Interventions that Retard Mammalian Aging

延缓哺乳动物衰老的干预措施

• 批准号: 10620826
• 负责人: DAVID E HARRISON
• 金额: $ 175万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620826
• 关键词: Acarbose; Adult; Age; Aging; Biology of Aging; Body Temperature; Clinic; Clinical Treatment; Collaborations; Communities; Data; Data Coordinating Center; Data Display; Data Pooling; Data Set; Databases; Dementia; Diabetes Mellitus; Disease; Dose; Elderly; Estradiol; Experimental Designs; Extensive Stage; Freezing; Future; Glycine; Growth; Hand Strength; Health; Health Benefit; Health Sciences; Human; Individual; International; Intervention; Joints; Laboratories; Link; Longevity; Mammals; Measures; Michigan; Modeling; Mollies; Mus; New Agents; Outcome; Outcome Measure; Pathology; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Policies; Progress Reports; Protocols documentation; Public Health; Reading; Recommendation; Reliability of Results; Reproducibility; Research; Research Institute; Resources; Rotarod Performance Test; Schedule; Scientist; Sirolimus; Site; Specimen; Standardization; Stress; System; Testing; Texas; The Jackson Laboratory; Tissue Sample; Tissues; Universities; Work; anti aging; cognitive function; comparative; data repository; experimental study; innovation; insight; longitudinal analysis; middle age; mouse model; pharmacologic; phenome; prevent; programs; response; sex; small molecule; successful intervention; therapy design; tissue fixing; trait; web site

PROJECT SUMMARY/ABSTRACT 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 retarding aging or postponing late life diseases. Interventions proposed by multiple collaborating scientists from the research community are tested, in parallel, at three sites (The Jackson Laboratory, University of Michigan and University of Texas), using identical, standardized protocols. Sufficient numbers of genetically heterogeneous mice are used to provide 80% power for detecting a 10% change in lifespan of 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: 1) increased emphasis on health outcomes (functional tests relevant to human health not necessarily linked to lifespan); 2) a Collaborative Interactions Program to provide tissues from ITP drug-treated mice to a growing, international network of scientific collaborators; and, 3) 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 The Jackson Laboratory will follow a wide variety of health outcomes measured with minimal stress, add more cognitive function tests, add longitudinal analyses, and study successful interventions in mouse models of aging diseases such as diabetes and dementia. The work proposed should allow the ITP to continue to make major contributions to mammalian aging biology.

项目摘要/摘要 鉴定延长小鼠寿命的小分子提供了对机制的新见解 哺乳动物的寿命确定，并可能为人类最终的抗衰老疗法奠定基础。 NIA干预测试计划（ITP）评估了提议通过延长鼠标寿命的代理 衰老或推迟晚期疾病。来自多个合作科学家提出的干预措施 在三个地点（密歇根大学杰克逊实验室和 德克萨斯大学），使用相同的标准化协议。足够数量的遗传异质 在汇总数据后，小鼠用于提供80％的功率来检测两性寿命的10％变化 来自任何两个测试地点。 72个这样的寿命实验涉及各种剂量的44个不同的剂量 代理商已在ITP的前15年开始启动。涉及37个实验 多种剂量的有效药物，可变的起始年龄或替代剂量时间表的比较测试。 对寿命的重大影响已记录在一个或两个性别中，然后证实了NDGA的确认， 雷帕霉素，阿果霉和17-α-雌二醇（17AE2），具有显着（但目前未确认）的作用 在protandim，甘氨酸和临时分析中指出的是Canagliflozin。生命周期试验正在进行18 新代理商。 ITP的生存结果还记录了从中间的三个代理商的寿命益处 年龄：雷帕霉素，阿卡罗贝斯和17AE2。上一个五年期为 ITP：1）越来越重视健康结果（与人类健康相关的功能测试无需 与寿命有关）； 2）一个协作互动计划，可为ITP药物处理的小鼠提供组织 不断发展的国际科学合作者网络； 3）公共访问的数据存储库和 显示引擎由杰克逊实验室的鼠标现象数据库托管。接下来的五个计划 年度包括额外的寿命（“第一阶段”）试验，发现的代理商的详细分析（“ II阶段”） 提高寿命，健康结果数据的持续增长以及与科学家的合作工作 药物对假定的衰老机制的影响以及与疾病的联系。杰克逊实验室的研究 遵循以最小的压力测量的各种健康结果，添加更多的认知功能测试，添加 纵向分析，并研究了型糖尿病等衰老疾病的小鼠模型的成功干预措施 和痴呆症。提出的工作应允许ITP继续为哺乳动物做出重大贡献 衰老生物学。

项目成果

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice.

• DOI: 10.1111/acel.12414
• 发表时间: 2016-02
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Thompson AC;Bruss MD;Price JC;Khambatta CF;Holmes WE;Colangelo M;Dalidd M;Roberts LS;Astle CM;Harrison DE;Hellerstein MK
• 通讯作者: Hellerstein MK

Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.

• DOI: 10.1111/acel.12170
• 发表时间: 2014-04
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Harrison DE;Strong R;Allison DB;Ames BN;Astle CM;Atamna H;Fernandez E;Flurkey K;Javors MA;Nadon NL;Nelson JF;Pletcher S;Simpkins JW;Smith D;Wilkinson JE;Miller RA
• 通讯作者: Miller RA

Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice.

• DOI: 10.1111/acel.13724
• 发表时间: 2022-12
• 期刊: Aging cell
• 影响因子: 7.8

Rapamycin ameliorates nephropathy despite elevating hyperglycemia in a polygenic mouse model of type 2 diabetes, NONcNZO10/LtJ.

• DOI: 10.1371/journal.pone.0114324
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Reifsnyder PC;Doty R;Harrison DE
• 通讯作者: Harrison DE

Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.

• DOI: 10.1111/j.1474-9726.2008.00414.x
• 发表时间: 2008-10
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Strong R;Miller RA;Astle CM;Floyd RA;Flurkey K;Hensley KL;Javors MA;Leeuwenburgh C;Nelson JF;Ongini E;Nadon NL;Warner HR;Harrison DE
• 通讯作者: Harrison DE