LAUSR

Age-related reduction of the adaptor protein TRAF3 compromises the innate immune response of monocytes from older individuals. Aging compromises innate immunity Older adults are more susceptible than younger adults to death resulting from influenza A virus (IAV) infection. Compared to monocytes from younger people, monocytes from older people produce less interferons and exhibit reduced induction of antiviral genes in response to IAV infection. Molony et al. found that this innate response to infection was compromised in cells from older individuals because of age-related changes in signaling downstream of the cytosolic RNA sensor RIG-I. Monocytes from older individuals contained less of the adaptor protein TRAF3, which is required for the induction of both interferons and the interferon regulatory transcription factor IRF8. Knocking down IRF8 compromised the interferon response of monocytes from younger individuals to RIG-I stimulation, and expressing IRF8 restored the RIG-I–induced interferon production in monocytes from older individuals. Restoring the abundance of TRAF3 or the induction of IRF8 in older individuals may therefore represent a potential therapeutic strategy for reducing age-related IAV mortality. Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid–inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor–associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG-I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I–induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV.