Metabolic Adaptation After 2 Years of Caloric Restriction in Non-Obese Humans

描述（由申请人提供）：众所周知，热量限制可以延长许多物种的平均和最大寿命。最广泛接受的衰老理论之一是氧化应激理论，该理论假设由活性氧（ROS）产生的氧化损伤随着时间的推移而积累，导致衰老疾病的发展，如癌症、心血管疾病、虚弱和最终死亡。由于ROS是能量代谢的副产品，我们假设热量限制将导致与ROS介导的氧化损伤减少相关的代谢适应（能量消耗的减少大于代谢体型的减少）。更具体地说，我们假设在呼吸室中测量的能量消耗（24小时久坐和睡眠）的减少将大于基于无脂肪质量和脂肪质量变化的预期，并且这种适应与交感神经和甲状腺系统活动的减少有关。此外，我们将确定这种代谢适应的程度是否与热量限制诱导的脂质（尿异前列腺素），蛋白质（血液中）和DNA（有核血细胞）氧化应激标志物的减少有关。我们将首次确定代谢适应是否持久并取决于能量平衡状态，因为研究将在25%卡路里限制1年（可能仍处于负能量平衡）和2年（现在处于能量平衡）后进行。拟定研究将作为热量限制随机临床试验（CALERIE）的辅助研究进行。重要的是，我们的数据将与另一项辅助研究（PI，SR Smith）中体外和体内测量的线粒体功能进行比较。公共卫生相关性：拟议的研究旨在测试一个主要假设，该假设解释了为什么热量限制会增加几乎所有动物物种的寿命。这个假说“生活理论的速率”指出，动物的预期寿命与其每单位重量的代谢率呈负相关。我们建议在50名志愿者中测试“生活率”（能量代谢）的降低是否与体温和氧化应激的伴随降低有关，每天消耗25%的热量，持续2年。低体温和低氧化应激都预示着更长的寿命。

DESCRIPTION (provided by applicant): Calorie restriction is known to prolong average and maximum life spans in many species. One of the most widely accepted theories of aging is the oxidative stress theory which hypothesizes that oxidative damage produced by reactive oxygen species (ROS) accumulates over time leading to the development of diseases of aging such as cancer, cardiovascular disease, frailty and eventually death. Since ROS is a byproduct of energy metabolism, we hypothesize that calorie restriction will cause a metabolic adaptation (decrease in energy expenditure larger than accounted for by the decrease in metabolic body size) associated with a decrease in ROS-mediated oxidative damage. More specifically, we hypothesize that the decrease in energy expenditure (24-hour sedentary and sleeping) measured in a respiratory chamber will be larger than that expected on the basis of the changes in fat-free mass and fat mass and that this adaptation is associated with reduced activities of the sympathetic and thyroid systems. Furthermore, we will determine whether the magnitude of this metabolic adaptation is related to the calorie restriction-induced decrease in markers of oxidative stress to lipids (urinary isoprostanes), proteins (in blood) and DNA (nucleated blood cells). We will determine for the first time whether the metabolic adaptation is long lasting and dependent on the state of energy balance since studies will be performed after 1 year (probably still in negative energy balance) and after 2 years (now in energy balance) of 25% calorie restriction. The proposed study will be conducted as an ancillary study of a randomized clinical trial of calorie restriction (CALERIE). Importantly, our data will be compared to those obtained on mitochondrial function measured in vitro and in vivo in another ancillary study (PI, SR Smith). PUBLIC HEALTH RELEVANCE: The proposed studies have been designed to test one of the major hypotheses explaining why caloric restriction increases lifespan in almost all animal species. This hypothesis "rate of living theory" states that life expectancy of an animal is inversely related to its metabolic rate per unit of weight. We propose to test whether a lowering of the "rate of living" (energy metabolism) is associated with an accompanying decrease in body temperature and oxidative stress in 50 volunteers consuming 25% less calories per day for 2 years. Both low body temperature and low oxidative stress are predictive of longer life.