Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8⁺ T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency.

衰老与免疫反应不足和全身性炎症增加有关。为了揭示这些变化背后的调控程序，我们应用了系统免疫学方法，分析了PBMC，纯化的单核细胞，B细胞和T细胞中的染色质可及性和转录组。对来自77位年轻和老年供体的样品进行的分析显示，PBMC具有新颖而强大的衰老特征，同时在与T细胞信号传导相关的启动子和增强子上同时发生系统性染色质关闭，并且潜在的随机性染色质开放主要在静止和受阻部位出现。染色质可及性和转录组的组合分析发现了随着年龄的增长而激活/失活的免疫分子，并鉴定了IL7R的沉默基因和IL-7信号通路基因作为潜在的生物标志物。此标记由记忆CD8 ⁺ T细胞承担，该细胞在衰老相关的NF-κB和STAT因子结合中丧失。因此，我们的研究提供了一种独特而全面的方法来鉴定候选生物标志物，并提供了与衰老相关的免疫缺陷的机制性见解。