Aging is a prominent risk factor for COVID-19 disease severity and mortality in humans. To gain insight into the age-associated alterations of host responses, we performed flow cytometry and single-cell RNA sequencing (scRNA-seq) on lungs and bronchoalveolar lavage (BAL) from young and aged wildtype C57BL/6 mice at days 0, 3, 10, and 21 after infection with the mouse-adapted SARS-CoV-2 strain MA10. We revealed that disease severity and infection kinetics were age-related, as reported in humans, with increased morbidity and mortality in aged mice. During the acute phase of infection, aged animals had a higher local inflammatory response than young mice, as evidenced by the rapid accumulation of neutrophils and inflammatory monocytes in the lung parenchyma and BAL. During the post-acute phase of disease, these features further divided, with aged mice displaying prolonged proinflammatory responses, as well as deficits in cellular and humoral responses. Using scRNA-seq, we identified 33 clusters in the lung. Differential gene expression revealed several age-dependent and dynamic changes within various immune, epithelial, and endothelial cell types. Cell-cell interactions following infection are also altered in the lung by aging. Taken together, our findings suggest that advanced age is associated with a prolonged inflammatory state, poorly induced adaptive immune responses, and altered cell-cell interactions following SARS-CoV-2 infection.

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