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Neurodegenerative Disorders and Dietary Interventions for Successful Brain Aging
Posted on: August 19, 2005

While there are many examples of people who live for 100 years or more with little evidence of a decline in brain function, many others are not so fortunate and experience a neurodegenerative disorder, such as Alzheimer disease or Parkinson disease. Although an increasing number of genetic factors that may affect the risk for neurodegenerative disorders are being identified, emerging findings suggest that dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disorder. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons. Epidemiologic findings suggest that high-calorie diets and folic acid deficiency increase the risk for Alzheimer disease and Parkinson disease; studies of animal models of these disorders have shown that dietary restriction (reduced calorie intake or intermittent fasting) and dietary supplementation with folic acid can reduce neuronal damage and improve behavioral outcome. Animal studies have shown that the beneficial effects of dietary restriction on the brain result in part from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although additional studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to age-related neurodegenerative disorders, particularly in persons with a genetic predisposition to such disorders.

Levels of homocysteine in the blood increase with age, and persons with elevated homocysteine levels are at increased risk for vascular disease, heart attack, and stroke. Many patients with Alzheimer disease and Parkinson disease have elevated homocysteine levels; a recent prospective study of the Framingham Heart Study cohort revealed that persons with elevated homocysteine levels are at increased risk for Alzheimer disease. Cells produce homocysteine from the amino acid methionine; homocysteine is metabolized by remethylation to methionine by enzymes that require folic acid and cobalamin (vitamin B12) or is converted to cysteine by cystathionine β-synthase, a pyridoxine (vitamin B6)-dependent enzyme. Patients with a genetic deficiency of cystathionine β-synthase exhibit a clinical phenotype that includes mental retardation, cerebral atrophy, and seizures. Folic acid deficiency can result in hyperhomocysteine- mia, and data suggest that many patients with Alzheimer disease have very low plasma levels of folic acid. Studies of animal models of Alzheimer disease and Parkinson disease have shown that, by decreasing homocysteine levels, dietary folic acid can be neuroprotective. In an amyloid precursor protein mutant mouse model of Alzheimer disease, homocysteine levels increased and hippocampal neurons degenerated when the mice were maintained on a folate-deficient diet. In a model of Parkinson disease, damage to dopaminergic neurons was increased and motor dysfunction was enhanced in mice maintained on a folate-deficient diet. These findings suggest that homocysteine may increase the risk for Alzheimer disease and Parkinson disease by rendering neurons vulnerable to age-related increases in oxidative stress. Folic acid deficiency and homocysteine may endanger neurons by promoting the accumulation of DNA damage by impairing DNA repair. The increased DNA damage may then trigger a form of programmed cell death called apoptosis.


Table 1. Evidence That Calorie Intake Affects the Risk for Alzheimer Disease and Parkinson Disease


Table 2. Evidence That Elevated Homocysteine Levels and Low Folate Levels May Increase the Risk for Alzheimer Disease and Parkinson Disease

Neurodegenerative disorders are proving very difficult to treat, and this fact emphasizes the importance of identifying ways to prevent these diseases. The emerging epidemiologic and experimental data described earlier, together with the fact that dietary restriction consistently increases life span in all mammals studied to date, provide a strong rationale for future studies in humans to determine whether dietary restriction will reduce the risk for age related neurodegenerative disorders. Dietary restriction may not only benefit obese persons (body mass index > 25 kg/m2); it may also reduce the risk for disease in persons whose body weights are within the "normal" range (body mass index between 20 and 25 kg/m2). The current average daily calorie intake of Americans is approximately 2700 for women and more than 3000 for men. When a person reaches a low body mass index (≤20 kg/m2), a daily calorie intake in the range of 1600 to 2200 calories would be expected to promote optimal health. However, randomized, controlled trials with well-defined end points are required to establish an optimum range of calorie intake before recommendations can be confidently made. Because homocysteine level has been established as an independent risk factor for cardiovascular disease and stroke, it is important that homocysteine levels be measured and that (if levels are elevated) diet be appropriately modified to reduce homocysteine levels. Plasma homocysteine concentrations typically range between 5 and 15 μmol/L. The risk for cardiovascular disease, stroke, and Alzheimer disease increases considerably when homocysteine levels are greater than 10 μmol/L; it is reasonable to expect the same is true for Parkinson disease. Dietary supplementation with 400 μg of folic acid can decrease homocysteine levels by 2 to 5 μmol/L in most persons; thus, a folic acid concentration of 15 μmol/L could mean a two to fourfold decrease in risk for Alzheimer disease.. An increasing number of genetic factors that either cause or increase the risk for neurodegenerative disorders are being identified. Genetic mutations can cause rare forms of Alzheimer disease (amyloid precursor protein, presenilin 1, and presenilin 2), Parkinson disease (α-synuclein and parkin), Huntington disease (huntingtin), and amyotrophic lateral sclerosis (Cu/Zn-superoxide dismutase). Data from transgenic mice expressing a disease-causing mutation suggest that the course of some of these inherited disorders can be modified by dietary factors. On the other hand, dietary restriction had no beneficial effect on disease onset and actually accelerated disease progression in Cu/Zn-SOD mutant mice. Dietary modifications may be particularly useful in persons who may have a genetic predisposition for a neurodegenerative disorder. Examples include persons with an ?4 allele of apolipoprotein E who are at increased risk for Alzheimer disease and those with the C677T polymorphism in methyl tetrahydrofolate reductase who have elevated homocysteine levels. Although we have focused on dietary restriction and folate, many different dietary factors probably influence the health of the brain. For example, animal studies have suggested that creatine, antioxidants (such as vitamin E and flavonoids), and anti-inflammatory agents have neuroprotective actions. On the other hand, emerging evidence suggests that consumption of diets high in saturated fats and cholesterol can increase the risk for Alzheimer disease and amyotrophic lateral sclerosis. Collectively, the available data suggest that a brain-healthy diet is very similar to a heart-healthy diet. Specific dietary components may affect brain functions. For example, data suggest that tryptophan (a precursor of the neurotransmitter serotonin) can affect mood, whereas dietary choline (a precursor of acetylcholine) can affect learning and memory. While the emerging data suggest that dietary factors can affect the risk for age-related neurodegenerative disorders (Tables 1 and 2), it is unclear whether they will have any major effect on the course of these disorders in symptomatic patients. No current evidence shows that dietary restriction or folic acid supplementation will benefit symptomatic patients, and we have not found any clear benefit of short-term dietary restriction (days to weeks) in animal models of neurodegenerative disorders. However, as methods for early diagnosis of Alzheimer disease and Parkinson disease improve, it will be of considerable interest to perform clinical trials of caloric restriction in patients who are in early preclinical stage of the disease. Clinical trials of folic acid in patients with Alzheimer disease are in progress and should provide an answer as to whether this approach will be beneficial.

Source: Mark P. Mattson, PhD; Gene-Diet Interactions in Brain Aging and Neurodegenerative Disorders; (2003), Annals of Internal Medicine; September 2; Volume 139; Number 5.
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