Center for Testing Potential Anti-Aging Interventions

鉴定延长小鼠寿命的小分子提供了新的见解， 哺乳动物寿命决定的机制，并可能为最终的 人类的抗衰老疗法NIA干预测试计划（ITP）评估代理商 提出通过延缓衰老或推迟晚年来延长小鼠寿命 疾病研究中多位合作科学家提出的干预措施 社区进行了测试，在三个地点平行（杰克逊实验室，密歇根大学 和德克萨斯大学），使用相同的标准化方案，并使用足够数量的 基因异质性小鼠的寿命变化提供80%的功率检测 在汇总任何两个试验中心的数据后，任何性别均为10%。72个这样的寿命 实验，涉及各种剂量的44种不同的代理，已开始在前十五年 多年的ITP。37个实验涉及多剂量的比较试验， 有效的药物、可变的起始年龄或替代的给药方案。显著影响 已经记录了一种或两种性别的长寿，然后证实了NDGA， 雷帕霉素、阿卡波糖和17-α-雌二醇（17 aE 2），具有显著（但目前未证实） 在中期分析中，还观察到Protandim、甘氨酸和卡格列净的影响。寿命试验 目前正在招募18名新特工。ITP生存结果也记录了寿命 受益于三种药物开始在中年：雷帕霉素，阿卡波糖，和17 aE 2。的 在过去的五年中，ITP引入了三个新的特点： 健康结果（与人类健康有关的功能测试，不一定与寿命有关），a 合作互动计划，以提供组织从ITP药物治疗的小鼠，以一个开放的， 不断增长的国际科学合作者网络，以及可公开访问的数据 存储库和显示引擎由杰克逊的小鼠表型数据库托管 实验室下一个五年期的计划包括额外的寿命期（“第一阶段”）试验， 对发现可延长寿命的药物进行详细分析（“第二阶段”）， 健康结果，并与科学家合作，研究药物对假设的 衰老机制和疾病的联系。在得克萨斯州的研究，旨在补充和扩展 联合ITP的发现，将继续我们的研究的年龄特异性和基础的性 生命延长药物的二态性我们将继续对这些影响的临床前工作 药物对衰老小鼠的健康寿命和功能缺陷的影响。拟议的工作应允许 ITP将继续为哺乳动物衰老生物学做出重大贡献。

Identification of small molecules that extend mouse lifespan provides new insights into mechanisms of longevity determination in mammals, and may lay the groundwork for eventual anti-aging therapies in humans. The NIA Interventions Testing Program (ITP) evaluates agents proposed 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 tested, in parallel, at three sites (Jackson Laboratories, University of Michigan and University of 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. Seventy-two such lifespan experiments, involving various doses of 44 distinct agents, have been initiated in the first fifteen years of the ITP. Thirty-seven experiments have involved comparative tests of multiple doses of effective agents, variable starting ages, or alternative dosing schedules. Significant effects on longevity, in one or both sexes, have been documented and then confirmed for NDGA, rapamycin, acarbose, and 17-α-estradiol (17aE2), with significant (but currently unconfirmed) effects also noted for Protandim, glycine and, in an interim analysis, canagliflozin. Lifespan trials are now underway for 18 new agents. ITP survival results have also documented longevity benefits from three agents started in middle-age: rapamycin, acarbose, and 17aE2. The previous five year period has introduced three new features to the ITP: increased emphasis on health outcomes (functional tests relevant to human health not necessarily linked to lifespan), a Collaborative Interactions Program to provide tissues from ITP drug-treated mice to an open, growing, international network of scientific collaborators, and a publicly accessible data repository and display engine hosted by the Mouse Phenome Database at the Jackson Laboratory. Plans for the next five-year period include additional lifespan ("Stage I") trials, detailed analyses ("Stage II") of agents found to increase lifespan, continued growth in data on health outcomes, and collaborative work with scientists to study drug effects on postulated aging mechanisms and links to disease. Studies at Texas, aimed to complement and extend joint ITP discoveries, will continue our research on the age specificity of and basis for the sexual dimorphism of life-extending drugs. We will continue pre-clinical work on the effects of these agents on healthspan and functional deficits in aging mice. The work proposed should allow the ITP to continue making major contributions to mammalian aging biology.