Neurodegenerative disorders are increasingly common as life expectancy increases.
Effective means of preventing and treating cardiovascular disease, diabetes, and many types of cancer have been developed during the past 50 years, resulting in a striking increase in the number of persons older than 70 years of age.
In addition to advances in the management of chronic disease, the demographic shift that resulted from altered birth rates in the 1940s and 1950s (leading to the "Baby Boomer" generation) has contributed to the increased number of older adults.
The result is a progressive increase in the number of people with Alzheimer disease and Parkinson disease, two incurable brain disorders that take a heavy toll on patients and their relatives, as well as the health care system.
Alzheimer disease involves the progressive degeneration and death of neurons in brain regions, such as the hippocampus and basal forebrain that are involved in learning, memory, and emotional behaviors.
Parkinson disease involves the progressive degeneration of neurons in the substantia nigra, resulting in the patient's inability to control body movements.
Although the cause of most cases of Alzheimer disease and Parkinson disease is not known, some cases result from a specific genetic abnormality.
For example, mutations in three different genes (amyloid precursor protein, presenilin 1, and presenilin 2) cause early onset, dominantly inherited Alzheimer disease; mutations in α-synuclein cause some cases of Parkinson disease.
Although Alzheimer disease and Parkinson disease are usually considered as distinct disorders in which different populations of neurons in the brain degenerate, they share several features of the neurodegenerative process.
Both disorders involve increased oxidative stress, metabolic impairment, and abnormal protein aggregation.
An early event in Alzheimer disease, which is believed to trigger synaptic dysfunction and neuronal death, is increased production and aggregation of β-amyloid peptide.
This process occurs mainly in regions of the brain, such as the hippocampus and associated cortical structures, that are involved in learning and memory processes.
During the process of aggregation, the amyloid peptide generates reactive oxygen species, resulting in membrane lipid peroxidation and impairment of membrane ion-motive adenosine triphosphatases and glucose transporters.
By this mechanism, amyloid disrupts cellular ion homeostasis and renders neurons vulnerable to excitotoxicity and apoptosis.
Mitochondrial dysfunction involving impairment of complex I and increased oxyradical production play major roles in the degeneration of dopaminergic neurons in Parkinson disease.
Therefore, antioxidants and agents that preserve mitochondrial function can improve outcome, as has been demonstrated in animal models of Parkinson disease.
The factors that initiate the degeneration of dopaminergic neurons in the substantia nigra of patients with Parkinson disease is unclear.
Evidence suggests roles for environmental toxins, such as pesticides and trace metals, in combination with the increased oxidative stress associated with the aging process.
A role for environmental neurotoxins in Parkinson disease is strengthened by the fact that several toxins, including MPTP (1-methyl-4-phenyl-1,2,3,6-tetrapyridine) and rotenone, can induce Parkinson-like clinical symptoms and neuropathologic changes in rodents, nonhuman primates, and humans.
Overeating is a major modifiable risk factor for several age-related diseases, including cardiovascular disease and type 2 diabetes mellitus.
Recent findings suggest that calorie intake also influences the risk for Alzheimer disease and Parkinson disease.
A prospective study of a large cohort of people in New York City revealed that those with low calorie or low-fat diets had significantly lower risks for Alzheimer disease and Parkinson disease than did those with higher calorie intake.
Of interest, the risks for Alzheimer disease and Parkinson disease were more strongly correlated with calorie intake than with weight or body mass index.
One interpretation of the latter finding is that persons who have a metabolic constitution that allows them to maintain a normal body weight, even with a high caloric intake, may be at increased risk for Alzheimer disease and Parkinson disease.
Dietary restriction induces a mild cellular stress response in neurons as a result of its effects on energy availability and activity in neuronal circuits.
Neurons respond to this stress by increasing the production of proteins that enhance cellular stress resistance; examples include neurotrophic factors, protein chaperones (such as heat-shock proteins), and antiapoptotic proteins (such as Bcl-2).
A similar mechanism may stimulate neurogenesis and synaptic plasticity.
Peripheral effects of dietary restriction may also benefit the brain.
For example, enhanced insulin sensitivity and decreased homocysteine and cholesterol levels would be expected to prevent age-related damage to cerebral blood vessels and may also have more direct beneficial effects on neurons and glia.
A longitudinal, prospective, population-based study evaluated 2459 community-dwelling Yoruba residents of Nigeria and 2147 community-dwelling, genetically related African-American residents of Indianapolis.
The age adjusted incidence of dementia was significantly higher in the Indiana cohort that suggests the involvement of environmental factors in disease risk; different calorie intake in the two study samples (low in Nigeria and high in Indiana) is one possible factor.
Although not established in the latter study, one clear difference between the two study samples was calorie intake (low in Nigeria and high in Indiana).
Strong evidence that calorie intake may affect the risk for neurodegenerative disorders comes from animal studies.
Rats maintained on dietary restriction for 2 to 4 months exhibit increased resistance of hippocampal neurons to degeneration caused by the amnestic toxin kainic acid; this resistance led to a profound deficit in learning and memory in rats fed ad libitum but little or no memory deficit in rats maintained on dietary restriction.
In another study, the vulnerability of hippocampal and cortical neurons to excitotoxicity and apoptosis was decreased in presenilin 1 mutant mice maintained on dietary restriction.
In a model of Parkinson disease, the vulnerability of midbrain dopaminergic neurons to MPTP toxicity was decreased and motor function was improved by dietary restriction.
Of interest, dietary restriction not only is neuroprotective; it also stimulates neural stem cells in the brain to produce new nerve cells and might thereby promote the reconstruction of neuronal circuits damaged by injury or disease.
Recent studies of rodents have revealed cellular and molecular mechanisms underlying the beneficial effects of dietary restriction on the brain (Figure 1).
Dietary restriction increases the production of neurotrophic factors, particularly brain-derived neurotrophic factor in many different regions of the brain.
Brain-derived neurotrophic factor can enhance learning and memory, can protect neurons against oxidative and metabolic insults, and can stimulate neurogenesis; these actions may protect neurons against age-related neurodegenerative disorders.
Dietary restriction also induces the production of protein chaperones, such as heat-shock protein 70 and glucose-regulated protein 78, which are known to help cells resist various insults.
Therefore, it appears that dietary restriction promotes neuronal survival, plasticity, and even neurogenesis by inducing a mild cellular stress response that involves activation of genes that encode proteins designed to promote neuronal growth and survival (Figure 1).