Interventions that Retard Mamalian Aging

描述(由申请人提供)：NIA干预测试计划是一项多地点转化性研究计划，旨在评估假想通过延缓衰老或延缓老年疾病而延长小鼠寿命的药物。最初，由来自研究界的多名合作科学家提出的干预措施在三个地点(杰克逊实验室、密歇根和德克萨斯州)进行平行测试，使用相同的标准化方案，并使用足够数量的遗传异质小鼠，在汇集来自任何两个测试地点的数据后，提供80%的功率来检测寿命的变化，无论性别为10%。在ITP的头四年里，已经开始了18个这样的“第一阶段”试验，在每个年度周期中测试4-5种新的药物。在第一个年度小鼠队列中测试的两种药物，阿司匹林和NDGA，显著增加了雄性小鼠的存活率。给20个月大的小鼠服用雷帕霉素，然后在867只雌性小鼠中92%和1098只雄性小鼠中96%死亡的情况下(2008年12月1日)进行评估，结果表明，雷帕霉素显著延长了雄性小鼠的寿命，雄性小鼠的P&lt；0.0001和雌性小鼠的P&lt；0.0001，在所有三个地点都有显著的相似结果。雷帕霉素治疗还导致男性和女性的最长寿命显著延长(P&lt；两性均为0.001)。雷帕霉素在9个月大时开始使用也显示出有益的效果，在第三组队列研究中，现在达到了中位存活年龄，在雄性(p=0.008)和雌性(p=0.0001)小鼠中都有显著意义。未来五年的计划包括完成所有正在进行的第一阶段试验，并每年启动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第二阶段研究将评估不同剂量的雷帕霉素对存活率的影响，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。这三个实验室在小鼠的寿命和生物标记物分析方面都有经验，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，密歇根的病理学和统计分析，以及德克萨斯州的药理学/毒理学。 相关性：在多个实验室中确定可以延长遗传异质性小鼠的平均和/或最长寿命的药物将为临床治疗提供建议，以防止或延缓随年龄增长的有害变化。此外，识别据称具有抗衰老作用的未经证实的治疗对健康的危害也将对公共健康有利。

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 (The Jackson Laboratory, 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.