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

摘要 根据美国人口普查局的数据，2010年美国有4780万65岁以上的老年人。 预计到2050年将增加一倍以上。这对医疗保健费用的影响是巨大的。 确定老年人口中疾病和虚弱风险增加的成员是一项重要的公共卫生工作， 势在必行虚弱和许多慢性衰老疾病都与慢性炎症有关。事业 慢性炎症是未知的。一个潜在的病因是免疫系统的终身刺激， 急性和慢性感染。慢性抗原刺激可导致“免疫衰老”状态， 与炎症介质的慢性分泌有关。持久性病毒，凭借其能力， 建立潜伏期，理想地准备驱动慢性抗原刺激。在这个项目中，我们假设， 老年人将表现出更高的病毒负荷，这将导致免疫刺激增加和慢性 炎症，并且这种负担将能够预测虚弱和年龄的倾向和时间- 相关疾病。为了解决这一假设，我们将测量血液中的病毒负荷，并将其与 炎性基因表达谱和T细胞活化/衰老的标志物，以验证这些作为 用于预测慢性疾病和虚弱的“生物标志物”。这将通过两个大型老龄化队列来完成 他们正在收集血液，沿着大量的问卷调查和测试，以评估慢性病的存在。 疾病和脆弱。我们提出了以下具体目标：（1）测量血液病毒组（包括 噬菌体）在老年人群和年轻对照中的作用。我们将确定RNA的存在 和DNA病毒以及噬菌体在年轻人和老年人的血液室使用 鸟枪测序和RNA-Seq.巨细胞病毒的存在和活性作为一种潜在的驱动因素， 免疫老化将通过监测抗CMV免疫应答来评估。(2)为了评估 慢性炎症在老年人群和年轻的控制，并与这些证据 免疫老化和病毒特异性免疫反应。我们将确定系统性 通过测量受试者血液中的细胞因子和炎症的基因表达谱， PBMC。我们将通过流式细胞术评估淋巴细胞活化、衰老和病毒特异性活性的程度。 细胞仪(3)为了将血液病毒组、全身性炎症的证据和 测试对象的慢性疾病和虚弱，并产生潜在的炎症和病毒“生物标志物” 用于检测衰老的并发症。使用特定目标1和2的数据，我们将病毒连接到 负荷（包括噬菌体）和慢性炎症标志物之间的相互关系以及与临床结局的关系 以横截面和混合横截面/纵向方式。这个跨学科的项目不应该 不仅提供了衰老并发症的生物标志物，而且还提出了潜在的干预措施， 减缓老龄人口中慢性病和虚弱的发展。

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.