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: 10491673
• 负责人: Mark Morris Davis
• 金额: $ 350万
• 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/10491673
• 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 prognostic; 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; 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，我们每年都会跟踪斯坦福·埃里森（Stanford Ellison）的免疫系统变化的动力 纵向老化（SELA）队列，由〜150年Young（20-40）和老年人组成 我们在高分辨率下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，HAI对年度流感疫苗的反应和标准化的临床 评估。鉴于时间长度和分析的深度，Sela队列是一个独特的资源。 使用一种利用数据的高维和纵向性质的新型系统方法 使我们能够增加对免疫衰老的洞察力并描述个人的免疫基线 稳态状态随着连续体和轨迹缓慢移动，远远超出了通常 从横截面分析获得。我们利用它来构建可靠的免疫年龄（IMM-AGE）， 它捕获了一个终生的免疫细胞子集组成和单个细胞反应的变化过程 价值。 Imm-age仅部分与年代年龄相关，但具有预后的临床价值 在健康的老年人中，全因态度超出了公认的危险因素。此外，使用Sela我们 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牢固联系， 与现有标准临床测试相比，与Imm-age相关，可提供更好和更早的检测。理解 人类免疫变化和通过定量图案过程的镜头衰老，使我们进行了可测试 我们将在这里探索的假设。具体来说，我们的两个研究项目解决了两个问题 - （1）什么 驱动免疫衰老； （2）它与免疫响应，疾病的严重程度和治疗有何关系？到 回答这些问题，我们将继续进行Sela的纵向分析，现在具有更多的表观遗传和 环境数据并招募其他队列：健康的双胞胎队列（40-60岁），当前的Sela差距 还有一个关于早期免疫老化的信息；一群老年人大力锻炼身体和生活良好 可以利用以区分生物衰老的特征，以及通过生活方式进行修改的特征 在2011年测量了免疫参数；还有两个额外的队列，第一个心脏移植受试者和 妇女健康计划中的第二个受试者，以及有关心血管状态的回顾性信息。这些 后者队列将使我们能够从有关免疫老化关系的已发表研究中提出的假设进行测试 与心血管疾病及其与流感史的联系，这是一种观察到的流行病学关联 机制尚不清楚迄今为止。最后，我们将使用来自12+以上的SELA的疫苗接种样本 绘制流感特异性B和T细胞响应历史记录的年份，并测试该信息是否与免疫 - 年龄，可以帮助预测老年人的流感疫苗反应，这是当前未解决的主要临床问题 含义。这项工作的见解将导致指标的完善，其与人类生理的联系以及 提供一种方法来评估免疫年龄如何在慢性和急性年龄相关条件中发挥作用。