Center for Testing Potential Anti-Aging Interventions

描述（由申请人提供）：NIA干预测试项目是一个多站点的转化研究项目，旨在评估通过延缓衰老或延缓晚年疾病来延长小鼠寿命的药物。来自研究界的多名合作科学家提出的干预措施最初在三个地点（杰克逊实验室、密歇根州和德克萨斯州）并行进行测试，使用相同的标准化方案，并使用足够数量的基因异质小鼠，在汇集任何两个测试地点的数据后，提供80%的功率来检测男女寿命的10%变化。在ITP的头四年里，已经开始了18个这样的“第一阶段”试验，每个年度周期测试4-5种新药。在第一个年度小鼠队列中测试的两种药物阿司匹林和NDGA显著提高了雄性小鼠的存活率。在小鼠20个月大时给予雷帕霉素，然后在一个时间点（2008年12月1日）进行评估，在这个时间点上，867只雌性小鼠中有92%死亡，第2队列中有1098只雄性小鼠中有96%死亡，雷帕霉素产生了显著的寿命延长，雄性和雌性的p < 0.0001，在所有三个地点都有显著的平行结果。雷帕霉素治疗还导致男性和女性的最大寿命显著增加（男女均p < 0.001）。在一项队列3研究中，雷帕霉素在9个月大时也显示出有益的效果，现在已经达到中位生存年龄，在雄性（p = 0.008）和雌性（p = 0.0001）小鼠中都很显著。未来五年的计划包括完成所有正在进行的第一阶段试验，并每年开展三个或更多新的第一阶段试验。此外，一项更详细的雷帕霉素II期研究将评估不同剂量的雷帕霉素对生存的影响，测试一系列年龄敏感特征和提出的机制途径，记录横断面病理学，并提供小鼠和组织供其他人分析。这三个实验室都在老鼠的寿命和生物标志物分析方面有经验，此外还将为合作带来特殊的专业知识：杰克逊实验室的年龄敏感特征测量，密歇根的病理和统计分析，德克萨斯的药理学/毒理学。

DESCRIPTION (provided by applicant): The NIA Interventions Testing Program represents a multi-site translational research program to evaluate agents hypothesized to extend mouse lifespan by retardation of aging or postponement of late life diseases. Interventions proposed by multiple collaborating scientists from the research community are initially tested, in parallel, at three sites (Jackson Laboratories, Michigan and Texas), using identical, standardized protocols, and using sufficient numbers of genetically heterogeneous mice to provide 80% power for detecting changes in lifespan of 10%, for either sex, after pooling data from any two of the test sites. Eighteen such 'Phase I' trials have been started in the first four years of the ITP, with 4-5 new agents tested in each annual cycle. Two agents tested in the first annual mouse cohort, aspirin and NDGA, produced significant increases in survival of male mice. Rapamycin, given to mice at 20 months of age and then evaluated at a point (Dec 1, 2008) where 92% of 867 female mice, and 96% of 1098 male mice from Cohort 2 had died, produced robust lifespan increases with p < 0.0001 for males and p < 0.0001 for females, with significant parallel results at all three sites. Rapamycin treatment also led to a significant increase in maximum lifespan both in males and in females (p < 0.001 in each sex). Rapamycin also shows a beneficial effect when initiated at 9 months of age, in a Cohort 3 study now reaching the median survival age, significant in both male (p = 0.008) and female (p = 0.0001) mice. Plans for the next five years include completion of all ongoing Phase I trials and initiation of three or more new Phase I trials each year. In addition, a more elaborate Phase II study of Rapamycin will evaluate the effects of varying doses of this agent on survival, test a range of age-sensitive traits and proposed mechanistic pathways, document cross-sectional pathology, and provide mice and tissues for analyses by others. Each of the three laboratories has experience in lifespan and biomarker analysis in mice, and in addition will bring special expertise to the collaboration: measures of age-sensitive traits at the Jackson Laboratory, pathology and statistical analysis at Michigan, and pharmacology/toxicology at Texas. RELEVANCE: Identification of agents that can extend mean and/or maximum longevity in genetically heterogeneous mice in multiple laboratories will suggest research directions leading to clinical treatments designed to prevent or retard deleterious changes with age. In addition, identifying health dangers of unproven treatments that are purported to have anti-aging actions will also have public health benefits.