Exceptional Aging Across the Life Span: Framingham Study

描述（由申请人提供）：我们建议全面表征异常健康老龄化及其决定因素，测量两代社区居住成年人的成年寿命。危险因素（RFs）和与常见疾病相关的行为已经被发现可以预测健康老龄化。目前尚不清楚的是，与随时间平均的RF水平或在老年时测量的RF相比，在成年生命周期中发生的RF变化轨迹是否与对健康老龄化的更大影响相关。与长寿和健康老龄化有关的遗传因素在很大程度上仍然未知。考虑到人类衰老的复杂性，很可能有许多基因参与了一个广泛的基本功能网络，这些功能网络是衰老的基础。来自纵向弗雷明汉心脏研究（FHS）原始队列和后代队列（原始队列的成年子女及其配偶）的数据可用于跟踪成年生命周期内的RF水平，记录疾病的发生，并将RF轨迹与衰老联系起来。FHS拥有一个全面的基因数据库，可用于识别与长寿和健康老龄化相关的遗传因素。我们假设，异常健康老龄化的改善，定义为没有合并症、身体和认知障碍以及虚弱，与终生RFs水平的降低和已知可预测心血管和其他主要疾病的行为直接相关。我们建议使用遗传力和全基因组关联研究（GWAS）来检查遗传决定因素对长寿和健康衰老特征的贡献。该建议有以下具体目标：目标1。目的：研究存活至65岁以上的FHS原始队列和后代队列中异常健康老龄化的患病率。目标2。研究与老年时获得的RF水平或随时间平均的RF水平相比，成年早期和中期前瞻性测量的RF轨迹和总体Framingham风险评分是否能更好地预测健康老龄化。目标3。利用遗传力分析估计遗传因素对长寿和健康老龄化差异的影响。目标4。利用来自550k基因组扫描的现有基因分型数据，通过GWAS识别影响遗传长寿和健康衰老表型的遗传变异。该项目的见解可能从根本上有助于理解负责健康老龄化的机制，从而为中老年人的健康促进和疾病预防工作确定方向，从而使老年人能够享受更多的健康时光。公共卫生相关性：监测老年人的健康状况并确定促进健康长寿的遗传和非遗传因素是重要的公共卫生优先事项。从这项建议中获得的知识可能导致采取干预措施，预防与年龄有关的疾病和残疾，使老年人有更多的时间保持健康。

DESCRIPTION (provided by applicant): We propose to comprehensively characterize exceptionally healthy aging and its determinants measured across the adult life span in two generations of community-dwelling adults. Risk factors (RFs) and behaviors associated with common conditions have been found to predict healthy aging. It is not known whether the trajectory of RF changes occurring over the adult life span is associated with a greater impact on healthy aging than RF levels averaged over time or RFs measured in old age. Genetic factors related to longevity and healthy aging remain largely unknown. Given the complexity of human aging, it is likely that many genes contribute to a broad network of basic functions underlying aging. Data from the longitudinal Framingham Heart Study (FHS) original cohort and offspring cohort (adult children of the original cohort and their spouses) can be used to track RF levels over the adult life span, document the occurrence of disease, and relate RF trajectories to aging. The FHS has a comprehensive genetics database that can be used to identify genetic factors related to longevity and healthy aging. We postulate that improvements in exceptionally healthy aging, defined as the absence of comorbidity, physical and cognitive impairment, and frailty, are directly related to decreases in lifetime levels of RFs and behaviors known to predict cardiovascular and other major diseases. We propose to examine the contribution of genetic determinants to longevity and healthy aging traits using heritability and genome-wide association studies (GWAS). The proposal has the following specific aims: Aim 1.To characterizes the prevalence of exceptionally healthy aging among FHS original cohort and offspring cohort who survive to at least age 65 years. Aim 2. To examine whether early and mid-adulthood trajectories of prospectively measured RFs and overall Framingham risk score are better predictors of healthy aging compared to RF levels obtained at old age or RF levels averaged over time. Aim 3. To estimate the genetic contribution to the variance in longevity and healthy aging using a heritability analysis. Aim 4. To identify genetic variants that influence heritable longevity and healthy aging phenotypes through a GWAS using extant genotyping data from a 550k genome scan. Insights from this project may contribute fundamentally to the understanding of the mechanisms responsible for healthy aging and in turn identify directions for health promotion and disease prevention efforts in middle-aged and older adults so that older persons can enjoy more time in good health. PUBLIC HEALTH RELEVANCE: Surveillance of the health of older adults and identification of factors, both genetic and non-genetic, that promote a long and healthy life are important public health priorities. Knowledge gained from this proposal may lead to interventions that prevent age-related disease and disability so that older persons spend more time in good health.