Calorie Restriction and immune Response in Humans

但前提是。 衰老与免疫系统的调节受损有关，这是导致 老年人感染性、炎症性和肿瘤性疾病的发病率及其影响因素 疾病后恢复期延长。此外，这些变化被证明是对 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 老年人的免疫功能受损，T细胞是主要贡献者，据报道与年龄相关的变化 在体内和体外测量包括人类在内的所有物种的T细胞功能。卡路里限制 在动物模型中，(Cr)已被证明影响许多年龄敏感的免疫反应，但 关于CR对人体免疫反应的影响，目前还缺乏相关信息。初步结果来自 NIA支持的两步多中心临床试验的试点阶段，以确定阿司匹林的生物学效应 人类的CR[减少能量摄入的长期影响的综合评估 (CALERIE)阶段1]，显示CR显著改善了迟发性皮肤过敏反应， 以及T细胞增殖，同时减少T细胞抑制因子PGE2的产生。 因此，我们假设在成人受试者中进行长期CRR干预将增强免疫力。 反应，如T细胞介导的功能改善和减少产生 炎症介质。此外，我们假设这些CR介导的T细胞效应 是由于PGE2的产生减少和/或T细胞的内在变化。 我们建议利用NIA支持的第二阶段登记的受试者来检验这一假设 多中心随机对照临床试验，CALERIE第二阶段。CALERIE第二阶段的总体目标是 为了在成人受试者中测试从基础能量摄入量开始的两年，25%的CR对生理的影响， 代谢，身体成分，年龄相关疾病的危险因素，及其潜在的不良影响。 本项目的具体目标是确定2年，25%CR对T细胞介导的T细胞功能的影响 成人受试者，以及探索其潜在的机制。特别是CR对免疫功能的影响 细胞形态、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的产量，将在25%的CR之前和1年和2年后进行评估。 这项研究的结果将是关于CR对免疫反应的影响的第一个文献。 人类是一种具有生物学意义和临床相关性的标记，在各种疾病中对CR敏感 动物模型。拟议的研究还将探索CR诱导的潜在机制 调节免疫反应，并将为亲本CALERIE阶段2增加有价值的信息 通过深入了解CR引起的健康效应的细胞和分子机制进行研究。

PROVIDED. 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 CRintervention 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.