Calorie Restriction and immune Response in Humans

提供了 衰老与免疫系统的调节受损有关，这有助于增加免疫系统的功能。 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病率以及 病后恢复期延长。此外，这些变化被证明是预测 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，T细胞是主要贡献者， 包括人在内的所有物种的T细胞功能的体内和体外测量。热量限制 (CR)在动物模型中已显示影响许多年龄敏感性免疫应答，但 缺乏与CR对人类免疫应答的影响相关的信息。的初步结果 两步NIA支持的多中心临床试验的试验阶段，以确定 人类CR [减少能量摄入长期影响的综合评估 （CALERIE）1期]，显示CR显著改善迟发型超敏反应皮肤反应， 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的CR干预将增强免疫功能。 应答，如通过改善的T细胞介导的功能和减少的 炎症介质。此外，我们假设这些CR介导的对T细胞的作用 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第二阶段招募的受试者来检验这一假设， 多中心随机对照临床试验，CALERIE II期。CALERIE第二阶段的总体目标是 在成人受试者中测试2年、25% CR（相对于基线能量摄入）对生理学的影响， 代谢、身体组成、年龄相关病理学的风险因素及其潜在的不良反应。 本项目的具体目的是确定2年，25% CR对T细胞介导的功能的影响， 成人受试者，以及探讨其潜在的机制。特别是CR对免疫功能的影响 细胞谱、特异性T细胞亚群的增殖能力、细胞内和细胞外IL-2、IFN γ，以及 将在25% CR之前和之后1年和2年评价PGE2产生。 这项研究的结果将是CR对免疫应答影响的第一个文件， 在人类中，一种具有生物学意义和临床相关性的标记物，在各种疾病中对CR敏感。 动物模型拟议的研究还将探讨CR诱导的潜在机制。 调节免疫反应，并将为母公司CALERIE第2阶段增加有价值的信息 通过深入了解CR诱导的健康效应的细胞和分子机制来进行研究。

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.