In previous studies we had shown that intermittent fasting (IF) is neuroprotective in rodent models of Alzheimers and Parkinsons diseases and stroke. The neuroprotective mechanism involves induction of a mild beneficial cellular response as indicated by increased expression of heat-shock proteins and brain-derived neurotrophic factor (BDNF). We have found that IF increases BDNF levels in the brain, ameliorates diabetes, suppresses neuronal degeneration in the striatum and cortex, and extends survival in a mouse model of Huntingtons disease. In a more recent study we have shown that dietary restriction is beneficial in a monkey model of Parkinsons disease. We have recently provided evidence that dietary lipids may modulate risk of AD and ALS. Levels of cholesterol and long-chain ceramides are increased in membranes of cells in the brains of AD patients and spinal cords of ALS patients. Additional data in studies of cell culture and animal models of AD and ALS suggest that ceramides may play an important role in the cell death process in these disorders. Because levels of cholesterol, sphingolipids and ceramides can be modulated by changes in diet, our data suggest that dietary lipids may modify the vulnerability of neurons to age-related diseases. In other studies we have shown that IF can improve glucose metabolism (increased insulin sensitivity) and cardiovascular risk factors (decreased blood pressure and superior cardiovascular stress adaptation) in rats. The latter effects of IF were mimicked by intermittent feeding of rats a diet supplemented with 2-deoxyglucoe, a non-metabolizable analog of glucose. Interestingly, IF and caloric restriction also increase heart rate variability in a manner suggesting that these diets increase parasympathetic tone, while decreasing sympathetic tone. Thus, IF and caloric restriction exert physiological actions that would be expected to reduce the risk of diabetes and cardiovascular disease. In our efforts to establish the mechanism by which dietary restriction protects neurons we have found that dietary restriction increases the expression of mitochondrial uncoupling proteins and enzymes of the plasma membrane redox system, resulting in a decrease in oxidative stress and stabilization of cellular energy homeostasis in neurons. We have performed massive gene array analysis of the effects of gene expression in multiple brain regions as part of the AGEMAP (atlas of gene expression in mouse aging project) project. In another study we correlated changes in brain gene expression with behavioral, endocrine and biochemical alterations male and female rats maintained on diets with different levels of energy. In human studies we have found that an alternate day caloric restriction diet improves symptoms and decreases markers of oxidative stress and inflammation in asthma patients. In a meal frequency study, we found that consuming one large meal versus three smaller meals each day results in complex changes in physiology, some of which may be beneficial and others detrimental for health. Most recently, we have screened a panel of 'biopesticides'to identify naturally occurring chemicals that can activate adaptive stress response pathways in neurons and so can protect the neurons against dysfunction and degeneration in experimental models of neurodegenerative disorders. This project identified the phytochemical plumbagin as a lead candidate neuroprotective agent that we are currently further evaluating in preclinical studies. Finally, we have found that dietary energy intake affects neural circuits in the brain involved in drug addiction, and that dietary energy intake can counteract several adverse effects of cocaine on neural plasticity and behavioral features of addiction. Preclinical evaluation of drugs for neurological disorders is usually performed on overfed rodents, without consideration of how metabolic state might affect drug efficacy. Using a widely employed mouse model of focal ischemic stroke, we found that that the NMDA receptor antagonist dizocilpine (MK-801) reduces brain damage and improves functional outcome in mice on the usual ad libitum diet, but exhibits little or no therapeutic efficacy in mice maintained on an energy-restricted diet. Thus, NMDA receptor activation plays a central role in the mechanism by which a high dietary energy intake exacerbates ischemic brain injury. These findings suggest that inclusion of subjects with a wide range of energy intakes in clinical trials for stroke may mask a drug benefit in the overfed/obese subpopulation of subjects. In a collaborative study of human subjects we compared the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. The study was a randomized comparison of a 25% energy restriction as IER (∼2710 kJ/day for 2 days/week) or CER (∼6276 kJ/day for 7 days/week) in 107 overweight or obese (mean ( s.d.) body mass index 30.6 ( 5.1) kg m(-2)) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk;insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P-value for difference between groups = 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER;difference between groups for fasting insulin was -1.2 (-1.4 to -1.0) μU ml(-1) and for insulin resistance was -1.2 (-1.5 to -1.0) μU mmol(-1) l(-1) (both P = 0.04). Our findings show that IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk. In another study we found that mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice. We conclude that dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome.
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