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“非常健康” 老龄化”--没有疾病、残疾或功能限制的老年生活--是努力提高 生活和资源利用。目前对“健康老龄化”的研究集中在全身炎症标志物上 (e.g.,白细胞介素-6）或器官/代谢功能的复合指数（“健康老化指数”，HAI），两者都是lim- 由于（1）缺乏对代谢早期变化的敏感性;（2）缺乏对分子途径的特异性 （3）在成年早期缺乏调查（当“老化”可能是可逆的）; (4)少数研究非裔美国人，在高风险的年龄相关的发病率。在准备这一申请时， 我们在一项针对近300名非裔美国男性的试点研究中应用了代谢物分析， 老年白人和非裔美国人的NIA研究，确定与HAI相关的代谢物（氧化 压力，一氧化氮信号，肠道微生物代谢），其中一些可能是非洲裔美国人所独有的。 在这里，我们假设与多维衰老表型相关的循环代谢物， 老年人的结果将定义可能是种族特异性的“异常健康老龄化”的途径， 有“过早”衰老风险的年轻人中的失调。为了解决这个假设，我们将利用两个很好的- 特征性的，双胞胎美国队列，跨越寿命（老年人：年龄73±3 N=1312;年轻人：心脏，年龄32±4 N=2376; R 01-HL136541）。在目标1中，我们定义了与种族特异性健康衰老有关的代谢途径， 基于代谢物与经验证的年龄相关表型之间的相关性（人种异质性） （身体、神经认知功能、血管结构、身体成分）。我们将评估身份认同的决定因素- 健康途径，包括饮食质量、身体活动和心理社会压力（非洲人较穷， 美国人）。在目标2中，我们确定了与老年人“异常健康衰老”相关的代谢物（自由 从残疾，痴呆，癌症，心血管疾病），他们的途径，种族特异性，并与重叠 目标1中确定的路径。在目标3中，我们将机器学习技术应用于代谢物，以获得一个类 在健康ABC中为异常健康的老龄化提供了一个预测菲耶尔，并将此预测规则应用于CARDIA中的年轻人， 识别有不健康衰老风险的年轻人。然后，我们调查是否标记为早产的个体， 老化在几十年后发展出不利的老化表型（神经认知、身体、血管、临床结果）。 该提案通过定义代谢代谢，解决了NIA的核心使命（直接响应PA-17-088） 这是跨种族和极端生活的“异常健康老龄化”的基础。我们利用丰富的表型 在健康ABC内，在CARDIA内资助的努力，以及一个在老龄化流行病学，代谢和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，将为我国生物医学领域提供丰富的分子生物学资源。 为研究生物衰老的机制和生物标志物提供非典型资源。

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.