Exceptional Aging Across the Life Span: Framingham Study

描述(由申请人提供)：我们建议全面描述在两代社区居住的成年人中测量的异常健康的老龄化及其决定因素。与常见疾病相关的危险因素(RF)和行为已被发现可以预测健康老龄化。目前尚不清楚成人一生中射频变化的轨迹是否与随着时间推移而平均的射频水平或老年测量的RFs相比，对健康老龄化的影响更大。与长寿和健康衰老相关的遗传因素在很大程度上仍不清楚。考虑到人类衰老的复杂性，很可能有许多基因对衰老潜在的基本功能的广泛网络做出贡献。来自纵向Framingham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)的数据可以用来跟踪成人一生中的射频水平，记录疾病的发生，并将射频轨迹与衰老联系起来。FHS拥有一个全面的遗传学数据库，可以用来识别与长寿和健康衰老有关的遗传因素。我们假设，异常健康老龄化的改善，定义为没有共病、身体和认知障碍以及虚弱，与一生中RFs水平的下降以及已知的预测心血管和其他主要疾病的行为直接相关。我们建议使用遗传性和全基因组关联研究(GWAS)来检验遗传决定因素对长寿和健康衰老特征的贡献。该提案有以下具体目标：目的1.描述FHS原始队列和活到至少65岁的后代队列中异常健康老龄化的流行情况。目的2.检验与老年RF水平或随时间平均的RF水平相比，前瞻性测量的RFS和总体Framingham风险评分的成年期早期和中期轨迹是否能更好地预测健康老龄化。目的3.用遗传力分析估计长寿和健康老龄化的遗传贡献率。目的4.利用现有的550k基因组扫描的基因分型数据，通过GWAs鉴定影响可遗传寿命和健康衰老表型的遗传变异。该项目的见解可能有助于从根本上了解导致健康老龄化的机制，进而确定促进中老年人健康和预防疾病努力的方向，使老年人能够享受更多的健康时间。公共卫生相关性：监测老年人的健康状况并确定促进长寿和健康寿命的遗传和非遗传因素是重要的公共卫生优先事项。从这项提议中获得的知识可能导致预防与年龄有关的疾病和残疾的干预措施，从而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.