High resolution longitudinal immune monitoring for elucidating immune aging dynamics

自2007年以来，我们每年都与斯坦福大学埃里森一起跟踪免疫系统变化的动态 纵向老龄化（SELA）队列，由约150名不同年龄段的年轻人（20-40岁）和老年人（60岁以上）组成 我们在高分辨率下确定细胞亚群表型和细胞因子反应的年龄，全血 基因表达，血清细胞因子，每年流感疫苗接种的HAI反应，以及标准化的临床 评价鉴于分析的时间和深度，拉美经济体系的这一组是一种独特的资源。 使用一种新的系统方法，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老化，并描述个体的免疫基线 自我平衡状态是缓慢地沿着一个连续体和一个轨迹移动，远远超出了正常情况下 从横截面分析得出。我们利用这一点来建立一个可靠的免疫年龄指标（IMM-AGE）， 其捕获免疫细胞亚群组成和细胞应答的变化的终生过程， 值IMM-AGE仅与实际年龄部分相关，但在以下方面具有预后临床价值： 健康老年人的全因死亡率超出了公认的风险因素。此外，我们还利用拉美经济体系， 已经确定了心血管疾病和基于免疫的预测标志物之间的几个强有力的联系， 与IMM-AGE相关，其提供比现有标准临床测试更好和更早的检测。理解 人类免疫变异和衰老通过透镜的定量图案化过程使我们能够测试 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 驱动免疫老化;（2）它与免疫反应、疾病严重程度和治疗有何关系？到 回答这些问题，我们将继续拉美经济体系的纵向分析，现在有更多的表观遗传和 环境数据，并招募更多的队列：一个健康的双胞胎队列（40-60岁），拉美经济体系目前的一个缺口 和一个早期免疫老化的信息;一群老年人积极锻炼和生活良好， 可以用来区分生物老化的特征和那些可以通过生活方式改变的特征， 在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， 妇女健康倡议中的第二个受试者，具有心血管状态的回顾性信息。这些 后面的队列将使我们能够测试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史的联系，这是一种观察到的流行病学关联， 迄今为止，机制尚不清楚。最后，我们将使用从SELA采集的超过12+的疫苗接种后样本 多年来绘制流感特异性B和T细胞反应史，并测试这些信息，再加上免疫- 年龄，可以帮助预测老年人的流感疫苗反应，这是一个目前尚未解决的问题，主要临床 影响对这项工作的深入了解将导致该指标的改进，其与人类生理学的联系， 提供了一种方法来评估免疫老化如何在慢性和急性年龄相关疾病中发挥作用。

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.