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

Advanced aged mice exhibited markedly increased mortality following viral infection compared to young and aged mice.

• Three age groups were compared: young (2-6 months), aged (15-18 months), and advanced aged (20-29 months) mice
• Infections were performed with murine cytomegalovirus (MCMV) or influenza virus
• Increased mortality was observed in advanced aged mice despite viral loads comparable to younger mice
• Survival differences were assessed alongside organ pathology measurements

Advanced aged mice maintained viral loads comparable to younger mice despite worse outcomes.

• Viral burden was assessed across young (2-6 months), aged (15-18 months), and advanced aged (20-29 months) mice
• This finding indicates that increased mortality and pathology in advanced aged mice was not attributable to impaired viral clearance
• The dissociation between viral load and disease severity suggests immune-mediated pathology as the primary driver of poor outcomes

Advanced aged mice showed heightened systemic and tissue inflammatory cytokine production following viral infection.

• Cytokine production was assessed using serum cytokine analysis and flow cytometry
• Elevated cytokine responses were observed in both systemic circulation and tissue compartments
• This hyperinflammatory response was associated with increased morbidity and mortality in advanced aged animals

Advanced aged mice exhibited reduced antigen-specific T cell responses following viral infection.

• Immune cell phenotypes were assessed using flow cytometry
• Reduction in antigen-specific T cell responses was observed in advanced aged (20-29 months) compared to younger mice
• This finding was paralleled in elderly humans with SARS-CoV-2 infection, who also displayed reduced expression of T cell-associated genes in transcriptomic datasets

Advanced aged mice showed increased frequencies of NK cells and non-antigen-specific bystander T cell activation.

• NK cell frequencies and bystander T cell activation were measured by flow cytometry
• The shift toward innate and non-specific immune activation occurred alongside reduced antigen-specific T cell responses
• This immune remodeling pattern suggests an age-driven shift from adaptive to innate-dominated antiviral immunity

Coagulopathy with thrombolytic clot formation was observed exclusively in advanced aged mice following viral infection.

• Coagulopathy was assessed using histology and tissue pathology analysis
• Thrombolytic clot formation was not observed in young (2-6 months) or aged (15-18 months) mice
• This finding was exclusive to advanced aged (20-29 months) animals infected with MCMV or influenza virus

Transcriptomic analysis revealed enrichment of inflammatory and coagulation pathways in influenza-infected advanced aged mice.

• RNA sequencing was performed on influenza-infected mice across age groups
• Inflammatory and coagulation pathway enrichment was specific to advanced aged mice
• These transcriptomic findings paralleled publicly available transcriptomic datasets from elderly humans infected with SARS-CoV-2

Elderly humans with SARS-CoV-2 infection displayed reduced expression of T cell-associated genes, paralleling findings in advanced aged mice.

• Analysis was performed using publicly available transcriptomic datasets from SARS-CoV-2-infected human cohorts across age groups
• Reduced T cell-associated gene expression in elderly humans mirrored the reduced antigen-specific T cell responses observed in advanced aged mice
• Both mouse and human data showed enrichment of inflammatory pathways with aging during viral infection

Most preclinical models rely on young animals and fail to account for age-related immune remodeling relevant to viral infection outcomes.

• Young animals used in most preclinical studies are typically 2-6 months of age
• Age-related immune remodeling is not captured in standard young-animal models
• The study highlights the importance of modeling advanced aging in preclinical studies of viral infection