Interaction of Genotype and Level of Dietary Restriction on Lifespan and Aging

描述（由申请人提供）：在过去的三十年里，饮食限制（DR）已经成为延缓衰老的“黄金标准”。由于DR已被证明可以延长从无脊椎动物到啮齿动物等多种生物的寿命，因此DR被视为一种普遍的衰老干预措施。然而，最近的一项研究表明，动物的基因型是动物对DR作出反应能力的主要决定因素，例如，研究的41个重组自交系（RI）小鼠中有三分之二在喂食40% DR（比随意喂食的小鼠少40%的饮食）时没有反应或寿命缩短。这项拨款的总体目标是利用九种遗传多样性的小鼠RI系来探索基因型和DR水平之间的相互作用。我们假设DR会延长所有基因型的寿命并延缓衰老；然而，DR的影响将是基因型和剂量依赖的，也就是说，一个水平的DR并非对所有基因型都是最佳的。这项研究的全面设计，使我们第一次能够准确地了解遗传多样性如何影响DR对寿命和衰老的影响。特定目的1：确定DR是否以基因型和剂量依赖的方式影响寿命。在对40% DR的反应中表现出最大多样性的9个RI系雌性小鼠的寿命将被随意喂食，或比每个RI系随意喂食的食用量少10%、20%或40%。根据我们的假设，我们预测所有9条RI线将显示增加

DESCRIPTION (provided by applicant): Over the past three decades, dietary restriction (DR) has become the "gold standard" against which manipulations that retard aging are compared. Because DR has been shown to increase the lifespan of a wide variety of organisms ranging from invertebrates to rodents, DR is viewed as a universal aging intervention. However, a recent study suggests that the genotype of an animal is a major determinant in the ability of the animal to respond to DR, e.g., two-thirds of the 41 recombinant inbred (RI) lines of mice studied either did not respond or showed reduced lifespan when fed 40% DR (40% less diet than that consumed by mice fed ad libitum). The overall goal of this grant is to explore the interaction between genotype and the level of DR using nine genetically diverse RI lines of mice. We hypothesize that DR will increase lifespan and delay aging in all genotypes; however, the effect of DR will be both genotype- and dose-dependent, i.e., one level of DR is not optimal for all genotypes. The comprehensive design of this study, allows us for the first time to obtain an accurate view of how genetic diversity impacts the effect of DR on lifespan and aging. Specific Aim 1: To determine whether DR affects lifespan in a genotype- and dose-dependent manner. The lifespans of nine RI lines of female mice that show maximum diversity in response to 40% DR will be fed ad libitum or 10, 20, or 40% less diet than the amount consumed by each RI line fed ad libitum. Based on our hypothesis, we predict that all nine RI lines will show an increase in lifespan; however, the level of restriction necessary to obtain an increase in lifespan will vary with genotype. Specific Aim 2: To determine whether DR affects end-of-life pathology in a genotype- and dose-dependent manner. Because a reduction in most age-related pathologies is a hallmark feature of DR, we will conduct a comprehensive pathological analysis of all the female mice that die in Aim 1. We predict that the increase in lifespan by DR will be accompanied by a reduction/delay in most age-related pathological lesions, which would support the premise that DR increases lifespan by retarding aging. We also predict that the effect of DR on end-of-life pathological lesions will be genotype- and DR dose-dependent. Specific Aim 3: To identify potential pathways involved in the anti-aging mechanism of DR. We will measure the levels of transcripts in RNA isolated from liver and epididymal fat of mice fed AL and the three DR diets for 12 months using Illumina Mouse microarrays. Employing unbiased analyses of our microarray data, we will identify pathways that are altered significantly by DR. Because we will have transcriptome data on 27 cohorts of mice fed DR (nine strains of mice fed 10, 20, and 40% DR), we are in a unique position to identify gene profiles that have the greatest predictive power to identify the cohorts of mice that show a significant increase in lifespan when placed on a DR diet, and from these data, we can identify potential mechanisms key in the life-extending action DR.