CALERIE Competitive Renewal

描述（由申请人提供）：所有生理系统都经历与年龄相关的功能衰退，可以将其描述为“原发性老化”。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）来延迟甚至预防。在人类中，第一个关于能量限制效果的实验是由Keyset.al20世纪50年代进行的。在这些经典的实验中，瘦志愿者消耗了他们习惯卡路里摄入量的50%。当校正体表面积、体重和细胞质量时，基础代谢率降低。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，并且已经观察到显着的CR益处。在2001年和2002年，国家老龄化研究所（NIA）发布了申请，以进行详细的临床研究，以了解CR在人类中的影响。声明的目的是，"...了解持续CR对人体生理学、代谢、身体组成、年龄相关病理学风险因素的影响。及其潜在的负面影响。“该计划的第一阶段已经完成，经过详细和全面的发展过程，第二阶段的研究已经开始。把握度计算表明，为了解决主要研究结局以及重要的次要和探索性结局，应入组250例受试者。然而，到2009年3月，我们预计只随机分配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，全部补充250名参与者。具体目标是：（1）将两个主要结局的统计功效维持在最初计划的水平;（2）将重要次要和探索性结局的统计功效提高到相对于仅入组150人的研究更可接受的水平;（3）以快速的方式完成2期研究的志愿者入组，并最大限度地减少参与者脱落;（4）采取详细的程序，以保障干预的准确性，并对结果的确定保持质量控制;（5）将生物样本储存在中央储存库中，并为更大的科学界进行机制研究提供机会;（6）进行详细的统计分析。 相关性（参见说明）：CALERIE是第一个全面的研究，以确定是否在动物研究中观察到的热量限制的有益影响延伸到人类。最终，CALERIE将进一步加深我们对人类衰老过程的基本生物学知识。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.