tetano
Editor, Senior Moderator
J Med Virol
. 2025 Dec;97(12):e70730.
doi: 10.1002/jmv.70730. Integrative Multi-Omics Analysis Reveals Age-Associated Molecular Mechanisms in SARS-CoV-2 Infection
Xiaoyue Tang[SUP] 1 [/SUP], Yan Xiao[SUP] 2 [/SUP], Jingchuan Zhong[SUP] 2 [/SUP], Tao Ding[SUP] 1 [/SUP], Qiaochu Wang[SUP] 1 [/SUP], Chunmei Shi[SUP] 1 [/SUP], Zhiyi Zhang[SUP] 1 [/SUP], Yehong Yang[SUP] 1 [/SUP], Yue Wu[SUP] 1 [/SUP], Jiangfeng Liu[SUP] 1 [/SUP], Lili Ren[SUP] 2 3 [/SUP], Juntao Yang[SUP] 1 4 [/SUP]
Affiliations
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.
Keywords: SARS‐CoV‐2; aging; complement; inflammatory responses; kinase; multi‐omics.
. 2025 Dec;97(12):e70730.
doi: 10.1002/jmv.70730. Integrative Multi-Omics Analysis Reveals Age-Associated Molecular Mechanisms in SARS-CoV-2 Infection
Xiaoyue Tang[SUP] 1 [/SUP], Yan Xiao[SUP] 2 [/SUP], Jingchuan Zhong[SUP] 2 [/SUP], Tao Ding[SUP] 1 [/SUP], Qiaochu Wang[SUP] 1 [/SUP], Chunmei Shi[SUP] 1 [/SUP], Zhiyi Zhang[SUP] 1 [/SUP], Yehong Yang[SUP] 1 [/SUP], Yue Wu[SUP] 1 [/SUP], Jiangfeng Liu[SUP] 1 [/SUP], Lili Ren[SUP] 2 3 [/SUP], Juntao Yang[SUP] 1 4 [/SUP]
Affiliations
- PMID: 41378745
- DOI: 10.1002/jmv.70730
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.
Keywords: SARS‐CoV‐2; aging; complement; inflammatory responses; kinase; multi‐omics.