Aging Biomarkers: Integrating Omic Profiles with Mechanistic Measures

衰老生物标志物：将组学概况与机械测量相结合

• 批准号: 10445057
• 负责人: JINGZHONG DING
• 金额: $ 56.27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445057
• 关键词: Adult; Adverse effects; Age; Aging; Animal Model; Animals; Autophagocytosis; Bioenergetics; Biological; Biological Aging; Biological Markers; Biopsy; Blood; Blood Circulation; Brain; Caloric Restriction; Cells; Clinical Trials; Code; Cognitive; Development; Dietary Practices; Digit structure; Disease; Elderly; Epigenetic Process; Gait speed; Genetic; Health; Human; Individual; Intervention; Life Cycle Stages; Longevity; Longitudinal cohort study; Measures; Metabolic; Methylation; Mitochondria; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Mus; Myocardium; Outcome; Participant; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Persons; Pharmacology; Phenotype; Physical Function; Physical Performance; Physical activity; Population; Process; Randomized Clinical Trials; Reporting; Rodent Model; Sampling; Site; Skeletal Muscle; Smoking; Testing; Therapeutic Intervention; Time; Transcript; Walking; age related; aged; biomarker panel; cardiometabolism; cognitive function; comorbidity; cost; epigenomics; experimental study; fly; follow-up; gene network; genome-wide analysis; healthspan; healthy aging; intervention effect; middle age; monocyte; mortality; nonhuman primate; novel; potential biomarker; predictive marker; transcriptomics

The objective of this study is to develop and validate biomarkers that reflect mechanisms of biological aging. At least five pharmacologic compounds approved for human use extend health span and life span in rodent models. Parallel approaches in humans would require studies lasting 40+ years and are infeasible. Rather, the field needs reliable human biomarkers that indicate beneficial (or adverse) effects of an intervention on aging-related pathways over shorter time periods. Epigenomics and resultant transcriptomic changes may unite mechanisms of biological aging implicated in animal studies and unravel novel pathways. In a genome- wide analysis of monocyte samples in 1,200 persons (aged 55-94 years) from the Multi-Ethnic Study of Atherosclerosis (MESA), we identified 1,794 age-associated methylation sites and 2,704 age-associated transcripts, which over-represented several networks, including mitochondrial bioenergetics and autophagy. We further demonstrated associations of these gene networks with aging-related diseases independent of age. In addition to omic profiles, functional phenotyping may provide further advantages as biomarkers of the aging process. For example, our studies in older adults indicate the bioenergetic capacity of peripheral blood mononuclear cells is positively associated with physical function measures even when controlling for age. We predict that these epigenetic, transcriptomic, and functional markers will be associated with the development of aging-related comorbidities and are responsive to caloric restriction. We propose to utilize existing longitudinal assessments of monocyte epigenetic/transcriptomic profiles and age-related health outcomes from 1,800 middle-aged and older adults (55-94 years) in the MESA study. Leveraging an ongoing randomized clinical trial (VEGGIE) of caloric restriction in 200 adults (40-70 years), we also propose to add skeletal muscle biopsy (N=80). The specific aims are: 1) to determine whether aging-related monocyte transcriptomic/epigenomic pathways individually or in combination predict changes in aging-related diseases over an 8-year follow up (N=1,800); and 2) To determine whether caloric restriction shifts aging-related monocyte transcriptomic/epigenomic pathways (N=200) and bioenergetic measures in circulating cells and skeletal muscle (N=80) towards a younger pattern and whether these changes individually or in combination correlate with changes in aging-related metabolic, physical and cognitive health outcomes. The proposed study will generate a panel of biomarkers reflecting a comprehensive battery of aging pathways by integrating transcriptomic and epigenomic profiles with bioenergetics in circulation and skeletal muscle, from an existing longitudinal cohort study and an ongoing clinical trial of caloric restriction, to efficiently and cost-effectively validate potential biomarkers through multiple convergent strategies.

本研究的目的是开发和验证反映生物衰老机制的生物标志物。 至少五种药理化合物被批准用于人类，可延长啮齿动物的健康寿命和寿命 模型。在人类身上采用并行方法需要持续 40 多年的研究，而且是不可行的。相当， 该领域需要可靠的人类生物标志物来表明干预措施的有益（或不利）影响 较短时间段内与衰老相关的途径。表观基因组学和由此产生的转录组变化可能 结合动物研究中涉及的生物衰老机制并揭示新的途径。在基因组中—— 对来自多种族研究的 1,200 人（年龄 55-94 岁）的单核细胞样本进行了广泛分析 动脉粥样硬化 (MESA)，我们确定了 1,794 个与年龄相关的甲基化位点和 2,704 个与年龄相关的甲基化位点 转录本，过度代表了几个网络，包括线粒体生物能学和自噬。 我们进一步证明了这些基因网络与衰老相关疾病的关联，与年龄无关。 除了组学特征之外，功能表型分析还可以作为衰老的生物标志物提供进一步的优势 过程。例如，我们对老年人的研究表明外周血的生物能能力 即使在控制年龄的情况下，单核细胞也与身体功能指标呈正相关。我们 预测这些表观遗传、转录组和功能标记将与 与衰老相关的合并症，并对热量限制有反应。我们建议利用现有的纵向 对 1,800 名单核细胞表观遗传/转录组谱和年龄相关健康结果的评估 MESA 研究中的中老年人（55-94 岁）。利用正在进行的随机临床试验 (VEGGIE) 对 200 名成年人（40-70 岁）的热量限制，我们还建议增加骨骼肌活检 （N=80）。具体目标是：1）确定衰老相关的单核细胞转录组/表观基因组是否 在 8 年的随访中，单独或组合的通路可预测衰老相关疾病的变化 （N=1,800）； 2) 确定热量限制是否会改变与衰老相关的单核细胞 循环细胞和骨骼中的转录组/表观基因组通路 (N=200) 和生物能测量 肌肉（N = 80）向更年轻的模式发展，以及这些变化是否单独或组合相关 与衰老相关的代谢、身体和认知健康结果的变化。拟议的研究将 通过整合生成一组反映衰老途径的综合生物标记物 转录组和表观基因组图谱以及循环和骨骼肌中的生物能学，来自现有的 纵向队列研究和正在进行的热量限制临床试验，以有效且具有成本效益 通过多种聚合策略验证潜在的生物标志物。