Dietary Modification Of Brain Aging And Neurodegenerative Disorders

在以前的研究中，我们已经证明间歇性禁食(IF)在阿尔茨海默病、帕金森病和中风的啮齿动物模型中具有神经保护作用。神经保护机制包括诱导温和的有益细胞反应，热休克蛋白和脑源性神经营养因子(BDNF)的表达增加表明。我们在亨廷顿病小鼠模型中发现，IF可以增加大脑中BDNF的水平，改善糖尿病，抑制纹状体和皮质中的神经元退化，并延长存活时间。在最近的一项研究中，我们表明限制饮食对帕金森氏病的猴子模型是有益的。我们最近提供的证据表明，饮食中的脂质可能会调节AD和ALS的风险。AD患者脑细胞膜和ALS患者脊髓中胆固醇和长链神经酰胺水平升高。在AD和ALS的细胞培养和动物模型研究中的更多数据表明，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。在其他研究中，我们已经证明IF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(降低血压和更好的心血管应激适应)。间歇喂食添加2-脱氧葡萄糖(一种葡萄糖的一种非代谢类似物)的饮食，可以模仿IF的后一种效应。有趣的是，IF和卡路里限制也增加了心率变异性，这表明这些饮食增加了副交感神经张力，同时降低了交感神经张力。因此，IF和卡路里限制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，稳定了神经元的细胞能量稳态。作为AGEMAP(小鼠衰老基因表达图谱)项目的一部分，我们对多个脑区基因表达的影响进行了大规模的基因阵列分析。在另一项研究中，我们将大脑基因表达的变化与行为、内分泌和生化变化联系起来，雄性和雌性大鼠以不同的能量水平饮食维持。在人类研究中，我们发现隔日限制卡路里饮食可以改善哮喘患者的症状，降低氧化应激和炎症的标记物。在一项饮食频率研究中，我们发现，每天吃一顿大餐而不是三顿小餐会导致复杂的生理变化，其中一些可能对健康有益，另一些可能对健康不利。最近，我们已经筛选了一组“生物杀虫剂”，以确定可以激活神经元适应性应激反应通路的自然产生的化学物质，从而在神经退行性疾病的实验模型中保护神经元免受功能障碍和变性的影响。该项目确定了植物化学白花素作为主要候选神经保护剂，目前我们正在临床前研究中对其进行进一步评估。最后，我们发现饮食能量摄入影响了参与药物成瘾的大脑神经回路，饮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个不利影响。

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.