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

基因型和饮食限制水平对寿命和衰老的相互作用

• 批准号: 8703962
• 负责人: ARLAN G. RICHARDSON
• 金额: $ 48.32万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703962
• 关键词: Affect; Aging; Animal Feed; Animals; Body Weight; Caloric Restriction; Carbohydrates; Cessation of life; Communities; DBA/2 Mouse; DR1 gene; Data; Diet; Dose; Exhibits; Fatty acid glycerol esters; Female; Food; Gene Expression Profile; Genes; Genetic Variation; Genotype; Goals; Gold; Grant; Inbreeding; Incidence; Intervention; Intramural Research Program; Invertebrates; Lesion; Life; Lipids; Liver; Longevity; Macaca mulatta; Measures; Micronutrients; Minerals; Mouse Strains; Mus; Onset of illness; Organism; Outcome; Pathology; Pathway interactions; Physiological; Play; Positioning Attribute; Proteins; RNA; Recombinants; Reducing diet; Reporting; Research; Research Design; Rodent; Role; Shock; Testing; Time; Transcript; Vitamins; age related; anti aging; base; cohort; dietary restriction; end of life; feeding; food consumption; male; public health relevance; response

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.

在过去的三十年里，饮食限制(DR)已经成为反对 对延缓衰老的操作进行了比较。因为DR已经被证明可以延长广泛的 从无脊椎动物到啮齿动物的各种有机体，DR被视为普遍的衰老干预措施。 然而，最近的一项研究表明，动物的基因型是决定动物生存能力的主要因素 对DR有反应的动物，例如，在所研究的41个重组近交系(RI)小鼠中，三分之二没有 当喂食40%的DR时，反应或表现出寿命缩短(比喂AD的小鼠少40%的饮食 Libitum)。这项资助的总体目标是探索基因和DR水平之间的相互作用。 9个遗传多样性的RI系小鼠。我们假设DR将延长寿命并延缓衰老 所有的基因类型；然而，DR的影响将是基因和剂量依赖的，即一个水平的 DR并不适用于所有的基因类型。这项研究的全面设计，让我们第一次 准确了解基因多样性如何影响DR对寿命和衰老的影响。 具体目标1：确定DR是否以一种基因和剂量依赖的方式影响寿命。这个 对对40%DR反应表现出最大多样性的9个RI系雌性小鼠的寿命将给予广告 Libitum或比每个RI行随意喂养的消耗量少10%、20%或40%的饮食。基于我们的 假设，我们预测所有9个RI线都将显示出寿命的延长；然而，限制的程度 延长寿命所需的时间将因不同的基因而异。 具体目标2：确定DR是否影响与基因和剂量相关的生命末期病理 举止。由于大多数与年龄相关的病理改变的减少是DR的一个显著特征，我们将进行 对在目标1中死亡的所有雌性小鼠进行综合病理分析。我们预测 DR的寿命将伴随着大多数与年龄相关的病理损害的减少/延迟，这将 支持DR通过延缓衰老来延长寿命的前提。我们还预测，DR对 生命末期的病理损害将是基因和DR剂量依赖的。 具体目标3：确定参与Dr.We Will抗衰老机制的潜在途径 测定饲喂AL和3种DR的小鼠肝脏和附睾脂中RNA的转录水平 使用Illumina小鼠微阵列进行为期12个月的饮食。对我们的微阵列数据进行无偏见的分析， 我们将确定博士显著改变的途径，因为我们将在27号获得转录组数据 喂养DR的小鼠队列(9个品系的小鼠分别喂养10%、20%和40%的DR)，我们处于一个独特的位置来识别 具有最大预测能力的基因图谱，可以识别出表现出显著 在DR饮食中延长寿命，从这些数据中，我们可以确定潜在的关键机制 在延长生命的行动中，Dr。