Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type‐2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cummulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain‐derived neurotrophic factor (BDNF), protein chaperones such as heat‐shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2‐deoxy‐d‐glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.

Abbreviations used

AD Alzheimer's disease ALS amyotrophic lateral sclerosis APP amyloid precursor protein BDNF brain‐derived neurotrophic factor BrdU bromodeoxyuridine CNTF ciliary neurotrophic factor 2‐DG 2‐deoxy‐ d ‐glucose DR dietary restriction HD Huntington's disease HSP heat‐shock protein IRS‐1 insulin receptor substrate‐1 MPTP 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine NT‐3 neurotrophin‐3 PD Parkinson's disease SOD superoxide dismutase

The impact of calorie intake on lifespan and susceptibility to disease The mean and maximum lifespans of a range of organisms including yeast, roundworms, rodents and monkeys can be increased by up to 50% simply by reducing their calorie intake (Weindruch and Sohal 1997; Lin et al. 2000; Sze et al. 2000; NIA primate study, unpublished data). Caloric restriction reduces the incidence of age‐related cancers, cardiovascular disease and deficits in immune function in rodents (Weindruch and Sohal 1997). Conversely, overeating is a risk factor for cardiovascular disease, many types of cancers, type‐2 diabetes and stroke (Lebovitz 1999; Levi 1999; Brochu et al. 2000). Less appreciated is evidence suggesting that DR reduces disease risk and extends lifespan in individuals that are not ‘overweight’ (Roth et al. 2002; Walford et al. 2002). The latter studies provide strong associations between biomarkers of caloric restriction and lifespan extension in humans. The carbohydrates, fats and proteins in food are metabolized to glucose which is then utilized as the major source for ATP production in cells. Although such biochemical energy production is required to sustain cell viability and functions, excessive energy production may cause cells to become damaged and ‘spoiled’, and thereby susceptible to disease. Because organisms evolved in environments in which food supplies were present in varied locations and amounts, the organisms had to adapt to such changing food availability. One such adaptation is the ability to store energy reserves in the forms of glycogen and lipids. When food supplies are scarce, the cells of organisms are faced with an energetic stress that may induce changes in gene expression that result in adaptive changes in cellular metabolism and the increased ability of the organism to resist stress. When food supplies are plentiful, as in most laboratory animal colonies and human populations in industrialized countries, individuals consume more calories than are necessary for the maintenance of their health. Two different paradigms of DR have been widely employed because of their highly reproducible abilities to increase lifespan in rats and mice. In one paradigm the animals receive food daily, but are limited to a specified amount which is typically 30–50% less than the ad libitum consumption of the control group. The second paradigm involves periodic fasting in which the animals are deprived of food for a full day, every other day, and are fed ad libitum on the intervening days. Analyses of various physiological parameters in animals maintained on these two different DR regimens have revealed several similar changes including decreased body temperature, decreased heart rate and blood pressure, and decreased glucose and insulin levels (Table 1). These DR regimens have also been shown to have beneficial effects on the brain. For example, DR retards age‐related increases in the levels of glial fibrillary acidic protein and oxidative damage to proteins and DNA (Dubey et al. 1996; Major et al. 1997). Analysis of the levels of mRNAs encoding thousands of proteins in the brains of young and old rats, which had been fed either ad libitum or DR diets, revealed numerous age‐related changes in gene expression that were attenuated by DR (Lee et al. 2000c). The genes in which expression was affected by aging and counteracted by DR included those involved in oxidative stress responses, innate immunity and energy metabolism (Table 2). These kinds of studies are providing novel insight into how DR affects the function and plasticity of the nervous system. Table 1. Physiological responses to dietary restriction Parameter Daily CR Periodic fasting Body weight decrease decrease or no change Body fat decrease decrease Body temperature decrease decrease Blood pressure decrease decrease Heart rate decrease decrease Blood glucose decrease decrease Blood insulin decrease decrease IGF‐1 levels decrease increase β‐hydroxybutyrate no change increase HDL increase increase Homocysteine decrease decrease Table 2. Examples of the effects of dietary restriction on changes in gene expression in the brain during aging Change during aging Gene Usual diet Dietary restriction Energy‐related Cytochrome oxidase decreased expression little or no change in expression Glucose‐6‐phosphatase decreased expression no change in expression Fructose‐1,6‐bisphosphatase increased expression no change in expression Creatine kinase increased expression increased expression Stress‐related HSP‐70 no change or decrease no change or increase GRP‐78 no change or decrease no change or increase Gadd153 increased expression increased expression Proteasome z subunit decreased expression decreased expression Inflammation‐related GFAP increased expression little or no change in expression Complement C1q increased expression little or no change in expression Complement C4 increased expression small increase in expression Plasticity‐related NMDA receptor NR1 decreased expression little or no change in expression BDNF decreased expression little or no change in expression TrkB decreased expression not determined α‐Synuclein decreased expression decreased expression

