Age-driven shifts in T and NK cell responses amplify inflammation and coagulopathy during viral infection in mice and humans

Introduction Advanced age is associated with increased morbidity and mortality following acute viral infections, including SARS-CoV-2. Despite this, most preclinical models rely on young animals and fail to account for age-related immune remodeling. How advanced aging alters antiviral immune responses and contributes to immune-mediated pathology remains incompletely understood. Methods Young (2–6 months), aged (15–18 months), and advanced aged (20–29 months) mice were infected with murine cytomegalovirus (MCMV) or influenza virus. Survival, viral burden, cytokine production, immune cell phenotypes, and tissue pathology were assessed using flow cytometry, histology, serum cytokine analysis, and RNA sequencing. Mouse findings were compared with publicly available transcriptomic datasets from SARS-CoV-2–infected human cohorts across age groups. Results Advanced aged mice exhibited markedly increased mortality and organ pathology following viral infection despite maintaining viral loads comparable to younger mice. These outcomes were associated with heightened systemic and tissue inflammatory cytokine production, reduced antigen-specific T cell responses, and increased frequencies of NK cells and non-antigen-specific bystander T cell activation. Coagulopathy with thrombolytic clot formation was observed exclusively in advanced aged mice. Transcriptomic analysis revealed enrichment of inflammatory and coagulation pathways in influenza-infected advanced aged mice, paralleling findings in elderly humans with SARS-CoV-2 infection, who also displayed reduced expression of T cell–associated genes. Discussion These findings demonstrate that advanced age profoundly alters antiviral immune responses, shifting immunity away from effective antigen-specific T cell responses toward inflammatory and innate pathways that contribute to immune-mediated pathology. The results highlight the importance of modeling advanced aging in preclinical studies and suggest that age-dependent immune imbalance may underlie increased inflammation, coagulopathy, and mortality during viral infection in both mice and humans.