Senolytic Treatment Reduces Acute and Chronic Lung Inflammation in an Aged Mouse Model of Influenza

ABSTRACT Influenza A virus continues to pose a significant global health burden, with older individuals experiencing disproportionate morbidity and mortality. Although aging is associated with the accumulation of senescent cells, the extent to which cellular senescence contributes to influenza severity remains poorly understood. The aim of this study was to evaluate the therapeutic potential of the senolytic drug ABT‐263, a B cell lymphoma‐2 inhibitor, in mitigating both acute and chronic damage in an aged mouse model of influenza. Early administration of ABT‐263, beginning one day prior to infection, did not prevent body weight loss, reduce pulmonary viral load, or improve clinical scores in aged mice. However, ABT‐263 treatment significantly reduced lung inflammation in aged mice, coinciding with changes in the expression of senescence‐associated markers. ABT‐263 also reduced intestinal inflammation and mitigated virus‐induced gut dysbiosis, a known contributor to disease severity and secondary outcomes. Although the treatment lowered antigen‐specific CD8 + T cell responses, it did not affect influenza‐specific antibody production nor pulmonary defense against reinfection. Notably, ABT‐263 reduced long‐term pulmonary sequelae including edema, type II hyperplasia, emphysema and epithelial damage. Overall, ABT‐263 therapy partially mitigates influenza severity in aged mice, primarily through dampening acute and chronic inflammation. Most of these effects were age‐dependent, suggesting a role for pre‐existing senescent cells.