Meal size versus meal frequency: beyond calorie intake It has been assumed that all of the benefits of DR feeding regimens are the result of a reduction in cummulative calorie intake (Weindruch and Sohal 1997). However, we have recently documented a clear dissociation between caloric intake and beneficial effects of DR in a study that compared the effects of periodic fasting (alternate day feeding) and limited daily feeding on various physiological parameters and neuronal vulnerability to excitotoxicity in C57BL/6 mice (Anson et al., submitted). We had noted that, in contrast to Sprague–Dawley rats which lose weight when maintained on a periodic fasting regimen, C57BL/6 mice did not lose weight. Measurement of food intake revealed that on the days they had access to food the C57BL/6 mice on the periodic fasting regimen consumed twice as much food as mice fed ad libitum(Table 4). Remarkably, however, the mice on periodic fasting exhibited ‘anti‐aging’ physiological changes equal to or greater than those maintained on the reduced calorie diet, including decreased plasma insulin and glucose levels, and reduced body temperature. Moreover, levels of the ketone body β‐hydroxybutyrate were increased in the mice on the periodic fasting regimen, but not in the mice on the limited daily feeding regimen, suggesting a change in cellular energy metabolism pathways (Anson et al., submitted). Periodic fasting was more effective than limited daily feeding in protecting hippocampal neurons against excitotoxic injury. These findings suggest that increasing the time interval between meals is beneficial, even when the size of the meals are increased to a level that results in no overall decrease in caloric intake. Table 4. Evidence that decreased meal frequency, without caloric restriction, can exert anti‐aging and neuroprotective effects in C57BL/6 mice Change compared with mice fed ad libitum Parameter Intermittent fasting Caloric restriction Food intake little or no change decreased by > 30% Body weight little or no change decreased by > 30% Blood glucose 30% decrease 30% decrease Blood insulin 80% decrease 70% decrease Blood β‐hydroxybutyrate 100% increase 50% decrease Neuronal vulnerability* large decrease modest decrease The findings just described, while surprising, provide strong support for the hypothesis that many of the beneficial effects of DR are the result of a mild cellular stress response. Indeed, we have found that periodic fasting is much more effective than limited daily feeding in increasing the expression of HSP‐70 and neurotrophic factors in the brain (W. Duan, Z. Guo and M. P. Mattson, unpublished data).

Future directions There is much to learn about the effects of food intake (how much and how often) on the cellular and molecular biology of the nervous system, and its functional capabilities. Progress in this important area of investigation would be bolstered by the use of invertebrates such as Caenorhabditis elegans and Drosophila in which genes that mediate effects of food intake on the nervous system might be rapidly identified (Wolkow 2002). Gene expression analyses of neural tissues from normal rodents maintained on various DR and overeating regimens, and of rodent models of obesity, may reveal novel genes upon which to focus future research efforts. Studies of the effects of food intake on the cellular and molecular pathogenesis of neuronal degeneration in models of neurodegenerative disorders should continue, as well as parallel epidemiological and clinical investigations in humans. Being able to control food intake using pharmacological and gene therapy approaches is a current focus of translational research in the obesity field, but should also be pursued from the standpoint of neurodegenerative disorders. Finally, an all‐out campaign to educate the public about the devastating consequences of overeating should be deployed. The available data suggest that the nervous system is highly vulnerable to excessive calorie intake, just as is the case with the cardiovascular systems and most other organ systems. When extrapolated to humans, the data obtained from the kinds of animal studies described above suggest that a daily calorie intake in the range of 1800–2200 calories for moderately active adults may dramatically reduce the risk of age‐related disorders of the nervous system including AD, PD and stroke. Foregoing one or two meals a day might be an alternative to reducing meal size.