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研究所一起跟踪免疫系统的动态变化 纵向老龄化(SELA)队列，由约150名不同年龄的年轻人(20-40岁)和老年人(60岁)组成 我们以高分辨率全血测定细胞亚群表型和细胞因子反应的年龄 基因表达、血清细胞因子、对每年接种流感疫苗的HAI反应以及标准化临床 评估。考虑到分析的时间长度和深度，SELA队列是一个独特的资源。 使用一种新的系统方法，利用数据的高维和纵向性质 使我们对免疫老化有了更深入的了解，并描述了个人的免疫基线 动态平衡状态：沿着连续体和轨迹缓慢移动的状态，远远超出正常情况 通过横断面分析得出。我们利用这一点建立了一个可靠的免疫年龄(IMM-AGE)指标， 它捕捉了免疫细胞亚群组成和细胞反应的终身变化过程 价值。IMM-AGE仅与实际年龄部分相关，但在临床预后方面有价值 在健康的老年人中，除了公认的危险因素外，所有原因的死亡率也是如此。此外，使用Sela WE 已经确定了心血管疾病和基于免疫的预测标记物之间的几个强烈联系， 与免疫成像相关，提供比现有标准临床测试更好和更早的检测。理解 人类的免疫变异和老化通过晶状体的量化图案化过程使我们变得可测试 我们将在这里探讨的假设。具体地说，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；以及(2)它与免疫反应、疾病严重程度和治疗有何关系？至 回答这些问题，我们将继续SELA的纵向剖析，现在有更多的表观遗传学和 环境数据，并招募更多的队列：健康的双胞胎队列(40-60岁)，目前SELA的缺口 和一个早期免疫老化的信息；一群老年人积极锻炼并生活得很好， 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 在2011年测量了免疫参数；以及另外两个队列，首先是心脏移植受试者和 妇女健康倡议中的第二个对象，具有关于心血管状况的回顾信息。这些 后一群人将允许我们检验我们发表的关于免疫衰老关系的研究提出的假说。 心血管疾病及其与流感病史的联系，一个观察到的流行病学关联，其 到目前为止，机制还不清楚。最后，我们将使用从SELA收集的超过12个疫苗接种后的样本 几年来绘制流感特异性B和T细胞反应历史图，并测试这些信息与免疫- 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 这意味着什么。对这项工作的见解将导致该指标的完善，它与人类生理学的联系，以及 提供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.