Feb. 11, 2003 Decreasing meal frequency and caloric intake protects nerve cells from genetically induced damage, delays the onset of Huntington's disease-like symptoms in mice, and prolongs the lives of affected rodents, according to investigators at the National Institute on Aging (NIA) Intramural Research Program. This animal study* is the first to suggest that a change in diet can influence the course of Huntington's disease.
"If reducing food intake has the same effects in humans as it does in mice, then it may be theoretically possible to delay the onset of the disease and extend the lives of Huntington's patients by prescribing low-caloric diets or diets with reduced meal frequency," says Mark Mattson, Ph.D., chief of the NIA's Laboratory of Neurosciences. The study will be published in the Proceedings of the National Academy of Sciences Online Early Edition the week of February 10 (doi:10.1073/pnas.0536856100).
In the study, NIA scientists found that when mutant huntingtin, the abnormal human gene that causes Huntington's disease (HD), was introduced into mice, these mice exhibited clinical signs of the disease, including abnormal metabolism. This altered metabolism, a diabetes-like condition also found in humans with HD, caused the mice to progressively lose weight despite having good appetites. As the mice aged, they developed difficulties controlling their body movements, lost body weight, and eventually died. When the NIA investigators examined the brains of these mice, they discovered that nerve cells in the striatum, a brain region that normally helps control body movements, had degenerated, just like human nerve cells affected by HD. Previously, Dr. Mattson found that reducing the food intake of rats and mice by maintaining them on low-calorie diets or by intermittent fasting--depriving the animals of food for a 24-hour period every other day--can improve glucose metabolism and can protect brain nerve cells in experimental models of Parkinson's disease and stroke. These results appear to hold true for the HD mouse model as well.
In the current study, HD mice maintained on an intermittent fasting diet during adulthood developed clinical signs of the disease about 12 days later than Huntington's mice allowed to eat as much as they wanted. The HD mice on the intermittent fasting diet also lived 10 to 15 percent longer. In addition, the fasting mice were better able to regulate their glucose levels and did not lose body weight as quickly as mice on an unrestricted diet.
NIA investigators found three major differences between brains of the fasting HD mice and the HD mice allowed to eat at will. First, fasting mice had fewer degenerated nerve cells. Second, fasting mice had elevated levels of heat-shock protein-70 (HSP-70), which is known to increase cellular resistance to stress. In contrast, HSP-70 levels were diminished in mice feeding at will. Third, fasting mice had higher levels of BDNF (brain-derived neurotrophic factor), a nerve cell growth factor. BDNF stimulates the growth and survival of nerve cells, suggesting that its elevated presence in response to fasting may protect nerve cells from the adverse effects of the mutant Huntington's gene.
Dr. Mattson hypothesizes that BDNF also has an important role in helping the body regulate energy metabolism. In related NIA studies, mice that have a genetic deficiency in BDNF are diabetic. Increasing BDNF levels in the brain improves glucose regulation in these mice. But it remains unclear whether the abnormal regulation of glucose metabolism associated with HD involves a BDNF pathway. "We're looking at BDNF very carefully," Dr. Mattson said. "We're exploring the idea that increasing the levels of BDNF in the brain can forestall Huntington's disease without a change in diet."
Huntington's disease, a familial disease passed from parent to child, is found in every country of the world. In the United States alone, about 30,000 people have HD; estimates of its prevalence are about 1 in every 10,000 persons. At least 150,000 others have a 50 percent risk of developing the disease passed to them by an affected parent, and thousands more of their relatives live with the possibility that they, too, might develop HD.
The disease results from genetically programmed degeneration of nerve cells, called neurons, in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Specifically affected are cells of the basal ganglia, structures deep within the brain that have many important functions, including coordinating movement. Within the basal ganglia, HD especially targets neurons of the striatum, particularly those in the caudate nuclei and the pallidum. Also affected is the brain's outer surface, or cortex, which controls thought, perception, and memory.
HD can reach the point where speech is slurred and vital functions, such as swallowing, eating, speaking, and especially walking, continue to decline. Some individuals cannot recognize other family members. Many, however, remain aware of their environment and are able to express emotions. Until recently, scientists understood very little about HD and could only watch as the disease continued to pass from generation to generation.
Since the 1930s, investigators have consistently found that laboratory rats and mice live up to 40 percent longer than usual when fed a diet that has at least 30 percent fewer calories than they normally would consume. So far, caloric restriction has increased the lifespans of nearly every animal species studied, including protozoa, fruit flies, mice, and other laboratory animals.
Many gerontologists are particularly intrigued by findings suggesting that calorie-restricted diets have prevented or slowed down development of many age-related diseases and age-related changes in animals, including kidney disease, diabetes, several types of tumors, and declines in immune function.
The NIA leads the Federal effort supporting and conducting biomedical, clinical, social, and behavioral research on aging. This effort includes research into the causes and treatment of Alzheimer's disease, Parkinson's disease, stroke and other neurodegenerative disorders associated with age. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information Web site, http://www.nia.nih.gov .
*W. Duan, Z. Guo, H. Jaing, M. Ware, X-J. Li, and M. P. Mattson, "Dietary Restriction Normalizes Glucose Metabolism and Brain-Derived Neurotrophic Factor Levels, Slows Disease Progression and Increases Survival in Huntington Mutant Mice" Proceedings of the National Academy of Sciences Online Early Edition the week of February 10 ( http://www.pnas.org/cgi/doi:10.1073/pnas.0536856100 ).
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