Interventions that Retard Mamalian Aging

延缓哺乳动物衰老的干预措施

• 批准号: 8305570
• 负责人: DAVID E HARRISON
• 金额: $ 80.1万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305570
• 关键词: Adrenal Glands; Age; Age-Months; Aging; Animals; Aspirin; Autopsy; Behavioral; Biochemical; Biological Markers; Biology of Aging; Blood Urea Nitrogen; Body Composition; Clinical Treatment; Cognition; Collaborations; Communities; Creatinine clearance measurement; Cross-Sectional Studies; DEXA; DNA Damage; Data; Development; Disease; Dose; Elderly; Evaluation; Female; Genome Stability; Glycosylated Hemoglobin; Health; Health Benefit; Health Sciences; Heart; Hematopoietic stem cells; Human; Insulin-Like Growth Factor I; Intervention; Kidney; Laboratories; Lead; Link; Liver; Longevity; Lung; Mammals; Measures; Meta-Analysis; Metabolic; Methods; Michigan; Motor Activity; Mus; New Agents; Nordihydroguaiaretic Acid; Outcome; Pancreas; Pathology; Pathway interactions; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; Pilot Projects; Proteins; Protocols documentation; Public Health; Reporting; Research; Risk; Route; Scientist; Series; Signal Transduction; Sirolimus; Site; Skeletal Muscle; System; Testing; Texas; The Jackson Laboratory; Tissues; Translational Research; Universities; Work; age related; anti aging; base; cohort; design; experience; feeding; follow-up; human FRAP1 protein; insight; insulin sensitivity; isoprostaglandin F2alpha type-III; male; mortality; phase 1 study; phase 2 study; prevent; programs; research study; respiratory; sex; therapy design; trait

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.

描述（由申请方提供）：NIA干预试验项目代表了一项多中心转化研究项目，旨在评价假设可通过延缓衰老或延缓晚期疾病来延长小鼠寿命的药物。来自研究界的多位合作科学家提出的干预措施最初在三个地点（密歇根州和得克萨斯州的杰克逊实验室）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性小鼠，以提供80%的功效，在汇集任何两个测试地点的数据后，检测10%的寿命变化。在ITP的前四年，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个新药物。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。在20月龄时给予小鼠雷帕霉素，然后在867只雌性小鼠中的92%和来自队列2的1098只雄性小鼠中的96%死亡的时间点（2008年12月1日）进行评价，产生了稳健的寿命增加，雄性p <0.0001，雌性p <0.0001，所有三个地点的结果均具有显著性平行。雷帕霉素治疗还导致雄性和雌性的最大寿命显著增加（每种性别p <0.001）。雷帕霉素在9月龄开始时也显示出有益效果，在队列3研究中，现在达到中位存活年龄，在雄性（p = 0.008）和雌性（p = 0.0001）小鼠中均显著。未来五年的计划包括完成所有正在进行的I期试验，并每年启动三项或更多新的I期试验。此外，雷帕霉素的更详细的II期研究将评估不同剂量的这种药剂对存活率的影响，测试一系列年龄敏感性特征和提出的机制途径，记录横截面病理学，并提供小鼠和组织供他人分析。这三个实验室都拥有小鼠寿命和生物标志物分析的经验，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性特征测量，密歇根州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：在多个实验室中鉴定可以延长遗传异质性小鼠的平均和/或最大寿命的药物将表明研究方向，从而导致旨在预防或延缓随年龄的有害变化的临床治疗。此外，识别未经证实的声称具有抗衰老作用的治疗方法的健康危险也将对公共卫生有益。