CALERIE Competitive Renewal

描述（由申请人提供）：所有生理系统都会经历与年龄相关的功能衰退，这可以被描述为“原发性衰老”。越来越多的证据表明，许多这些变化可以通过长期的热量限制（CR）来延缓甚至阻止。在人类中，Keys等人在20世纪50年代进行了第一次关于能量限制效果的实验。在这些经典的实验中，瘦弱的志愿者消耗了他们惯常摄入热量的50%。根据体表面积、体重和细胞质量进行调整后，基本代谢率有所下降。然而，也有营养不良的迹象，许多微量营养素缺乏。除了这个实验之外，大多数信息来自动物模型，并且已经观察到显著的CR益处。在2001年和2002年，国家老龄化研究所（NIA）发布了申请申请，要求对CR对人类的影响进行详细的临床研究。声明的目的是，“……了解持续CR对人体生理、代谢、身体成分、年龄相关病理风险因素的影响……以及潜在的负面影响。”该项目的第一阶段已经完成，经过详细和全面的开发过程后，第二阶段的研究已经开始。功率计算表明，为了解决主要研究结果，以及重要的次要和探索性结果，应该招募250名参与者。然而，到2009年3月，我们预计只会随机抽取170名参与者。因此，本申请要求供资以完成第2阶段的研究，其中有250名参与者。具体目标是：(1)在原计划水平上保持两个主要结果的统计效力；(2)将重要的次要和探索性结果的统计能力提高到更容易接受的水平，而不是只纳入150人的研究；(3)尽快完成2期研究志愿者的招募，尽量减少受试者退出；(4)制定详细的程序，以保障干预的保真度，并保持对结果确定的质量控制；(5)在中央储存库中储存生物样品，并为更大的科学界提供机理研究的机会；(6)进行详细的统计分析。

DESCRIPTION (provided by applicant): All physiological systems experience age-associated decrements in function that can be described as "primary aging." There is mounting evidence that many of these changes can be delayed or even prevented by long-term caloric restriction (CR). In humans, the first experiments on the effect of energy restriction were performed by Keys et.al in the 1950s. In these classic experiments, lean volunteers consumed 50% of their habitual caloric intake. There was a decrease in basic metabolic rate when adjusted for body surface area, body weight, and cell mass. However, there were also indications of malnutrition with deficiencies in many micronutrients. Beyond this experiment, most information comes from animal models, and significant CR benefits have been observed. In 2001 and 2002, the National Institute on Aging (NIA) issued Requests for Application to perform detailed clinical studies into the effects of CR in humans. The stated purpose was,"... to gain knowledge about the effects in humans of sustained CR on physiology, metabolism, body composition, risk factors for age-related pathologies ... and its potential adverse effects." Phase 1 of the program has been completed, and following a detailed and comprehensive developmental process, the Phase 2 study has begun. Power calculations indicate that to address the primary study outcomes, as well as important secondary and exploratory outcomes, 250 participants should be enrolled. By March 2009, however, we anticipate randomizing only 170 participants. The present application therefore requests funding to complete the Phase 2 study with the full complement of 250 participants. The Specific Aims are: (1) maintain statistical power for the two primary outcomes at the originally planned levels; (2) increase statistical power for important secondary and exploratory outcomes to more acceptable levels relative to a study with only 150 enrolled; (3) complete enrollment of volunteers into the Phase 2 study in an expeditious manner and minimize participant drop-out; (4) undertake detailed procedures to safeguard the fidelity of the intervention and maintain quality control over the outcome determinations; (5) store biological samples in a central repository, and provide opportunities for mechanistic studies by the greater scientific community; and, (6) perform detailed statistical analyses. RELEVANCE (See instructions): CALERIE is the first comprehensive study to determine whether the salutary effects of caloric restriction observed in animal studies extend to human beings. Ultimately, CALERIE will further our knowledge of the basic biology of the human aging process. It may also contribute to development of practical strategies for retardation of aging and age-related diseases.