Aging is accompanied by expression changes in multiple genes, and the brain is one of the tissues most vulnerable to aging. Since the α7 nicotinic acetylcholine receptor (nAChR) subunit has been associated with neurodevelopmental disorders and cognitive decline during aging, we hypothesized that its absence might affect gene expression profiles in aged brains. To study whether transcriptional changes occur due to aging, α7 deficiency, or both, we analyzed whole-brain transcriptomes of young (8 weeks) and aged (2 years) α7-deficient and wild-type control mice, using Mouse Genome 430 2.0 microarray. Highly significant expression changes were detected in 47 and 1,543 genes [after Bonferroni and false discovery rate (FDR) correction] in the brains of aged mice compared to young mice, regardless of their genotype. These included genes involved in immune system function and ribosome structure, as well as genes that were previously demonstrated as differentially expressed in aging human brains. Genotype-dependent changes were detected in only three genes, Chrna7 which encodes the α7 nAChR subunit, and two closely linked genes, likely due to a "mouse background effect." Expression changes dependent on age-genotype interaction were detected in 207 genes (with a low significance threshold). Age-dependent differential expression levels were approved in all nine genes that were chosen for validation by real-time RT-PCR. Our results suggest that the robust effect of aging on brain transcription clearly overcomes the almost negligible effect of α7 nAChR subunit deletion and that germ line deficiency of this subunit has a minor effect on brain expression profile in aged mice.