Exploring the Biological Mechanisms of Severe COVID-19 in the Elderly: Insights from an Aged Mouse

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global health crisis, particularly affecting the elderly, who are more susceptible to severe outcomes. However, definitive parameters or mechanisms underlying the severity of COVID-19 in elderly people remain confused. Thus, this study seeks to elucidate the mechanism behind the increased vulnerability of elderly individuals to severe COVID-19. We employed an aged mouse model with a mouse-adapted SARS-CoV-2 strain to mimic the severe symptoms observed in elderly patients with COVID-19. Comprehensive analyses of the whole lung were performed using transcriptome and proteome sequencing, comparing data from aged and young mice. For transcriptome analysis, bulk RNA sequencing was conducted using an Illumina sequencing platform. Proteomic analysis was performed using mass spectrometry following protein extraction, digestion, and peptide labeling. We analyzed the transcriptome and proteome profiles of young and aged mice and discovered that aged mice exhibited elevated baseline levels of inflammation and tissue damage repair. After SARS-CoV-2 infection, aged mice showed increased antiviral and inflammatory responses; however, these responses were weaker than those in young mice, with significant complement and coagulation cascade responses. In summary, our study demonstrates that the increased vulnerability of the elderly to severe COVID-19 can be attributed to an attenuated antiviral response and the overactivation of complement and coagulation cascades.

2019冠状病毒病（COVID-19）由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发，已造成全球公共卫生危机，尤其对老年群体影响深重，该群体更易出现重症结局。然而，老年人群感染新冠后出现重症的确切致病参数与潜在发病机制仍尚未明确。因此，本研究旨在阐明老年个体对新冠重症易感性升高的内在机制。我们采用鼠适应型SARS-CoV-2毒株构建老年小鼠模型，以模拟老年新冠患者的重症症状。本研究通过转录组与蛋白质组测序技术对全肺组织开展全面分析，并对比老年小鼠与年轻小鼠的测序数据。转录组分析方面，我们依托Illumina测序平台完成了批量RNA测序（bulk RNA sequencing）；蛋白质组分析则在完成蛋白质提取、酶解与肽段标记后，采用质谱技术进行检测。我们对年轻与老年小鼠的转录组与蛋白质组表达谱进行分析后发现，老年小鼠的基础炎症水平与组织损伤修复通路活性均显著升高。感染SARS-CoV-2后，老年小鼠的抗病毒与炎症应答有所增强，但此类应答强度弱于年轻小鼠，且补体与凝血级联反应显著激活。综上，本研究表明，老年群体对新冠重症易感性升高的原因可归结为抗病毒应答减弱以及补体与凝血级联通路的过度激活。