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
基本信息
- 批准号:9147267
- 负责人:
- 金额:$ 53.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdverse effectsAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmygdaloid structureAmyloid beta-ProteinAndrogensAnimal ModelAnimalsAnxietyAttenuatedAutonomic nervous systemAutopsyBehavioralBiological MarkersBlood PressureBody Weight decreasedBrainBrain DiseasesBrain InjuriesBrain StemBrain-Derived Neurotrophic FactorC-reactive proteinCarbohydratesCardiovascular systemCell Culture TechniquesCell Death ProcessCell membraneCellsCeramidesCerebral cortexChemicalsCholesterolCocaineCognitionCongenital neurologic anomaliesCorpus striatum structureDataDepositionDiabetes MellitusDietDiet ModificationDietary ComponentDietary FactorsDietary FatsDiseaseDrug AddictionEatingEffectivenessElderlyEnergy IntakeEstersExhibitsExperimental ModelsExposure toFastingFibroblast Growth Factor 2FrequenciesFunctional disorderHealthHealth BenefitHeartHeart RateHeat shock proteinsHeat-Shock Proteins 70Hippocampus (Brain)HumanHuntington DiseaseIndividualInflammatoryInjuryInsectaInsulinInsulin ResistanceInsulin-Like Growth-Factor Binding Protein 1Ischemic StrokeKetone BodiesKetonesLDL Cholesterol LipoproteinsLeadLearningLeptinMemoryMetabolic DiseasesModelingMolecularMolecular ChaperonesMonkeysMotorMusNerve DegenerationNeurodegenerative DisordersNeuronal PlasticityNeuronsNeuroprotective AgentsNeurosecretory SystemsObesityOverweightParkinson DiseasePathogenesisPathologyPathway interactionsPatientsPerformancePhysiologicalPhytochemicalPlantsPlayPotential EnergyPremenopauseProcessProteinsRandomizedRattusRegulationReportingResearchRestRiskRisk MarkerRodent ModelRoleSex Hormone-Binding GlobulinSphingolipidsSpinal CordStressStrokeSubstantia nigra structureSymptomsTestingTherapeuticToxinTriglyceridesWomanaddictionage relatedaging brainantioxidant enzymebasebehavior testbiological adaptation to stressbrain cellcytokinedietary restrictiondisorder riskdopaminergic neuronexperiencefeedingfruits and vegetablesfunctional disabilityfunctional outcomesglucose-regulated proteinsheme oxygenase-1human subjecthyperphosphorylated tauimprovedindexinginsulin sensitivitymen&aposs groupmiddle agemortalitymouse modelmutantneural circuitneurochemistryneurotrophic factornovelplumbaginpost strokepreclinical studyresilienceresponsesynucleinward
项目摘要
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.
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. 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 further found that intermittent fasting suppresses activation of the so-called 'inflammasome' in brain cells, which was associated with improved functional outcome in the mouse stroke model. 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 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Abeta; deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the hippocampus and amygdala. These findings demonstrate a therapeutic benefit of a diet containing a ketone ester in a mouse model of Alzheimer's disease.
Based on our own research and evolutionary considerations, we developed a novel hypothesis to explain the beneficial effects of diets rich in fruits and vegetables on health, including brain health. Plants do not have the option of fleeing predators. As a consequence, they have developed an elaborate set of chemical defenses to ward off insects and other creatures that want to make them into a meal. Toxins that plants use against predators are consumed by us at low levels in fruits and vegetables. Exposure to these chemicals causes a mild stress reaction that lends resilience to cells in our bodies. Adaptation to these stresses, a process called hormesis,
accounts for a number of health benefits, including protection against brain disorders, that we receive from eating vegetables and fruits.
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。
项目成果
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Mark Mattson其他文献
Mark Mattson的其他文献
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{{ truncateString('Mark Mattson', 18)}}的其他基金
Neuroprotective And Neurorestorative Signaling Mechanisms
神经保护和神经恢复信号机制
- 批准号:
8552362 - 财政年份:
- 资助金额:
$ 53.35万 - 项目类别:
Cellular And Molecular Pathogenesis Of Alzheimer
阿尔茨海默病的细胞和分子发病机制
- 批准号:
8736517 - 财政年份:
- 资助金额:
$ 53.35万 - 项目类别:
Synaptic Plasticity In Aging And Neurodegenerative Disorders
衰老和神经退行性疾病中的突触可塑性
- 批准号:
8736521 - 财政年份:
- 资助金额:
$ 53.35万 - 项目类别:
Dietary Modification Of Brain Aging And Alzheimer's Disease
大脑衰老和阿尔茨海默病的饮食调整
- 批准号:
9770106 - 财政年份:
- 资助金额:
$ 53.35万 - 项目类别:
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 - 财政年份:
- 资助金额:
$ 53.35万 - 项目类别:
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