Calorie Restriction and immune Response in Humans

描述（由申请人提供）：衰老与免疫系统调节功能受损有关，这导致老年人感染、炎症和肿瘤疾病的发病率增加，并且他们的病后恢复期延长。此外，在动物模型和人类中，这些变化被证明可以预测发病率和死亡率。虽然免疫系统的所有细胞都会导致老年免疫功能受损，但T细胞是主要的贡献者，在包括人类在内的所有物种的体内和体外T细胞功能测量中都报道了年龄相关的变化。在动物模型中，卡路里限制（CR）已被证明可以影响许多年龄敏感的免疫反应，但关于CR对人类免疫反应的影响的相关信息尚缺乏。nia支持的两步多中心临床试验（减少能量摄入的长期影响综合评估（CALERIE） 1期）的初步结果显示，CR显著改善了人体延迟型超敏性皮肤反应和T细胞增殖，同时减少了T细胞抑制因子PGE2的产生。因此，我们假设成人受试者的长期CR干预将增强免疫反应，正如T细胞介导的功能改善和炎症介质的产生减少所表明的那样。此外，我们假设这些cr介导的对T细胞的影响是由于PGE2生成的减少和/或T细胞的内在变化。我们建议使用NIA支持的多中心随机对照临床试验CALERIE二期二期的受试者来验证这一假设。CALERIE第2期的总体目标是测试2年25%的基线能量摄入对成人受试者生理、代谢、身体组成、年龄相关病理的危险因素及其潜在不良影响的影响。该项目的具体目的是确定2y， 25% CR对成人受试者T细胞介导功能的影响，并探索其潜在机制。具体来说，CR对免疫细胞谱、特异性T细胞亚群增殖能力、细胞内和细胞外IL-2、IFNy以及PGE2产生的影响将在25% CR治疗前和治疗后1年和2年进行评估。这项研究的结果将首次记录CR对人类免疫反应的影响，这是一种具有生物学意义和临床相关的标志物，在各种动物模型中显示对CR敏感。拟议的研究还将探索CR诱导的免疫反应调节的潜在机制，并通过深入了解CR诱导的健康效应的细胞和分子机制，为母体CALERIE 2期研究提供有价值的信息。

DESCRIPTION (provided by applicant): Aging is associated with impaired regulation of the immune system, which contributes to the increased incidence of infectious, inflammatory and neoplastic diseases observed in elderly subjects as well as their prolonged post-illness recovery periods. In addition, these changes were shown to be predictive of morbidity and mortality in animal models and humans. While all cells of the immune system contribute to the impaired immunity of old age, T cells are the main contributors, with age related changes reported in both in vivo and in vitro measures of T cell function across all species including humans. Calorie restriction (CR) has been shown to affect many age sensitive immunological responses in animal models, but information related to the effects of CR on immune response of humans is lacking. Preliminary results from the pilot phase of the two-step NIA-supported multi-center clinical trial to determine the biological effects of CR in humans [Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) Phase 1], showed that CR significantly improved delayed type hypersensitivity skin response, as well as T cell proliferation, in humans while decreasing production of T cell suppressive factor, PGE2. Thus, we hypothesize that long term CR intervention in adult subjects will enhance the immune response, as indicated by improved T cell-mediated function and reduced production of inflammatory mediators. Furthermore, we hypothesize that these CR-mediated effects on T cells are due to decrease in PGE2 production and/ or intrinsic changes in T cells. We propose to test this hypothesis utilizing subjects enrolled in the second phase of the NIA supported multi-center randomized controlled clinical trial, CALERIE Phase 2. The overall aim of CALERIE Phase 2 is to test the effects of 2 year, 25% CR from baseline energy intake, in adult subjects, on physiology, metabolism, body composition, risk factors for age-related pathologies, and its potential adverse effects. The specific aims of this project are to determine the effect of 2 y, 25% CR on T cell-mediated functions of adult subjects, as well as to explore its underlying mechanisms. Specifically the effect of CR on immune cell profile, proliferate ability of specific T cell subsets, intracellular and extracellular IL-2, IFNy, as well as PGE2 production, will be evaluated before, and following 1 and 2 years of 25% CR. The results from this study will be the first documentation of the impact of CR on immune response in humans, a biologically meaningful and clinically relevant marker shown to be sensitive to CR in various animal models. The proposed studies will also explore the underlying mechanisms of CR-induced modulation of the immune response and will add valuable information to the parent CALERIE Phase 2 studies by providing insight into the cellular and molecular mechanisms of CR induced health effects.