Benefits of dietary essential amino acid restriction

限制膳食必需氨基酸的好处

• 批准号: 8026460
• 负责人: JAMES R. MITCHELL
• 金额: $ 37.61万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026460
• 关键词: Acetaminophen; Amino Acids; Anabolism; Animals; Antioxidants; Binding; Blood; Body Weight; Body Weight decreased; Branched-Chain Amino Acids; Clinic; DNA Methylation; Data; Diet; Eating; Essential Amino Acids; Gene Expression; Genes; Glutathione; Goals; Health; Individual; Kidney; Knockout Mice; Laboratory Organism; Leucine; Literature; Liver; Longevity; Malnutrition; Mammals; Measures; Metabolic; Metabolic Diseases; Metabolism; Methionine; Molecular; Mus; Mutant Strains Mice; Nutrient; Organ; Oxidative Stress; Pathology; Pathway interactions; Phenotype; Phosphotransferases; Physiology; Proteins; Regimen; Reperfusion Injury; Resistance; Response Elements; Rodent; Role; Serum; Signal Transduction; Signal Transduction Pathway; Stress; TSC1 gene; Testing; Time; Tissues; Toxic effect; Translating; Translational Derepression; Tryptophan; Up-Regulation; Work; activating transcription factor; acute stress; blood glucose regulation; deprivation; detection of nutrient; dietary restriction; improved; inhibitor/antagonist; insight; insulin sensitivity; mouse model; renal ischemia; transcription factor

DESCRIPTION (provided by applicant): Dietary restriction (DR), or reduced food intake without malnutrition, is highly beneficial in a variety of experimental organisms using a number of endpoints, including glucose homeostasis, acute stress resistance and longevity. While energy restriction is commonly thought to the key to a successful DR regimen, a small but growing body of literature points to the dominant role of nutrient restriction. Long-term restriction of dietary methionine, an essential amino acid, results in increased lifespan, health span and acute stress resistance in experimental rodents. Although the phenotype resembles that of DR, it occurs in the absence of energy restriction. The benefits of methionine restriction are thought to involve perturbation of one or more methionine-requiring pathways, such as DNA methylation or glutathione biosynthesis. Our preliminary data indicate that short-term restriction of dietary methionine improves glucose homeostasis and stress resistance within as little as six days. Importantly, we have also found that restriction of two other essential amino acids - tryptophan and leucine - lend similar benefits. We hypothesize that restriction of any essential amino acid will rapidly trigger changes in animal physiology resulting in improved glucose homeostasis and increased stress resistance. Our aim is to elucidate relevant upstream amino acid sensing pathways and downstream effectors of oxidative stress resistance with the ultimate goal of translating these benefits to the clinic. PUBLIC HEALTH RELEVANCE: Long-term methionine restriction increases lifespan, health span and stress resistance in experimental rodents. Here we propose to test the ability of short-term methionine restriction to increase stress resistance and improve insulin sensitivity in mice. Our aim is to elucidate upstream nutrient sensing pathways and downstream effectors with the ultimate goal of translating these benefits to the clinic.

描述（由申请人提供）： 饮食限制（DR），或减少食物摄入量而不营养不良，是非常有益的，在各种实验生物体使用的一些端点，包括葡萄糖稳态，急性应激抗性和寿命。虽然能量限制通常被认为是成功的DR方案的关键，但越来越多的文献指出营养限制的主导作用。长期限制饮食蛋氨酸，一种必需氨基酸，导致实验啮齿动物寿命延长，健康寿命和急性应激抵抗力增加。虽然表型类似于DR，但它发生在没有能量限制的情况下。甲硫氨酸限制的益处被认为涉及干扰一个或多个甲硫氨酸需要途径，如DNA甲基化或谷胱甘肽生物合成。我们的初步数据表明，短期限制饮食蛋氨酸改善葡萄糖稳态和应激抵抗力在短短六天内。重要的是，我们还发现，限制其他两种必需氨基酸-色氨酸和亮氨酸-也有类似的好处。我们假设，限制任何必需氨基酸将迅速引发动物生理学的变化，从而改善葡萄糖稳态和增加应激抵抗力。我们的目的是阐明相关的上游氨基酸传感途径和下游效应的氧化应激抗性的最终目标是将这些好处转化为临床。 公共卫生关系： 长期蛋氨酸限制增加实验啮齿动物的寿命，健康寿命和抗应激能力。在这里，我们建议测试短期蛋氨酸限制的能力，以增加应激抵抗力和改善小鼠的胰岛素敏感性。我们的目标是阐明上游营养传感途径和下游效应器，最终目标是将这些益处转化为临床。