Dietary Modification Of Brain Aging And Neurodegenerative Disorders

大脑衰老和神经退行性疾病的饮食调整

• 批准号: 8552363
• 负责人: Mark Mattson
• 金额: $ 39.02万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552363
• 关键词: Adverse effects; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Androgens; Animal Model; Animals; Anthropometry; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Autonomic nervous system; Autopsy; Behavioral; Biological Markers; Blood Pressure; Body Weight decreased; Brain; Brain Injuries; Brain Stem; Brain-Derived Neurotrophic Factor; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cell Death Process; Cell membrane; Ceramides; Cerebral cortex; Chemicals; Cholesterol; Clinical Trials; Cocaine; Cognition; Cognitive deficits; Congenital neurologic anomalies; Corpus striatum structure; Curcumin; Data; Dementia; Diabetes Mellitus; Diet; Diet Modification; Dietary Component; Dietary Factors; Dietary Fats; Dietary Phytochemical; Disease; Drug Addiction; Effectiveness; Elderly; Energy Intake; Enzymes; Exhibits; Experimental Models; Fasting; Fibroblast Growth Factor 2; Frequencies; Functional disorder; Glutamates; Glutaminase; Health; Heart; Heart Rate; Heat shock proteins; Heat-Shock Proteins 70; Hippocampus (Brain); Human; Huntington Disease; Immune response; Impaired cognition; Individual; Inflammatory; Injury; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Ischemic Brain Injury; Ischemic Stroke; LDL Cholesterol Lipoproteins; Lead; Leptin; Lipids; Masks; Memory impairment; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Chaperones; Monkeys; Motor; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neuroprotective Agents; Neurosecretory Systems; Obesity; Overweight; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phytochemical; Play; Potential Energy; Preclinical Drug Evaluation; Premenopause; Process; Prolactin; Proteins; Randomized; Rattus; Receptor Activation; Receptors, Tumor Necrosis Factor, Type II; Regulation; Reporting; Rest; Risk; Risk Marker; Rodent; Rodent Model; Role; Sex Hormone-Binding Globulin; Sialic Acids; Signal Transduction; Sphingolipids; Spinal Cord; Stroke; Substantia nigra structure; Symptoms; Testing; Therapeutic; Treatment Efficacy; Triglycerides; Up-Regulation; Weight; Woman; addiction; adiponectin; age related; aging brain; biological adaptation to stress; cytokine; design; dietary restriction; disorder risk; dizocilpine; dopaminergic neuron; drug efficacy; excitotoxicity; experience; functional disability; functional outcomes; glucose-regulated proteins; heme oxygenase-1; human subject; improved; in vivo; indexing; inflammatory marker; insulin sensitivity; malignant breast neoplasm; middle age; mortality; mouse model; mutant; nervous system disorder; neural circuit; neurochemistry; neurotrophic factor; plumbagin; post stroke; preclinical study; response; synuclein

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. We 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 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. 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. 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. Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of -synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of -synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of -synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. 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. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. We found that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

在之前的研究中，我们已经表明间歇性禁食（IF）对阿尔茨海默病、帕金森病和中风的啮齿动物模型具有神经保护作用。热休克蛋白和脑源性神经营养因子（BDNF）的表达增加表明，神经保护机制涉及诱导轻度有益细胞反应。在亨廷顿氏病小鼠模型中，我们发现IF可增加脑内BDNF水平，改善糖尿病，抑制纹状体和皮层的神经元变性，并延长存活时间。在最近的一项研究中，我们已经证明饮食限制对帕金森病的猴子模型是有益的。我们最近提供的证据表明，膳食脂质可能调节AD和ALS的风险。阿尔茨海默病患者的大脑和ALS患者的脊髓的细胞膜中胆固醇和长链神经酰胺的水平升高。AD和ALS的细胞培养和动物模型研究的其他数据表明，神经酰胺可能在这些疾病的细胞死亡过程中发挥重要作用。由于胆固醇、鞘脂和神经酰胺的水平可以通过饮食的变化来调节，我们的数据表明，饮食中的脂质可能会改变神经元对年龄相关疾病的脆弱性。