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: 8148215
• 负责人: Mark Mattson
• 金额: $ 37.98万
• 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/8148215
• 关键词: Affect; Aging; Alzheimer' s Disease; Animals; Asthma; Atlases; Behavioral; Biochemical; Brain region; Brain-Derived Neurotrophic Factor; Caloric Restriction; Cell Death Process; Chemicals; Complex; Corpus striatum structure; Data; Diabetes Mellitus; Diet; Diet Modification; Dietary Component; Dietary Factors; Dietary Fats; Disease; Drug Addiction; Endocrine; Enzymes; Fasting; Female; Frequencies; Functional disorder; Gene Expression; Genes; Health; Heat shock proteins; Homeostasis; Human; Huntington Disease; Inflammation; Lead; Molecular; Monkeys; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neuroprotective Agents; Neurosecretory Systems; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathway interactions; Patients; Physiological; Physiology; Play; Rattus; Risk; Rodent Model; Role; Sphingolipids; Spinal Cord; Stress; Stroke; Symptoms; System; Testing; aging brain; biological adaptation to stress; diabetes risk; dietary restriction; dietary supplements; human subject; improved; male; preclinical study

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.

在之前的研究中，我们已经证明间歇性禁食 (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。 神经保护机制涉及诱导温和的有益细胞反应，如热休克蛋白和脑源性神经营养因子（BDNF）表达增加所表明的。 我们发现，IF 可以增加大脑中的 BDNF 水平，改善糖尿病，抑制纹状体和皮质的神经元变性，并延长亨廷顿病小鼠模型的生存期。在最近的一项研究中，我们表明饮食限制对于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会调节 AD 和 ALS 的风险。 AD 患者大脑和 ALS 患者脊髓细胞膜中的胆固醇和长链神经酰胺水平升高。 AD 和 ALS 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，因此我们的数据表明，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。 在其他研究中，我们表明间歇性间歇运动可以改善大鼠的葡萄糖代谢（增加胰岛素敏感性）和心血管危险因素（降低血压和增强心血管应激适应能力）。 通过间歇性喂食大鼠补充 2-脱氧葡萄糖（一种不可代谢的葡萄糖类似物）的饮食来模仿 IF 的后一种作用。 有趣的是，IF和热量限制也会增加心率变异性，这表明这些饮食会增加副交感神经张力，同时降低交感神经张力。因此，间歇性间歇运动和热量限制所发挥的生理作用有望降低糖尿病和心血管疾病的风险。 在我们努力建立饮食限制保护神经元的机制的过程中，我们发现饮食限制增加了线粒体解偶联蛋白和质膜氧化还原系统酶的表达，从而减少了氧化应激并稳定了神经元中的细胞能量稳态。 作为 AGEMAP（小鼠衰老项目基因表达图谱）项目的一部分，我们对多个大脑区域基因表达的影响进行了大规模基因阵列分析。 在另一项研究中，我们将大脑基因表达的变化与维持不同能量水平饮食的雄性和雌性大鼠的行为、内分泌和生化变化联系起来。在人体研究中，我们发现隔日热量限制饮食可以改善哮喘患者的症状并减少氧化应激和炎症的标志物。 在一项进餐频率研究中，我们发现每天吃一顿大餐与吃三顿小餐会导致生理学的复杂变化，其中一些可能有益于健康，而另一些可能对健康有害。最近，我们筛选了一组“生物农药”，以识别天然存在的化学物质，这些化学物质可以激活神经元中的适应性应激反应途径，从而可以保护神经元免受神经退行性疾病实验模型中的功能障碍和退化。 该项目确定植物化学白花丹素作为主要候选神经保护剂，我们目前正在临床前研究中进一步评估。 最后，我们发现膳食能量摄入会影响与药物成瘾有关的大脑神经回路，并且膳食能量摄入可以抵消可卡因对神经可塑性和成瘾行为特征的几种不利影响。