Energy-sensing Pathways, Healthy Aging and Longevity

描述（由申请人提供）：Kuakini医学中心（Kuakini）夏威夷健康跨度研究将集中一个由遗传、流行病学和老年科学家组成的多学科团队，利用创新方法进行二次数据分析。我们将使用现有的人类数据和来自45年Kuakini檀香山心脏项目/檀香山亚洲老龄化研究的标本，对日裔美国男性的衰老和慢性疾病进行纵向研究。我们的工作将集中在健康衰老的功能特征上（“健康寿命”），并将试图确定帮助人们健康地活到老年的遗传因素。虽然“成功”、“健康”或“有效”衰老等术语描述了一种慢性疾病最少的衰老模式，但对这种衰老的功能（身体和认知）特征了解甚少，对遗传或环境预测因素知之甚少。在最近的工作中，我们有1)使用基于性能的功能测量来操作健康衰老的表型2)在纵向研究中确定健康衰老和长寿的环境预测因子3)发现与健康衰老和长寿密切相关的基因（FOXO3A）变异；4)复制了CETP基因与长寿的关联，并将这一发现扩展到健康衰老。对于目前的研究，我们建议：1)通过对能量传感途径和感兴趣领域测序的候选基因进行两阶段巢式病例对照研究，确定与寿命相关的其他基因；2)对生存和健康生存的遗传预测因素进行前瞻性研究；3)对主要衰老相关性状变化率的遗传预测因子进行前瞻性研究。发现影响疾病和残疾易感性的生物学途径，可以通过确定新疗法的生物学靶点，对我们实现健康老年的能力产生巨大影响。我们的研究直接支持NIA的使命，即改善美国老年人的健康和福祉。

DESCRIPTION (provided by applicant): The Kuakini Medical Center (Kuakini) Hawaii Healthspan Study 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 functional characteristics of healthy aging over the lifespan ("healthspan") and will attempt to identify genetic factors that help 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 functional (physical and cognitive), characteristics of such aging are poorly understood and little is known about genetic or environmental predictors. 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) Found a gene (FOXO3A) with variants strongly associated with healthy aging and longevity; 4) Replicated the CETP gene association with longevity and extended the finding to healthy aging. For the current study, we propose to: 1) IDENTIFY additional genes associated with longevity using a two stage nested case-control study of candidate genes from energy sensing pathways and sequencing around areas of interest; 2) CONDUCT a prospective study of genetic predictors of survival and healthy survival; 3) CONDUCT a prospective study of genetic predictors of rate of change in major aging related traits. Discovery of biologic pathways that affect vulnerability to disease 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. PUBLIC HEALTH RELEVANCE: The Kuakini Medical Center (Kuakini) Hawaii Healthspan Study will investigate how people's genes affect their ability to achieve healthy old age. This study focuses on understanding physical and cognitive function over the lifespan and identifies genetic and environmental factors that enable people to survive to exceptional ages in good health. Research on factors that lead to healthy aging may help us develop therapies that result in less age-related disease and disability and increase quality of life at older ages.