High resolution longitudinal immune monitoring for elucidating immune aging dynamics

高分辨率纵向免疫监测阐明免疫衰老动态

• 批准号: 10190557
• 负责人: Mark Morris Davis
• 金额: $ 370万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190557
• 关键词: Acute; Address; Age; Aging; Alzheimer' s Disease; Antibodies; Antigens; Automobile Driving; B-Lymphocytes; Biological Aging; Biological Clocks; Blood Cells; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Chronology; Clinical; Communicable Diseases; Coupled; Cross-Sectional Studies; Data; Data Analyses; Deterioration; Development; Disease; Dizygotic Twins; Early Diagnosis; Elderly; Epidemiology; Epigenetic Process; Foundations; Future; Gene Expression; Heart Transplantation; Human; Immune; Immune response; Immune system; Immunologic Monitoring; Immunologics; Immunology; Individual; Inflammation; Influenza vaccination; Length; Life; Life Style; Link; Longitudinal Studies; Maps; Measures; Methods; Molecular; Morbidity - disease rate; Nature; Parkinson Disease; Pattern; Phenotype; Physiological; Physiology; Play; Populations at Risk; Premature aging syndrome; Process; Publishing; Recording of previous events; Registries; Research; Research Project Grants; Resolution; Resources; Risk Factors; Role; ST14 gene; Sampling; Science; Serum; Severity of illness; Standardization; Strenuous Exercise; System; T cell response; T-cell receptor repertoire; Testing; Therapeutic; Time; Twin Multiple Birth; Vaccination; Variant; Whole Blood; Women' s Health; Work; active lifestyle; adaptive immune response; base; cancer risk; clinical risk; cohort; cytokine; design; disorder risk; flu; high dimensionality; high throughput screening; immune function; individual variation; influenza virus strain; influenza virus vaccine; insight; lens; member; middle age; mortality; novel; predictive marker; prognostic; recruit; research clinical testing; response; seasonal influenza; vaccine response

Since 2007, we have annually tracked the dynamics of immune system changes with the Stanford Ellison Longitudinal Aging (SELA) cohort, which consists of ~150 young (20-40) and old (60+) individuals of various ages for which we determined cell subset phenotypes and cytokine responses at high resolution, whole blood gene expression, serum cytokines, HAI response to annual flu vaccination, and a standardized clinical evaluation. Given the length of time and the depth of profiling, the SELA cohort is a unique resource. Using a novel systems approach which leverages the high-dimensional and longitudinal nature of the data allowed us to gain increased insight into immune-aging and describe an individual’s immune baseline homeostatic state as shifting slowly along a continuum and a trajectory, well beyond what can normally be obtained from cross-sectional analyses. We utilized this to build a reliable metric of immune-age (IMM-AGE), which captures a life-long process of change in immune cell subset composition and cell responses in a single value. IMM-AGE only partially correlates with chronological age and yet has prognostic clinical value with respect to all-cause-mortality in healthy older adults beyond well-established risk factors. In addition, using SELA we have identified several strong links between cardiovascular disease and immune-based predictive markers, correlative to IMM-AGE, that offer better and earlier detection than existing standard clinical tests. Understanding human immune variation and aging through the lens of a quantitative patterned process led us to testable hypotheses which we will explore here. Specifically, our two research projects address two questions – (1) what drives immune-aging; and (2) how does it relate to immune response, disease severity, and treatment? To answer these questions we will continue the longitudinal profiling of SELA, now with more epigenetic and environmental data, and recruit additional cohorts: a healthy twin cohort (ages 40-60), a current gap in SELA and one informative of early immune aging; a cohort of older adults vigorously exercising and living well which can be leveraged to distinguish features of biological aging and those modifiable by lifestyle and for which we have measured immune parameters in 2011; and two additional cohorts, first of heart transplant subjects and second of subjects in the Women’s Health Initiative with retrospective information on cardiovascular state. These latter cohorts will allow us to test hypotheses raised from our published studies on the relation of immune-aging to cardiovascular disease and its connection to flu history, an observed epidemiological association whose mechanism has been unclear to date. Last, we will use post-vaccination samples from SELA collected over 12+ years to map flu-specific B and T cell response history and test whether this information, coupled with immune- age, can help predict flu vaccine responses in older adults, a currently unsolved problem with major clinical implications. Insights of this work will lead to refinement of the metric, its connection to human physiology, and provide a means to assess how immune-aging plays a role in the chronic and acute age associated conditions.

自 2007 年以来，我们每年都会与斯坦福埃里森 (Stanford Ellison) 追踪免疫系统变化的动态 纵向老龄化 (SELA) 队列，由约 150 名不同年龄层的年轻人 (20-40) 和老年人 (60+) 组成 我们以高分辨率、全血确定细胞子集表型和细胞因子反应的年龄 基因表达、血清细胞因子、每年流感疫苗接种后的 HAI 反应以及标准化临床 鉴于分析的时间长度和深度，SELA 队列是一种独特的资源。 使用一种新颖的系统方法，利用数据的高维和纵向性质 使我们能够更深入地了解免疫衰老并描述个人的免疫基线 稳态沿着连续体和轨迹缓慢变化，远远超出正常情况 我们利用它来建立可靠的免疫年龄指标（IMM-AGE）， 它捕获了免疫细胞亚群组成和细胞反应的终生变化过程 IMM-AGE 仅与实际年龄部分相关，但具有预后临床价值。 此外，我们还利用 SELA 来降低健康老年人的全因死亡率。 已经确定了心血管疾病和基于免疫的预测标记之间的几个紧密联系， 与 IMM-AGE 相关，比现有的标准临床测试提供更好、更早的检测。 通过定量模式过程的视角，人类免疫变异和衰老使我们能够进行可测试的研究 我们将在这里探讨的假设具体来说，我们的两个研究项目解决了两个问题——（1）什么。 促进免疫衰老；（2）它与免疫反应、疾病严重程度和治疗有何关系？ 为了回答这些问题，我们将继续对 SELA 进行纵向分析，现在有更多的表观遗传和 环境数据，并招募额外队列：健康双胞胎队列（40-60 岁），SELA 目前的缺口 以及一组关于早期免疫衰老的信息；一群积极锻炼和生活良好的老年人， 可以用来区分生物衰老的特征和那些可以通过生活方式改变的特征，而我们对此 2011 年测量了免疫参数；另外两个队列，第一个是心脏移植受试者， 女性健康倡议中的第二个主题，提供有关心血管状况的回顾性信息。 后面的队列将使我们能够检验我们发表的关于免疫衰老关系的研究中提出的假设 心血管疾病及其与流感病史的联系，这是一种观察到的流行病学关联，其 最后，我们将使用从 SELA 收集的 12 岁以上儿童的疫苗接种后样本。 多年绘制流感特异性 B 和 T 细胞反应历史图，并测试这些信息是否与免疫相关 年龄，可以帮助预测老年人的流感疫苗反应，这是目前主要临床尚未解决的问题 这项工作的见解将导致指标的完善、其与人类生理学的联系以及 提供了一种评估免疫衰老如何在慢性和急性年龄相关疾病中发挥作用的方法。