Senescent Factors Suppress Innate Antiviral Immunity in Aged Mice via Two Distinct Mechanisms

The accumulation of senescent cells contributes to age-related inflammation and heightened susceptibility to viral infection. The mechanisms by which cellular senescence and aging exacerbate virus-associated diseases remain poorly understood. Here we show that innate antiviral immunity is progressively impaired with aging in mice, in parallel with systemic accumulation of senescent cells. Mechanistically, senescent cells suppress innate antiviral response mostly via four senescence-associated secretory phenotype (SASP) factors. GDF15 and IGF1 trigger AKT-MEK-mediated inactivation of GSK3β, leading to suppression of the TBK1-IRF3 axis. IL1α and IL6 induce expression of p52 and RelB to suppress transcription of antiviral genes. Consistently, combined blocking of GDF15, IGF1, IL1α, and IL6 promotes innate antiviral immunity in aged mice. These findings reveal that SASP factors antagonize innate antiviral immunity through distinct pathways and suggest a potential strategy to restore immune competence to defend viral infection in aged individuals by targeting the four SASP factors.