Integrative Multi‐Omics Analysis Reveals Age‐Associated Molecular Mechanisms in SARS‐CoV‐2 Infection

The COVID-19 pandemic has disproportionately affected elderly individuals, who exhibit higher risks of severe disease and mortality. Although the precise molecular mechanisms underlying this disparity remain unclear, we employed an integrative multi-omics approach to analyze lung tissues from young, adult, and aged mice infected with the SARS-CoV-2 Beta variant (B.1.351). Conserved molecular signatures across age groups included the activation of antiviral immune response pathways (such as antigen processing and presentation, and cytokine-cytokine receptor interaction), and downregulation of metabolic regulatory pathways (such as cGMP-PKG signaling). Concurrently, we observed activation of three proinflammatory kinases-p38 delta mitogen-activated protein kinase (p38D), mechanistic target of rapamycin (mTOR), cytoplasmic tyrosine kinase (CTK)-along with inhibition of the antiviral kinase mammalian Ste20-like kinase 4 (MST4) across all age groups, suggesting conserved therapeutic targets. Our results also revealed age-dependent characteristics, with aged mice showing severe weight loss (> 15% by day 4 postinfection) and hyperactivation of complement and coagulation cascades compared to their younger counterparts. The upregulation of complement system proteins, including complement component 3 (C3), complement component 4b (C4b), and neutrophil/M1 macrophage markers S100 calcium-binding protein A8/A9 (S100A8/A9) in aged mice, coupled with a strong positive correlation (R² = 0.89) between C3 and S100A8, suggested S100A8-mediated complement activation. These findings elucidate how aging exacerbates SARS-CoV-2 pathogenesis through dysregulated immune and inflammatory responses, providing potential targets for age-tailored therapies to mitigate severe COVID-19 outcomes in the elderly.