Calorie Restriction and immune Response in Humans

描述（由申请方提供）：衰老与免疫系统调节受损相关，这导致在老年受试者中观察到的感染性、炎症性和肿瘤性疾病的发生率增加以及疾病后恢复期延长。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力受损，但T细胞是主要贡献者，在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年龄相关的变化。在动物模型中，热量限制（CR）已被证明会影响许多年龄敏感的免疫应答，但有关CR对人类免疫应答影响的信息尚缺乏。确定CR在人体中的生物学效应的两步NIA支持的多中心临床试验的初步结果[减少能量摄入长期效应的综合评估（CALERIE）第1阶段]显示，CR显著改善了人体迟发型超敏反应皮肤反应以及T细胞增殖，同时减少了T细胞抑制因子PGE 2的产生。因此，我们假设在成人受试者中的长期CR干预将增强免疫应答，如通过改善T细胞介导的功能和减少炎症介质的产生所指示的。此外，我们假设这些CR介导的T细胞的影响是由于减少PGE 2的生产和/或内在的变化在T细胞。我们建议利用入组NIA支持的多中心随机对照临床试验CALERIE II期第二阶段的受试者来检验这一假设。CALERIE II期研究的总体目标是在成人受试者中测试2年、25% CR（相对于基线能量摄入）对生理学、代谢、身体成分、年龄相关病理学风险因素及其潜在不良反应的影响。本项目的具体目的是确定2年，25% CR对成人受试者T细胞介导的功能的影响，以及探索其潜在的机制。具体而言，将在25%CR之前以及之后1年和2年评价CR对免疫细胞谱、特定T细胞亚群的增殖能力、细胞内和细胞外IL-2、IFN γ以及PGE 2产生的影响。本研究的结果将是CR对人体免疫应答影响的首次记录，这是一种具有生物学意义和临床相关性的标志物，在各种动物模型中对CR敏感。拟定的研究还将探索CR诱导的免疫应答调节的潜在机制，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CALERIE II期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.