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

新陈代谢对非洲裔和白种裔美国人健康老龄化的影响：Health ABC 研究

• 批准号: 9750581
• 负责人: Venkatesh Locharla Murthy
• 金额: $ 55.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750581
• 关键词: Address; Adult; African American; Age; Aging; American; Biochemical; Bioinformatics; Biological Aging; Biological Markers; Biology of Aging; Blood Vessels; Body Composition; Cardiovascular Diseases; Cardiovascular system; Caucasians; Censuses; Characteristics; Clinical; Communities; Data Science; Dementia; Diet; Elderly; Epidemiology; Exhibits; Freedom; Functional disorder; Funding; Goals; Health; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Investigation; Life; Life Cycle Stages; Longevity; Longitudinal Studies; Machine Learning; Malignant Neoplasms; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mission; Molecular; Morbidity - disease rate; Neurocognitive; Nitric Oxide; Obesity; Organ; Outcome; Oxidative Stress; Pathway interactions; Pattern; Performance; Phase; Phenotype; Physical Function; Physical activity; Physiology; Pilot Projects; Plant Roots; Population; Premature aging syndrome; Preparation; Psychosocial Stress; Quality of life; Race; Research; Resources; Risk; ST14 gene; Signal Transduction; Specific qualifier value; Specificity; Stress; Structure; Techniques; Youth; age related; base; biracial; caucasian American; circulating biomarkers; cohort; disability; emerging adult; experience; fitness; healthy aging; high risk; human old age (65+); improved; indexing; inflammatory marker; male; mental state; microbial; middle age; molecular phenotype; mortality; muscle strength; novel; prospective; sarcopenia; walking speed; young adult

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.

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％），其中 非裔美国人比例越来越多。了解哪些美国人暴露了“异常健康 衰老” - 不含疾病，残疾或功能限制的较老的生活 - 努力提高质量的核心 生活和资源利用。当前对“健康衰老”专注于系统性炎症标记的投资 （例如，白介素6）或器官/代谢功能的复合指数（“健康老化指数”，HAI），均为lim- （1）对代谢的早期变化缺乏敏感性； （2）缺乏分子途径的特异性 参与这些变化； （3）成年早期缺乏投资（当“老化”可能是可逆的情况下）； （4）关于非裔美国人的研究，在高风险中，与年龄相关的发病率。为了准备此应用程序， 我们在一项近300名非裔美国男性ABC的试点研究中应用了代谢物分析，这是一个混血儿 NIA对老年高加索人和非裔美国人的研究，确定与HAI相关的代谢物（氧化） 压力，一氧化氮信号传导，肠道微生物代谢），其中一些可能是非裔美国人所特有的。 在这里，我们假设与多维老化表型相关的循环代谢产物和 老年人的结果将定义可能是种族特定和 在有“早产”衰老风险的年轻人中失调。为了解决这一假设，我们将利用两个 特征是跨越生命的混蛋美国同伙（老年人：73±3 n = 1312; Young：Cardia，年龄32±4 n = 2376; R01-HL136541）。在AIM 1中，我们定义了在特定种族健康衰老中实施的代谢途径， 基于代谢产物和经过验证的与年龄相关的表型异质的关联 （物理，神经认知功能，血管结构，身体成分）。我们将评估鉴定的决定者 鉴定途径，包括饮食质量，体育锻炼和社会心理压力（非洲 - 较差 美国人）。在AIM 2中，我们确定了与“自由” 从残疾，痴呆症，癌症，心血管疾病），其途径，种族特异性和与 在AIM 1中确定的途径。在AIM 3中，我们将机器学习技术应用于代谢物以得出分类 - Fier对于健康ABC中的特殊健康衰老，并将此预测规则应用于Cardia的年轻人 确定有不健康衰老的风险的年轻人。然后，我们调查是否为早产的个人 数十年后的衰老发生不良老化表型（神经认知，身体，血管，临床结局）。 该建议通过定义代谢来解决NIA的核心任务（直接响应PA-17-088） 在种族和生活的极端情况下，“卓越健康衰老”的基础。我们利用丰富的表型 在健康ABC中，在CARDIA内的资助工作以及一支在衰老流行病学，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- 衰老社区的非应用资源用于生物衰老的机制和生物标志物的投资。