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.

在先前的研究中，我们表明，间歇性禁食（如果）在阿尔茨海默氏症和帕金森氏病和中风的啮齿动物模型中具有神经保护作用。 神经保护机制涉及诱导温和的有益细胞反应，如热休克蛋白和脑衍生的神经营养因子（BDNF）的表达增加所示。 我们发现，如果增加大脑中的BDNF水平，可以改善糖尿病，抑制纹状体和皮质中的神经元变性，并在亨廷顿疾病的小鼠模型中延长生存率。在最近的一项研究中，我们表明，饮食限制在帕金森氏病的猴子模型中是有益的。 我们最近提供了证据，表明饮食脂质可能调节AD和ALS的风险。 在AD患者的大脑中，胆固醇和长链神经酰胺的水平升高，ALS患者的脊髓水平升高。 对AD和ALS的细胞培养和动物模型的研究的其他数据表明，神经酰胺在这些疾病的细胞死亡过程中可能起重要作用。 由于胆固醇，鞘脂和神经酰胺的水平可以通过饮食变化来调节，因此我们的数据表明饮食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，我们已经表明，如果可以改善大鼠的葡萄糖代谢（胰岛素敏感性提高）和心血管危险因素（血压降低和高质量的心血管胁迫适应）。 通过对大鼠的间歇性喂养的饮食添加了含2-脱氧葡萄糖的饮食，这是一种葡萄糖的饮食。 有趣的是，如果和热量限制也以一种表明这些饮食会增加副交感神经的方式增加心率的变异性，同时降低同情性语气。因此，如果和热量限制会发挥生理作用，这将有望降低糖尿病和心血管疾病的风险。 为了建立饮食限制保护神经元的机制，我们发现饮食限制会增加质膜氧化还原系统的线粒体解偶联蛋白和酶的表达，从而减少氧化应激和稳定性神经元稳态的氧化应激和稳定性。 。 我们已经对基因表达在多个大脑区域的影响进行了巨大的基因阵列分析，这是AGEMAP的一部分（小鼠衰老项目中基因表达的地图集）项目。 在另一项研究中，我们将脑基因表达的变化与行为，内分泌和生化改变的男性和雌性大鼠保持在具有不同能量水平的饮食上。在人类研究中，我们发现替代的热量限制饮食可改善症状，并减少哮喘患者的氧化应激和炎症标志物。 在一项进餐频率研究中，我们发现每天食用一顿大餐与三顿较小的餐点会导致生理变化，其中一些可能是有益的，而另一些则对健康有害。最近，我们筛选了一组“生物农药”，以识别可以激活神经元中适应性应激反应途径的天然化学物质，因此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变性。 该项目将植物化学的铅笔素确定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，我们发现饮食能量摄入会影响与药物成瘾有关的大脑中的神经回路，并且饮食能量摄入可以抵消可卡因对成瘾神经可塑性和行为特征的几种不利影响。