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

描述（由申请人提供）：已知卡路里限制可以延长许多物种的平均寿命和最长寿命。最被广泛接受的衰老理论之一是氧化应激理论，该理论假设活性氧（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。由于活性氧是能量代谢的副产物，我们假设热量限制会导致代谢适应（能量消耗的减少大于代谢体型的减少），从而减少活性氧介导的氧化损伤。更具体地说，我们假设在呼吸室测量的能量消耗减少（24小时久坐和睡眠）将大于基于无脂量和脂肪量变化的预期，这种适应与交感神经和甲状腺系统活动减少有关。此外，我们将确定这种代谢适应的程度是否与卡路里限制引起的脂质（尿异前列腺素）、蛋白质（血液）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依赖于能量平衡状态，因为研究将在25%卡路里限制1年后（可能仍处于负能量平衡状态）和2年后（现在处于能量平衡状态）进行。拟议的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）中获得的体外和体内线粒体功能测量数据进行比较。公共卫生相关性：拟议的研究旨在验证一个主要假设，该假设解释了为什么热量限制会延长几乎所有动物的寿命。这种假说“存活率理论”指出，动物的预期寿命与单位体重的代谢率成反比。我们建议测试50名志愿者，在2年的时间里，每天少摄入25%的卡路里，是否降低了“生活速率”（能量代谢）与伴随的体温和氧化应激的降低有关。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.