Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.

中文翻译：

---

宿主微生物多组学分析揭示了与 COVID-19 免疫病理学相关的年龄依赖性免疫失调

年龄是 2019 年严重冠状病毒病 (COVID-19) 的主要危险因素，但这种关系背后的机制尚未完全了解。为了解决这个问题，我们在前瞻性、多中心队列中评估了衰老对血液和上呼吸道宿主免疫反应以及鼻微生物组的影响，该队列由 1031 名 18 至 96 年间因 COVID-19 住院的未接种疫苗的患者组成。老的。我们进行了质谱流式分析、血清蛋白分析、抗严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 抗体测定以及血液和鼻转录组学。我们发现，年龄较大与入院时 SARS-CoV-2 病毒丰度增加、病毒清除延迟以及血液和上呼吸道中 I 型干扰素基因表达增加相关。我们还观察到先天免疫信号通路的年龄依赖性上调和适应性免疫信号通路的下调。老年人的幼稚 T 细胞和 B 细胞数量较少，单核细胞数量较多。随着时间的推移，与年轻人相比，老年人表现出促炎基因和血清趋化因子的持续诱导，这表明炎症消退存在年龄依赖性损害。疾病严重程度的转录和蛋白质生物标志物随年龄而变化，最年长的成年人在严重疾病中表现出更高的促炎基因和蛋白质表达。总之，我们的研究发现，衰老与病毒清除受损、免疫信号失调以及促炎基因和蛋白质的持续和潜在病理性激活有关。