Laboratory for Anti-Geric Testing, Evaluation and Resea*

描述（由申请人提供）：抗Geric试验、评价和研究实验室 寻求资金进行一系列的干预措施，认为有可能延长寿命的遗传异质性小鼠的人口调查。 该方案将在I期筛选研究中每年测试五种新的干预措施，并在第3、4和5年对选定的干预措施进行更全面的II期研究。 I期方案的主要特征包括：（a）使用不对称分组，通过对对照动物进行过度采样来最大化统计功效;（B）使用单独的监测小鼠来记录药物分布和有效性;以及（c）对所有I期干预措施的生命表进行完整评估。 I期研究将包括对几种年龄敏感性状的评估，作为生物学年龄的间接指标，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）五种T细胞亚群;（d）白内障严重程度;和（e）学习和记忆测试。 将对所有I期小鼠进行有限尸检分析，并对所有II期小鼠和暴露于干预措施的I期小鼠进行全面尸检分析，发现干预措施在很大程度上延长或缩短寿命。 II期研究除了重复I期试验外，还将增加对免疫功能、肝酶热稳定性、眼透镜蛋白提取率、尾腱断裂时间的更全面检查，以及对年龄敏感的肝脏和肌肉mRNA进行基于阵列的分析。 初步探索建议采用四种干预措施：（a）吡格列酮，一种胰岛素敏感性增强剂，（B）吡哆胺，可抑制基于糖基化的交联，（c）α-苯基-N-叔丁基硝酮（PBN），一种自由基清除剂，和（d）pegvisomant，一种GH作用抑制剂。 该项目作为一个整体应该有两个重要的功能：提供对假设的关键测试，即特定种类的干预措施将延缓哺乳动物的衰老或晚年疾病;也许更重要的是，提供重要的新线索，以了解确实可以调节衰老和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.