Implications of metabolism on healthy aging in African and Caucasian Americans: the Health ABC study

项目摘要 到2060年，超过1亿的美国人将超过65岁(占美国人口的25%)， 非洲裔美国人的比例越来越高。了解哪些美国人表现出“异常健康” 老龄化“--没有疾病、残疾或功能限制的老年生活--是努力提高生活质量的核心 生命和资源利用。目前对“健康老龄化”的研究主要集中在全身炎症标志物上。 (例如，白介素6)或器官/代谢功能的综合指数(健康衰老指数，HAI)，两者都是LIM- (1)对新陈代谢的早期变化缺乏敏感性；(2)对分子途径缺乏特异性 与这些变化有关；(3)成年早期缺乏调查(当“衰老”可能是可逆的)； (4)对非洲裔美国人的研究很少，他们是与年龄相关的发病率的高危人群。在为本申请做准备的过程中， 我们在一项针对健康ABC的近300名非裔美国男性的初步研究中应用了代谢物图谱。 NIA对老年高加索人和非裔美国人的研究，确定与HAI(氧化)相关的代谢物 压力、一氧化氮信号、肠道微生物代谢)，其中一些可能是非裔美国人独有的。 在这里，我们假设循环代谢产物与多维衰老表型和 老年人的结果将定义“异常健康老龄化”的途径，这可能是种族特有的 处于“过早”衰老风险的青年中的调节失调。为了解决这个假设，我们将利用两个很好的- 具有特点的、跨越一生的混血美国队列(老年人：73±3 N=1312；年轻人：CARDIA，32±4岁 N=2376；R01-HL136541)。在目标1中，我们定义了与种族特定的健康衰老有关的代谢途径， 基于代谢物与确认的年龄相关表型之间的关联，这些表型因种族而异 (身体、神经认知功能、血管结构、身体成分)。我们将评估IDEN的决定因素- 特定的途径，包括饮食质量、体力活动和心理社会压力(在非洲较贫穷- 美国人)。在目标2中，我们确定了与老年人“异常健康的老龄化”有关的代谢物(自由 残疾、痴呆症、癌症、心血管疾病)、它们的途径、种族特异性以及与 在目标1中确定的途径。在目标3中，我们将机器学习技术应用于代谢物，以推导出一类- 健康ABC中异常健康的老龄化的预测，并将此预测规则应用于CARDIA的年轻人，以 识别有不健康老龄化风险的年轻人。然后我们调查被标记为早产儿的个体 几十年后，衰老会发展成不利的衰老表型(神经认知、生理、血管、临床结果)。 该提案通过定义新陈代谢来解决NIA的核心任务(直接响应PA-17-088) 为跨越种族和生活极端的“异常健康的衰老”奠定基础。我们利用丰富的表型 在Health ABC内，资助CARDIA内的工作，以及在老龄化流行病学、代谢方面经验丰富的团队 研究和数据科学方法。该项目的成功完成将提供丰富的分子Phe- 为老龄社区提供非典型资源，以研究生物衰老的机制和生物标志物。

Project Summary Over 100 million Americans will be over age 65 years by 2060 (representing 25% of the U.S. population), with an increasing proportion of African-Americans. Understanding which Americans exhibit “exceptionally healthy aging”—an older life free of illness, disability, or functional limitation—is central to efforts to improve quality of life and resource utilization. Current investigations on “healthy aging” focus on systemic inflammatory markers (e.g., interleukin-6) or composite indices of organ/metabolic function (the “healthy aging index,” HAI), both lim- ited by a (1) lack of sensitivity for early changes in metabolism; (2) lack of specificity for molecular pathways involved in these changes; (3) absence of investigation early in adulthood (when “aging” may be reversible); (4) few studies of African-Americans, at high-risk for age-related morbidity. In preparation for this application, we applied metabolite profiling in a pilot study of nearly 300 African-American males in Health ABC, a biracial NIA study of elderly Caucasians and African-Americans, identifying metabolites associated with HAI (oxidative stress, nitric oxide signaling, gut microbial metabolism), some of which may be unique to African-Americans. Here, we hypothesize that circulating metabolites associated with multi-dimensional aging phenotypes and outcomes in older adults will define pathways of “exceptional healthy aging” that may be race-specific and dysregulated in youth at risk for “premature” aging. To address this hypothesis, we will harness two well- characterized, biracial American cohorts that span life (elderly: age 73±3 N=1312; young: CARDIA, age 32±4 N=2376; R01-HL136541). In Aim 1, we define metabolic pathways implicated in race-specific healthy aging, based on association between metabolites and validated age-related phenotypes heterogeneous by race (physical, neurocognitive function, vascular structure, body composition). We will assess determinants of iden- tified pathways, including dietary quality, physical activity, and psychosocial stress (poorer in African- Americans). In Aim 2, we identify metabolites related to “exceptionally healthy aging” in the elderly (freedom from disability, dementia, cancer, cardiovascular disease), their pathways, race-specificity, and overlap with pathways identified in Aim 1. In Aim 3, we apply machine-learning techniques to metabolites to derive a classi- fier for exceptionally healthy aging in Health ABC and apply this prediction rule to young adults in CARDIA to identify young adults at risk for unhealthy aging. We then investigate whether individuals marked for premature aging develop adverse aging phenotypes decades later (neurocognitive, physical, vascular, clinical outcome). This proposal addresses a core mission of the NIA (directly responsive to PA-17-088) by defining a metabolic basis for “exceptional healthy aging” across race and at the extremes of life. We leverage rich phenotypes within Health ABC, funded efforts within CARDIA, and a team experienced in aging epidemiology, metabolic research, and data science approaches. Successful completion of this project will furnish a rich molecular phe- notypic resource to the aging community for investigation of mechanisms and biomarkers of biological aging.