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: 7579762
• 负责人: VISHWA DEEP DIXIT
• 金额: $ 24.59万
• 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/7579762
• 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; Obesity; Organ; Output; Participant; Phase; Phase II Clinical Trials; Polymorphism Analysis; Predisposition; Preventive; Primates; Process; Production; Proteins; 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; public health relevance; reconstitution; response; 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）：动物模型的研究表明，卡路里限制（CR）延长了健康的寿命。 NIH资助的减少能源摄入（Calerie）2期试验的长期影响的综合评估旨在检验以下假设：人类中的CR会导致动物模型中发生类似的适应性变化。当前的项目是一项对热量的辅助研究，该研究将评估一种重要的生物学机制，通过该机制，CR可能会对健康衰老产生有益的影响。胸腺产生对自蛋白不反应但拥有宽T细胞受体（TCR）曲目识别和清除任何可能异物抗原的T细胞的能力至关重要。随着年龄的增长，细胞免疫的下降是用脂肪细胞逐渐替代胸腺淋巴样和基质细胞室的直接结果，在称为胸腺互不e的过程中导致新的T细胞的产生减少。众所周知，TCR多样性由于胸腺胞菌的减少而导致衰老期间经历收缩。并且这会对免疫监视，并增加感染和癌症的风险。众所周知，CR在实验动物中具有免疫增强作用。我们最近确定了Ghrelin；在CR期间上调的饥饿诱导激素通过促进啮齿动物中胸腺的幼稚T细胞的产生来增强TCR多样性。因此，我们假设人类中的CR将通过促进胸腺的Naove T细胞产生生成Hagrelin的产生并增强TCR多样性。为了检验这一假设，我们建议确定25％Cr的持续时间是否在表征良好的卡利亚参与者中与对胸腺胞菌的正面或意外不利影响有关。分析将在基线开始，在Adbitum（Al）Fed和CR Calerie受试者的基线，6、12和24个月之前进行。该项目的总体目标是确定在人类的细胞和分子水平上，在动物模型中看到的CR诱导的胸膜效应是否反映。通过确定区域3长度多态性分析的互补性，（b）胸腺输出，通过定量T细胞受体切除圈和（c）（c）对胸腺尺寸，体积及其脂肪含量与化学磁磁共振成像的脂肪含量，通过确定区域3长度多态性分析，（b）胸腺输出的互补性来比较CR和AL组（A）TCR多样性之间的以下各种（A）TCR多样性。特定的目标＃2将确定生长素素是否是CR在这些受试者中的促胸腺疗法作用的主要介体。这项辅助研究产生的数据以及与卡利亚协调中心合作的分析，将提供第一个全面的CR影响影响和对其对人类适应性免疫系统的影响的机制的全面文件。公共卫生相关性：动物模型的研究表明，无营养不良的热量限制可增强健康的寿命并减少与年龄有关的疾病。随着年龄的增长，胸腺的新T淋巴细胞生产部位被脂肪取代并失去其功能。当前的应用将调查人类中2年的热量限制是否可以刺激胸腺的功能，从而回答与热量限制的功效有关的关键问题，以此作为增强健康非肥胖者免疫系统的预防方法。