Impact of Calorie Restriction on Thymopoiesis in Humans

热量限制对人类胸腺生成的影响

• 批准号: 7439477
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 24.58万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7439477
• 关键词: Adipocytes; Age; Aging; Ancillary Study; Animal Model; Animals; Antigens; Architecture; Biological; Biomedical Research; Blood; CD8-Positive T-Lymphocytes; Caloric Restriction; Cellular Immunity; Chemicals; Complementarity Determining Region III; Data; Diet; Disease; Documentation; Eating; Emigrant; Energy Intake; Enrollment; Excision; Family; Fasting; Fatty acid glycerol esters; Funding; Generations; Goals; Hormones; Human; Hunger; Immune; Immune response; Immune system; Immunologic Surveillance; Infection; Inflammation; Intervention; Length; Long-Term Effects; Longevity; Lymphoid; Magnetic Resonance Imaging; Malignant Neoplasms; Malnutrition; Mammals; Mediator of activation protein; Molecular; Mus; Neurosecretory Systems; Non obese; Normal Statistical Distribution; Numbers; Obesity; Organ; Output; Participant; Personal Satisfaction; Phase; Phase II Clinical Trials; Polymerase Chain Reaction; Polymorphism Analysis; Predisposition; Preventive; Primates; Process; Production; Proteins; Public Health; Randomized; Randomized Controlled Trials; Risk; Rodent; Rodent Model; Role; Serum; Site; Stromal Cells; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Thymic Tissue; Thymus Gland; Time; United States National Institutes of Health; Vaccination; Woman; Work; age related; base; complementarity-determining region 3; design; energy balance; feeding; ghrelin; healthy aging; human subject; improved; men; reconstitution; response; size; ward

DESCRIPTION (provided by applicant): Studies in animal models have demonstrated that calorie restriction (CR) prolongs healthy life-span. The NIH-funded Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) phase 2 trial is designed to test the hypothesis that CR in humans results in similar adaptive change that occurs in animal models. The current project is an ancillary study to CALERIE which will assess an important biological mechanism by which CR may have its salutary effects on healthy aging. The ability of thymus to produce T cells that are non-reactive to self proteins but possessing a broad T cell receptor (TCR) repertoire to recognize and clear any possible foreign antigen is critical to the survival of host. The decline in cellular immunity with age is a direct consequence of progressive replacement of thymic lymphoid and stromal cell compartment with adipocytes that results in reduced generation of new T cells in a process termed as thymic involution. It is well known that TCR diversity undergoes contraction during aging due to reduction in thymopoiesis; and that this adversely impacts immune-surveillance and increases the risk of infections and cancers. It is also known that CR has immune-enhancing effects in experimental animals. We have recently identified that, ghrelin; a hunger-inducing hormone that is upregulated during CR enhances the TCR diversity via promoting the generation of naive T cells from the thymus in rodents. Therefore, we hypothesize that CR in humans will increase ghrelin production and enhance TCR diversity via promoting the generation of naove T cells from the thymus. To test this hypothesis, we propose to ascertain if the duration of 2 years of 25% CR, in well characterized CALERIE participants, is associated with a positive or unintended adverse impact on thymopoiesis. The analyses will be performed before the start of intervention at baseline, 6, 12, and 24 month in ad libitum (AL) fed and CR CALERIE subjects. The overall goal of this project is to determine if CR induced pro- thymic effects seen in animal models are reflected at cellular and molecular levels in humans. The specific Aim #1 will compare the following between CR and AL groups (a) TCR diversity, by complementarity determining region 3 length polymorphism analysis, (b) thymic output, by quantitation of T cell receptor excision circles and (c) quantitative analysis of thymic size, volume and its fat content with chemical-shift magnetic resonance imaging. Specific Aim #2 will determine if ghrelin is a primary mediator of CR's pro-thymic effects in these subjects. The data generated from this ancillary study and analyses in cooperation with the CALERIE Co-ordinating Center, will provide the first comprehensive documentation of impact of CR and the mechanisms responsible for its effects on adaptive immune system of humans. PUBLIC HEALTH RELEVANCE: Studies in animal models have demonstrated that caloric restriction without malnutrition enhances healthy life span and reduces age-related diseases. With increasing age, thymus the site of production of new T lymphocytes gets replaced with fat and looses its function. The current application will investigate if 2 years of caloric restriction in humans can stimulate the function of the thymus and thus answer key questions related to efficacy of caloric restriction as a preventive approach to strengthen the immune system in healthy non-obese people.

描述（由申请人提供）：动物模型研究表明热量限制（CR）可以延长健康寿命。美国国立卫生研究院 (NIH) 资助的减少能量摄入长期影响综合评估 (CALERIE) 2 期试验旨在检验人类 CR 会导致动物模型中发生的类似适应性变化的假设。当前的项目是 CALERIE 的一项辅助研究，该研究将评估 CR 对健康衰老可能产生有益影响的重要生物学机制。胸腺产生对自身蛋白无反应但拥有广泛的 T 细胞受体 (TCR) 库以识别和清除任何可能的外来抗原的 T 细胞的能力对于宿主的生存至关重要。细胞免疫力随着年龄的增长而下降，是胸腺淋巴和基质细胞区室被脂肪细胞逐渐取代的直接结果，导致在称为胸腺复旧的过程中新 T 细胞的产生减少。众所周知，由于胸腺生成功能的减少，TCR 多样性在衰老过程中会经历收缩。这会对免疫监视产生不利影响，并增加感染和癌症的风险。众所周知，CR 对实验动物具有增强免疫的作用。我们最近发现，ghrelin；一种在 CR 期间上调的饥饿诱导激素通过促进啮齿类动物胸腺生成幼稚 T 细胞来增强 TCR 多样性。因此，我们假设人类的 CR 将通过促进胸腺生成幼稚 T 细胞来增加 ghrelin 的产生并增强 TCR 的多样性。为了检验这一假设，我们建议确定 CALERIE 参与者中 2 年 25% CR 的持续时间是否与对胸腺生成的积极或意外的不利影响相关。这些分析将在干预开始前、在基线、6、12 和 24 个月时对随意 (AL) 喂养和 CR CALERIE 受试者进行。该项目的总体目标是确定动物模型中观察到的 CR 诱导的前胸腺效应是否反映在人类的细胞和分子水平上。具体目标 #1 将比较 CR 和 AL 组之间的以下内容：(a) TCR 多样性，通过互补性决定区 3 长度多态性分析，(b) 胸腺输出，通过 T 细胞受体切除环定量，以及 (c) 胸腺输出通过化学位移磁共振成像测量胸腺的大小、体积及其脂肪含量。具体目标 #2 将确定 ghrelin 是否是这些受试者中 CR 促胸腺作用的主要介质。与 CALERIE 协调中心合作进行的这项辅助研究和分析产生的数据将提供第一份关于 CR 影响及其对人类适应性免疫系统影响的机制的全面记录。公共健康相关性：动物模型研究表明，在不出现营养不良的情况下限制热量可以延长健康寿命并减少与年龄相关的疾病。随着年龄的增长，产生新T淋巴细胞的胸腺被脂肪取代并失去其功能。目前的申请将调查人类两年的热量限制是否可以刺激胸腺功能，从而回答与热量限制作为增强健康非肥胖人群免疫系统的预防方法的功效相关的关键问题。