Benefits of dietary essential amino acid restriction

描述(由申请人提供)： 饮食限制(DR)，即在没有营养不良的情况下减少食物摄入量，在使用许多终点的各种实验生物体中非常有益，包括葡萄糖稳态、急性应激抵抗和长寿。虽然能量限制通常被认为是成功的DR方案的关键，但一小部分但不断增长的文献指出了营养限制的主导作用。蛋氨酸是一种必需的氨基酸，长期限制饮食可延长实验啮齿动物的寿命、健康寿命和急性应激抵抗力。虽然表型与DR相似，但它发生在没有能量限制的情况下。限制蛋氨酸的好处被认为涉及扰乱一个或多个蛋氨酸需要的途径，如DNA甲基化或谷胱甘肽的生物合成。我们的初步数据表明，短期限制饮食蛋氨酸可以在短短六天内改善血糖稳态和抗应激能力。重要的是，我们还发现，限制另外两种必需氨基酸--色氨酸和亮氨酸--也有类似的益处。我们假设，限制任何必需的氨基酸将迅速引发动物生理的变化，从而改善葡萄糖稳态和增强应激抗性。我们的目标是阐明氧化应激抵抗的相关上游氨基酸感知途径和下游效应因子，最终目标是将这些益处转化为临床应用。 公共卫生相关性： 长期的蛋氨酸限制延长了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，以增加应激抵抗和改善胰岛素敏感性的小鼠。我们的目标是阐明上游营养感知途径和下游效应，最终目标是将这些好处转化为临床。

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.