{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:15:06Z","timestamp":1788394506164,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The COVID\u201019 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\u2010omics approach to analyze lung tissues from young, adult, and aged mice infected with the SARS\u2010CoV\u20102 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\u2010cytokine receptor interaction), and downregulation of metabolic regulatory pathways (such as cGMP\u2010PKG signaling). Concurrently, we observed activation of three proinflammatory kinases\u2010p38 delta mitogen\u2010activated protein kinase (p38D), mechanistic target of rapamycin (mTOR), cytoplasmic tyrosine kinase (CTK)\u2013along with inhibition of the antiviral kinase mammalian Ste20\u2010like kinase 4 (MST4) across all age groups, suggesting conserved therapeutic targets. Our results also revealed age\u2010dependent characteristics, with aged mice showing severe weight loss (&gt;\u200915% 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\u2010binding protein A8\/A9 (S100A8\/A9) in aged mice, coupled with a strong positive correlation (R\u00b2\u2009=\u20090.89) between C3 and S100A8, suggested S100A8\u2010mediated complement activation. These findings elucidate how aging exacerbates SARS\u2010CoV\u20102 pathogenesis through dysregulated immune and inflammatory responses, providing potential targets for age\u2010tailored therapies to mitigate severe COVID\u201019 outcomes in the elderly.<\/jats:p>","DOI":"10.1002\/jmv.70730","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T12:22:02Z","timestamp":1765455722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Multi\u2010Omics Analysis Reveals Age\u2010Associated Molecular Mechanisms in SARS\u2010CoV\u20102 Infection"],"prefix":"10.1002","volume":"97","author":[{"given":"Xiaoyue","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xiao","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe M\u00e9rieux Laboratory Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingchuan","family":"Zhong","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe M\u00e9rieux Laboratory Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaochu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehong","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangfeng","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Ren","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe M\u00e9rieux Laboratory Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College Beijing China"},{"name":"Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1180-391X","authenticated-orcid":false,"given":"Juntao","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China"},{"name":"Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.777070"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13230"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.571416"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6912e2"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glaa089"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.934171"},{"issue":"5","key":"e_1_2_11_8_1","first-page":"617","article-title":"The Role of Immunosenescence and Inflammaging in the Susceptibility of Older Adults to SARS\u2010CoV\u20102 Infection","volume":"27","author":"Zia A.","year":"2026","journal-title":"Current Pharmaceutical Biotechnology"},{"issue":"18","key":"e_1_2_11_9_1","first-page":"3325","article-title":"Senescent Remodeling of the Immune System and Its Contribution to the Predisposition of the Elderly to Infections","volume":"125","author":"Dewan S. K.","year":"2012","journal-title":"Chinese Medical Journal"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2019.103992"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0059-4"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12979-023-00406-z"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14051475"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2021.04.021"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.663187"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.279155"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI142780"},{"issue":"1","key":"e_1_2_11_18_1","first-page":"149","article-title":"[Impaired Hemostasis in Elderly and Senile Patients With Mesenteric Thrombosis in Covid\u201019.]","volume":"37","author":"Kadnikov R. V.","year":"2024","journal-title":"Advances in Gerontology"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-81803-2"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.2217\/epi-2020-0168"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30763-0"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04441-6"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04442-5"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151570"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009892"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-020-00640-3"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021436"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2100433"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2020.108598"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-27279-4"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.364471"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0485-y"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-018-1173-4"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01298"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.002"},{"issue":"7","key":"e_1_2_11_40_1","first-page":"4040","article-title":"Eculizumab Treatment in Patients With COVID\u201019: Preliminary Results From Real Life ASL Napoli 2 Nord Experience","volume":"24","author":"Diurno F.","year":"2020","journal-title":"European Review for Medical and Pharmacological Sciences"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1638"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky869"}],"container-title":["Journal of Medical Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.70730","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jmv.70730","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.70730","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T07:11:24Z","timestamp":1771312284000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmv.70730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":41,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/jmv.70730"],"URL":"https:\/\/doi.org\/10.1002\/jmv.70730","archive":["Portico"],"relation":{},"ISSN":["0146-6615","1096-9071"],"issn-type":[{"value":"0146-6615","type":"print"},{"value":"1096-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-08-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70730"}}