Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL͞6 mice are maintained on an intermittent fasting (alternateday fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.caloric restriction ͉ hippocampus ͉ insulin ͉ ␤-hydroxybutyrate ͉ ketosis

SummaryWhen considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase lifespan, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, clinical trials have been initiated. However, even if results from these studies could eventually substantiate CR as an effective pro-longevity strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of 'CR mimetics'. The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), or affect stress signaling pathways (resveratrol), are being assessed as CR mimetics (CRM). Promising results have emerged from initial studies regarding physiological responses which resemble those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity (e.g. enhanced dopamine action and up-regulated neurotrophic factors). Ultimately, lifespan analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CRM. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor.

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We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell linederived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.brain-derived neurotrophic factor ͉ cell death ͉ dopamine P arkinson's disease (PD) results from the dysfunction and degeneration of dopamine (DA) neurons in the substantia nigra (SN) and DA axon terminals, resulting in progressive motor dysfunction (1). The risk of PD increases with advancing age, suggesting that cellular and molecular changes that occur in the brain during normal aging may promote the degeneration of DA neurons. In this regard, increased oxidative stress and impaired energy metabolism and protein turnover occur in DA neurons during normal aging, and these changes are greatly exacerbated in PD (2, 3). Although a small number of cases of PD result from inherited genetic mutations in one of three genes, ␣-synuclein, Parkin, or DJ-1 (4), most cases are sporadic with an unknown environmental cause(s). Nevertheless, studies of genetic and neurotoxin-based animal models of PD point to the involvement of oxidative stress and impaired energy metabolism and protein turnover in the pathogenesis of PD (3-6). There is currently no established intervention to prevent, or decrease the risk of, PD.Most studies of humans have concluded that a decrease in the number of DA neurons in the SN occurs during normal aging, with PD being an acceleration of this process (7-9). However, some investigators have reported no age-related decline in the number of DA neurons (10). Studies in rhesus monkeys have been more consistent in reporting age-related decline in the number of tyrosine hydroxylase (TH)-positive SN neurons (11, 12). However, because some monkey studies have reported increased numbers of THpositive nigral neurons after treatment with neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), an age-related decline in expression of TH could be an alternative explanation to the results suggesting an age-related loss of nigral neurons (13).In a wide range of laboratory animals, caloric restriction (CR) has been shown to prolong lifespan, decrease the incid...