Dietary Energy Restriction and Metabolic Aging in Humans

降低发病率和延缓死亡率被认为是衰老研究的主要目标，本研究建议开展为期2年的人类热量限制（CR）干预。一项为期1年的试点研究将在32名超重男性和女性中进行，以制定有效的CR方案，当以基线确定的能量需求的70%喂养时。作为该试验的一部分，我们将完善CR干预的所有方面，包括锻炼和行为咨询，并将获得有关结果可变性的必要信息，以进行主要研究的功效计算。受试者将被随机分配到两种具有不同膳食脂肪和血糖指数（GI）水平的饮食方案中（20%脂肪和中等GI vs 35%脂肪和低GI），饮食依从性和关键结果测量将在全年的5个时期确定。在设计干预措施时，将考虑诸如膳食种类、液体能量来源和膳食纤维等饮食因素。在确定了有效的CR方案后，将对117名超重的男性和女性进行为期2年的随机干预，分别给予70%、80%或100%的基线能量需求。这个假设将会被验证，与被喂食100%基线能量需求的对照组相比。待评估的参数包括免疫功能、氧化应激、空腹胰岛素、血红蛋白Alc和心肺功能。我们进一步假设，与对照受试者相比，随机分配到70%或80%基线能量需求的个体在甲状腺和生殖激素、骨密度、疾病发病率、情绪或认知功能方面不会发生不利变化。预期CR程度与结果变量变化之间的剂量-反应关系。作为研究的一部分，总能量消耗和静息代谢率、身体组成和体温的变化将被量化，以记录CR对能量代谢的影响。我们预计这项研究的结果将对我们理解CR与人类健康的相关性产生重大影响。此外，这项研究将有助于开发新的途径，长期治疗超重和肥胖。

Reducing morbidity and delaying mortality are recognized as major goals of aging research, and are addressed by this proposal to conduct a 2-year human caloric restriction (CR) intervention. A 1-year pilot study will be conducted in 32 overweight men and women to develop an effective CR regimen when fed at 70% of energy requirements determined at baseline. As part of this pilot we will refine all aspects of a CR intervention, including exercise and behavioral counseling, and will obtain necessary information on outcome variability with which to perform power calculations for the main study. Subjects will be randomized to two dietary regimens with different levels of dietary fat and glycemic index (GI) (20% fat and moderate GI vs. 35% fat and low GI) and dietary compliance and key outcome measurements will be determined at 5 periods throughout the year. Dietary factors such as dietary variety, liquid sources of energy, and dietary fiber will then be taken into account in the design of the interventions. Following identification of an effective CR regimen, a randomized 2- year intervention will be conducted in 117 overweight men and women fed 70%, 80% or 100% of energy requirements determined at baseline. The hypothesis will be tested that, compared to control subjects fed 100% of baseline energy requirements. The parameters to be evaluated will include immune function, oxidative stress, fasting insulin, hemoglobin Alc, and cardiopulmonary function. W further hypothesize that, compared control subjects, individuals randomized to 70% or 80% of baseline energy requirements will not experience adverse change sin thyroid and reproductive hormones, bone mineral density, disease incidence, mood or cognitive function. Dose-response relationships between the extent of CR and changes in outcome variables are anticipated. As part of the study, changes in total energy expenditure and resting metabolic rate, body composition and body temperature will be quantified to document the effects of CR on energy metabolism. We anticipate that the results of this study will have a major impact on our understanding of the relevance of CR to human health. In addition, this study will contribute to the development of new avenues for long- term treatment of overweight and obesity.