Aging Biomarkers: Integrating Omic Profiles with Mechanistic Measures

项目摘要 本研究的目的是开发和验证反映生物衰老机制的生物标记物。 至少五种被批准用于人类的药理化合物延长了啮齿动物的健康和寿命 模特们。在人类身上进行类似的方法需要持续40多年的研究，而且是不可行的。更确切地说， 该领域需要可靠的人类生物标记物来表明干预对人类健康的有利(或不利)影响。 在较短的时间段内与衰老相关的通路。表观基因组学和由此产生的转录变化可能 统一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1,200名55-94岁人群单核细胞样本的广泛分析 动脉粥样硬化(MESA)，我们确定了1794个与年龄相关的甲基化位点和2704个与年龄相关的甲基化位点 转录，这超过了几个网络，包括线粒体生物能量学和自噬。 我们进一步证明了这些基因网络与年龄无关的衰老相关疾病之间的关联。 除了基因组图谱，功能表型作为衰老的生物标记物可能提供更多的优势 进程。例如，我们对老年人的研究表明，外周血液的生物能量能力 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 预测这些表观遗传的、转录的和功能的标记将与 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 1800名受试者单核细胞表观遗传学/转录谱和年龄相关健康结局的评估 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 在200名成年人(40-70岁)限制热量(素食)的情况下，我们还建议增加骨骼肌活检 80例。具体目的是：1)确定与衰老相关的单核细胞转录/表观基因组 单独或组合的通路预测8年随访中衰老相关疾病的变化 (n=1800)；以及2)确定卡路里限制是否改变了衰老相关的单核细胞 循环细胞和骨骼中的转录/表观基因组途径(N=200)和生物能量测量 肌肉(N=80)朝向更年轻的模式，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全面老化途径的生物标记物 转录组和表观基因组图谱与循环和骨骼肌中的生物能量学，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，以有效和成本效益 通过多种融合策略验证潜在的生物标志物。

Project Summary 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.