Viral burden and systemic inflammation as biomarkers for chronic disease and frailty in aging

病毒负荷和全身炎症作为慢性疾病和衰老衰弱的生物标志物

• 批准号: 10153615
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 65.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153615
• 关键词: 21 year old; Activities of Daily Living; Address; Adult; Age; Age-Years; Aging; Antibody Response; Arizona; Bacteriophages; Biological Markers; Blood; Blood Cells; Blood Circulation; Budgets; Cardiovascular Diseases; Caring; Censuses; Chronic; Chronic Disease; Clinical; Clinical Research; Consumption; Cytokine Gene; Cytomegalovirus; DNA Viruses; Data; Detection; Development; Disease; Doctor of Philosophy; Elderly; Etiology; Exhibits; Flow Cytometry; Funding; Gene Expression Profiling; Genes; Genetic Transcription; Guidelines; Health Care Costs; Healthcare; Immune; Immune response; Immune system; Immunity; Immunization; Immunology; Indiana; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Lead; Link; Lymphocyte Activation; Malignant Neoplasms; Measurement; Measures; Mediator of activation protein; Medicare; Metabolic Diseases; Molecular; Monitor; Neurodegenerative Disorders; Organism; Outcome; Peripheral Blood Mononuclear Cell; Plasma; Population; Prospective cohort; Proteins; Public Health; Questionnaires; RNA Viruses; Research; Resources; Sampling; Shotgun Sequencing; Source; T-Cell Activation; T-Lymphocyte; Testing; Universities; Validation; Viral; Viral Load result; Virus; Virus Diseases; Virus Latency; acute infection; age related; aging population; biomarker panel; chronic infection; cohort; differential expression; disorder risk; frailty; gastrointestinal; immune activation; immunosenescence; member; reactivation from latency; recruit; senescence; systemic inflammatory response; transcriptome sequencing; virology; virome; young adult

Abstract According to the US Census Bureau there were 47.8 million people older than 65 living in the U.S. in 2015 and is projected to more than double by 2050. The implications on health care costs are substantial. Identifying members of the aging population at increased risk for disease and frailty is a major public health imperative. Frailty and many of the chronic diseases of aging coincide with chronic inflammation. The cause of chronic inflammation is not known. One potential etiology is lifelong stimulation of the immune system by acute and chronic infections. Chronic antigenic stimulation can lead to a state of “immunosenescence”, which is associated with chronic secretion of inflammatory mediators. Persistent viruses, by virtue of their ability to establish latency, are ideally poised to drive chronic antigenic stimulation. In this project we hypothesize that older adults will exhibit higher viral burden that will lead to increased immune stimulation and chronic inflammation, and that this burden will be able to predict propensity for and timing of frailty and age- related diseases. To address this hypothesis we will measure viral burden in the blood and link it to inflammatory gene expression profiling and markers of T cell activation/senescence to validate these as "biomarkers" for prediction of chronic disease and frailty. This will be done through two large aging cohorts which are collecting blood along with extensive questionnaires and tests to assess the presence of chronic diseases and frailty. We propose the following specific aims: (1) To measure the blood virome (including bacteriophages) in an elderly population and younger controls. We will determine the presence of RNA and DNA viruses as well as bacteriophages in the blood compartment of younger and older adults using shotgun sequencing and RNA-Seq. The presence and activity of cytomegalovirus as a potential driver of immune aging will be assessed by monitoring anti-CMV immune responses. (2) To assess markers of chronic inflammation in an elderly population and younger controls and correlate these with evidence of immune aging and viral specific immune responses. We will determine the degree of systemic inflammation in the blood of subjects through measurement of cytokines and gene expression profiling of PBMCs. We will assess the degree of lymphocyte activation, senescence, and virus-specific activity by flow cytometry. (3) To correlate the blood virome, evidence of systemic inflammation and the presence of chronic disease and frailty in test subjects and create a potential inflammatory and viral “biomarker” for the detection of the complications of aging. Using data from specific aims 1 and 2, we will connect viral burden (including bacteriophages) and markers of chronic inflammation to each other and to clinical outcomes in a cross-sectional and mixed cross-sectional/longitudinal manner. This interdisciplinary project should not only deliver biomarkers for the complications of aging, but also suggest potential interventions that might mitigate the development of chronic disease and frailty in the aging population.

抽象的 根据美国人口普查局的说法，在美国，有4780万人居住65人。 2015年，到2050年预计将增加一倍以上。对医疗保健费用的影响是巨大的。 确定人口老龄化的人的疾病风险增加和脆弱是一种主要的公共卫生 至关重要的。脆弱和许多衰老的慢性疾病与慢性炎症相吻合。原因 慢性炎症尚不清楚。一种潜在的病因是终生刺激免疫系统 急性和慢性感染。慢性抗原刺激会导致“免疫衰老”的状态，该状态 与炎症介质的长期分泌有关。持续的病毒，凭借其能力 建立潜伏期是理想的中毒以驱动慢性抗原刺激。在这个项目中，我们假设 老年人将暴露于更高的病毒负担，这会导致免疫刺激增加和慢性 炎症，这种燃烧将能够预测脆弱和年龄的可靠性和时间 相关疾病。为了解决这一假设，我们将测量血液中的病毒灼伤并将其联系 炎症基因表达分析和T细胞激活/敏感的标记以验证这些表达 预测慢性疾病和脆弱的“生物标志物”。这将通过两个大衰老队列完成 他们正在收集血液以及广泛的问卷和测试，以评估慢性的存在 疾病和脆弱。我们提出以下具体目的：（1）测量血液病毒蛋白（包括 噬菌体）在老年人和年轻的对照中。我们将确定RNA的存在 使用DNA病毒以及在年轻人和老年人的血液中的细菌 shot弹枪测序和RNA-Seq。巨细胞病毒作为潜在驱动力的存在和活动 免疫衰老将通过监测抗CMV免疫反应来评估。 （2）评估标记 老年人群和年轻对照中的慢性炎症，并将其与证据相关联 免疫衰老和病毒特异性免疫反应。我们将确定系统性的程度 通过测量细胞因子和基因表达分析的受试者血液的炎症 PBMC。我们将通过流量评估淋巴细胞激活，感应和病毒特异性活性的程度 （3）将血液病毒瘤相关联，全身炎症的证据和存在 测试受试者的慢性疾病和脆弱，并创建潜在的炎症和病毒“生物标志物” 用于检测衰老并发症。使用特定目标1和2的数据，我们将连接病毒 负担（包括细菌）和慢性炎症的标记和临床结果 以横截面和混合横截面/纵向方式。这个跨学科项目不应 仅提供衰老并发症的生物标志物，但也提出了可能的干预措施 减轻人口老龄化的慢性疾病和脆弱性的发展。