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.