CALERIE Competitive Renewal

描述(申请人提供)：所有生理系统都会经历与年龄相关的功能减退，这可以被描述为“初级衰老”。越来越多的证据表明，这些变化中的许多可以通过长期热量限制(CR)来延迟甚至防止。20世纪50年代，Keys等人在人类身上进行了关于能量限制影响的第一次实验。在这些经典实验中，苗条的志愿者消耗了他们习惯性卡路里摄入量的50%。根据体表面积、体重和细胞质量进行调整后，基础代谢率有所下降。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，大多数信息来自动物模型，并且已经观察到显著的CR益处。2001年和2002年，美国国家老龄研究所(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对人体的生理、新陈代谢、身体成分、年龄相关疾病的风险因素的影响……及其潜在的不良影响。”该方案的第一阶段已经完成，在经过详细和全面的开发过程后，第二阶段的研究已经开始。POWER计算表明，要解决主要研究结果以及重要的次要和探索性结果，应招募250名参与者。然而，到2009年3月，我们预计只随机选择170名参与者。因此，本申请要求提供资金，以完成第二阶段研究，参加人数达250人。具体目标是：(1)将两个主要成果的统计能力维持在最初计划的水平；(2)与只有150人参加的研究相比，将重要的次要和探索性成果的统计能力提高到更可接受的水平；(3)迅速完成第二阶段研究的志愿者招募，最大限度地减少参与者辍学；(4)采取详细程序，确保干预措施的准确性，并保持对结果确定的质量控制；(5)将生物样本储存在中央储存库，为更大的科学界进行机械研究提供机会；以及(6)进行详细的统计分析。 相关性(见说明书)：CALERIE是第一个确定在动物研究中观察到的卡路里限制的有益影响是否延伸到人类的综合研究。最终，CALERIE将进一步加深我们对人类衰老过程的基本生物学的了解。它还可能有助于制定延缓衰老和与年龄有关的疾病的实用战略。

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.