Calorie Restriction and immune Response in Humans

说明(申请人提供)：衰老与免疫系统调节受损有关，这是导致老年受试者传染病、炎症性和肿瘤性疾病发病率增加以及疾病后恢复期延长的原因之一。此外，这些变化被证明可以预测动物模型和人类的发病率和死亡率。虽然免疫系统的所有细胞都有助于老年免疫功能的受损，但T细胞是主要的贡献者，包括人类在内的所有物种的T细胞功能的体内和体外测量中都报告了与年龄相关的变化。在动物模型中，卡路里限制(CR)已被证明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不清楚。NIA支持的两步多中心临床试验的试点阶段的初步结果显示，CR显著改善了人类的迟发性超敏反应和T细胞增殖，同时减少了T细胞抑制因子PGE2的产生。这两步临床试验旨在确定CR对人类的生物学效应[减少能量摄入长期效应综合评估(CALERIE)阶段1]。因此，我们假设成人受试者长期CR干预将增强免疫反应，这表明T细胞介导的功能得到改善，炎性介质的产生减少。此外，我们假设这些CR介导的T细胞效应是由于PGE2产生的减少和/或T细胞的内在变化。我们建议利用NIA支持的多中心随机对照临床试验第二阶段CALERIE第二阶段的受试者来验证这一假设。CALERIE第二阶段的总体目标是测试两年的成人受试者，从基线能量摄入开始，25%的CR对生理、代谢、身体成分、年龄相关病理的危险因素及其潜在的不良影响的影响。本项目的具体目的是确定2y，25%CR对成年受试者T细胞介导的功能的影响，并探讨其潜在的机制。具体而言，将在25%CR前、后1年和2年评估CR对免疫细胞特性、特定T细胞亚群的增殖能力、细胞内和细胞外IL-2、IFNY以及PGE2产生的影响。这项研究的结果将是第一个关于CR对人类免疫反应影响的文献，在各种动物模型中，CR是一个具有生物学意义和临床相关性的标志物。拟议的研究还将探索CR诱导免疫反应调节的潜在机制，并将通过深入了解CR诱导的健康影响的细胞和分子机制，为母公司CALERIE第二阶段研究增加有价值的信息。

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.