the vulnerability of nerve cells in the brain to insults relevant to several different human age-related disorders."

Mattson's previous research showed that free radicals, highly reactive oxygen-based molecules that can cause mutations in DNA and damage to proteins in cells, play a major role in the damage to nerve cells that occurs in age-related neurodegenerative disorders such as Alzheimer's disease, stroke and Parkinson's disease.

"Formal studies of calorie intake and neurodegenerative disorders have not been performed in humans, but there appears to be a strong correlation between per capita food intake and the incidence of age-related neurodegenerative disorders," Mattson said. For example, people who live in Japan and China consume less food than Americans and Canadians, and have a lower apparent incidence of Alzheimer's disease.

For people between the ages of 20 and 50, Mattson recommends a calorie intake between 1,800-2,200 per day. "That's not starvation, but it is way lower than the average calorie intake," he said.

Additional research highlights the relevance of these findings to humans with Alzheimer's disease. Although most cases of Alzheimer's disease have no clear genetic basis, a small number of cases is caused by mutations in a gene called presenilin-1. Persons who inherit a defective presenilin-1 gene have a 100 percent chance of developing Alzheimer's disease at an early age (usually when they are 30-50 years old).

In collaboration with George Martin, Ph.D., and Bryce Sopher, Ph.D., of the University of Washington Medical Center in Seattle, Mattson introduced the defective human presenilin-1 gene that causes Alzheimer's disease into a fertilized mouse egg. The mouse that developed from the egg expressed the defective gene in all of its cells, including nerve cells in the brain.

Qing Guo, Ph.D., a postdoctoral scientist working in Mattson's laboratory, has studied these "Alzheimer's mice" and found that nerve cells in the hippocampus of their brains are hypersensitive to damage caused by kainic acid. The nerve cells suffer from an inability to regulate calcium levels properly, and from excessive production of free radicals. Drugs that stabilize calcium levels, and antioxidants such as vitamin E, protected the nerve cells against the "endangering" action of the presenilin-1 mutation.

These findings, published in this month's issue of the journal Nature Medicine, establish a direct link between a genetic defect that causes Alzheimer's disease and excitotoxic neuronal degeneration. Mattson's group is performing experiments to determine whether a reduced calorie diet can counteract the disease-causing effect of the defective presenilin-1 gene.

The studies were funded by the National Institute on Aging and the National Institute on Neurological Disorders and Stroke. Mattson and his research team, which includes Anna Bruce-Keller, Ph.D., research associate, and Gloria Umberger, graduate student, are trying to identify the specific molecular changes that occur in the brain cells of rats maintained on a calorie-restricted diet. Already they have evidence that certain genes are turned on, and that those genes may act to protect the nerve cells against free radicals.

University of Kentucky Medical Center

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