Aging-associated cognitive decline is affected by factors produced inside and outside the brain. Using multi-organ genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile, which was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain, partially restored cognitive function and hippocampal neurogenesis, and re- established IFN-II-dependent choroid plexus activity, lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with anti-viral response, at the brain’s choroid plexus, and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.