Defining the Healthy Aging Genotype - Hawaii Lifespan Study II

描述(由申请人提供)：Kuakini医学中心(Kuakini)夏威夷寿命研究II将集中一个由遗传学、流行病学和老年病科学家组成的多学科团队，使用创新的方法进行二级数据分析。我们将使用现有的人类数据和样本，来自45年的Kuakini檀香山心脏计划/檀香山亚洲老龄化研究(老龄化和慢性病的纵向研究)，在日裔美国男性中。我们的工作将集中在确定FOXO3a对健康衰老和长寿的作用机制(S)。我们将尝试确定人们健康长寿的新的遗传机制。虽然“成功的”、“健康的”或“有效的”衰老等术语描述了一种慢性疾病最少的衰老模式，但人们对这种衰老的遗传机制知之甚少。在最近的工作中，我们有：1)使用基于性能的功能测量的健康衰老表型的可操作性；2)在一项纵向研究中确定了健康衰老和长寿的环境预测因素；(3)复制了CETP基因对长寿的先前关联，并将该发现扩展到包括在健康衰老中的作用；4)发现了一个与健康衰老和长寿密切相关的新基因(FOXO3a)变异。在目前的研究中，我们最初的父母R01的更新建议-Kuakini Hawaii寿命研究-我们提出了以下目标：1)FOXO3a基因的高密度测序；2)重复最初的病例对照研究，增加184例Kuakini HHP病例(n=397例长寿病例；402例平均寿命对照)，以确定与长寿最密切的关联；3)对3,569名Kuakini HHP受试者进行纵向研究；4)使用287例Kuakini HHP受试者的细胞系进行基因表达/蛋白质功能之间的相关性测试。发现影响对年龄相关疾病和残疾易感性的生物途径，可能会通过确定新疗法的生物靶点，对我们实现健康老年的能力产生重大影响。我们的研究直接支持了NIA改善美国老年人健康和福祉的使命。

DESCRIPTION (provided by applicant): The Kuakini Medical Center (Kuakini) Hawaii Lifespan Study II will focus a multidisciplinary team of genetic, epidemiological, and geriatric scientists on the use of innovative approaches for secondary data analysis. We will use existing human data and specimens from the 45-year Kuakini Honolulu Heart Program/Honolulu Asia Aging Study (longitudinal studies of aging and chronic diseases), in Japanese-American men. Our work will focus on identifying the mechanism(s) of action of FOXO3A on healthy aging and longevity. We will attempt to identify novel genetic mechanisms by which people survive to older ages in good health. While terms such as "successful", "healthy" or "effective" aging describe a paradigm of aging with minimal chronic disease, the genetic mechanisms of such aging are poorly understood. In recent work we have: 1) operationalized phenotypes of healthy aging that use performance-based measures of function 2) identified environmental predictors of healthy aging and longevity in a longitudinal study, (3) replicated a previous association of the CETP gene on longevity and extended the finding to include a role in healthy aging 4) and discovered a novel gene (FOXO3A) variation that is strongly associated with healthy aging and longevity. For the current study, a renewal proposal of our original parent R01-the Kuakini Hawaii Lifespan Study-we propose the following aims: 1) High density sequencing of the FOXO3A gene; 2) Repeat the original case-control study with 184 additional Kuakini HHP cases (n=397 longevity cases; 402 average-lived controls) in order to identify the strongest association with longevity; 3) Conduct a longitudinal study for incident diseases, functional loss and mortality with 3,569 Kuakini HHP subjects; 4) Conduct tests of association between genotypes and gene expression/protein function using cell lines from 287 Kuakini HHP subjects. Discovery of biologic pathways that affect vulnerability to age-related diseases and disability could have a dramatic impact on our ability to achieve healthy old age by identifying biological targets for new therapies. Our study directly supports NIA's mission to improve the health and well-being of older Americans.