Laboratory for Anti-Geric Testing, Evaluation and Resea*

描述(申请人提供)：抗菌检测、评估和研究实验室 目前正在寻求资金，用于一系列干预措施的调查，这些干预措施被认为可能延长遗传异质性小鼠的寿命。该方案每年将在第一阶段筛选研究中测试五种新的干预措施，并在第三、四和五年对选定的干预措施进行更全面的第二阶段研究。第一阶段方案的主要特点包括：(A)使用不对称的分组分配，通过过度抽样对照动物来最大限度地提高统计能力；(B)使用单独的监测小鼠来记录药物分配和有效性；以及(C)对所有第一阶段干预措施的生命表进行完整的评估。第一阶段研究将包括对几个年龄敏感特征的评估，作为生物年龄的间接指标，包括(A)自发活动；(B)IGF-I、糖皮质激素和糖化血红蛋白水平；(C)五个T细胞亚群；(D)白内障严重程度；(E)学习和记忆测试。将对所有第一阶段小鼠进行有限的尸检分析，对所有第二阶段小鼠和那些暴露在干预措施下的第一阶段小鼠进行全面的尸检分析，这些干预措施被发现在很大程度上增加或减少了寿命。第二阶段的研究除了复制第一阶段使用的测试外，还将增加更全面的免疫功能、肝酶热稳定性、眼晶状体蛋白萃取率、尾腱断裂时间以及对年龄敏感的肝脏和肌肉mRNAs的基于阵列的分析。初步探索建议采取四种干预措施：(A)胰岛素敏感性增强剂吡格列酮，(B)抑制糖基化交联剂的吡哆胺，(C)自由基清除剂a-苯基-N-叔丁基硝酮(PBN)，以及(D)生长激素作用的抑制剂聚乙二醇胺。作为一个整体，该项目应该发挥两个重要作用：对特定种类的干预将延缓哺乳动物衰老或晚年疾病的假说进行关键测试；或许更重要的是，提供重要的新线索，通向确实可以调节衰老并延缓晚年疾病和残疾的生化或激素途径。

DESCRIPTION (provided by applicant): Laboratory for Anti-Geric Testing, Evaluation and Research Funding is sought for a series of investigations of interventions thought likely to extend life span in a population of genetically heterogeneous mice. The protocol will test five new interventions each year in Phase I screening studies, as well as conducting more comprehensive Phase II studies for selected interventions in Years 3, 4, and 5. Key features of the Phase I protocol include: (a) use of asymmetric group assignment to maximize statistical power by over sampling control animals; (b) use of separate monitor mice to document drug distribution and effectiveness; and (c) complete assessment of life table for all Phase I interventions. Phase I studies will include assessments of several age-sensitive traits as indirect indices of biological age, including (a) spontaneous activity; (b) IGF-I, glucocorticoid, and glycated hemoglobin levels, (c) five T cell subsets; (d) cataract severity; and (e) tests of learning and memory. Limited necropsy analyses will be done on all Phase I mice, and comprehensive necropsy analysis will be available for all Phase II mice and for those Phase I mice exposed to interventions found either to increase or to decrease longevity to a significant extent. Phase II studies will, in addition to replication of tests used in Phase I, add more comprehensive examinations of immune function, liver enzyme heat stability, eye lens protein extraction rates, tail tendon break time, and array-based analysis of age-sensitive liver and muscle mRNAs. Four interventions are suggested for initial exploration: (a) piaglitazone, an enhancer of insulin sensitivity, (b) pyridoxamine, which inhibits glycation-based cross links, (c) a-phenyl-N-tert-butyl nitrone (PBN), a scavenger of free radicals, and (d) pegvisomant, an inhibitor of GH action. The project as a whole should serve two important functions: providing critical tests of hypotheses that specific varieties of intervention will delay aging or late life illnesses in mammals; and, perhaps more importantly, provide important new leads to biochemical or hormonal pathways that can indeed modulate aging and delay late life illnesses and disabilities.