Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region- and cell-type-specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte- and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia- and endothelial-specific genes increase in all brain regions. In line with these changes, high-resolution immunohistochemistry demonstrated decreased numbers of oligodendrocytes and of neuronal subpopulations in the aging brain cortex. Finally, glial-specific genes predict age with greater precision than neuron-specific genes, thus highlighting the need for greater mechanistic understanding of neuron-glia interactions in aging and late-life diseases. Display omitted •Understanding the role of cell-type-specific changes in human brain aging•Glial-specific genes shift their regional expression patterns during aging•Oligodendrocytes and neuronal subpopulations are decreased in the aging neocortex•Microglia-specific genes globally increase their expression during aging Human brain aging is determined by a complex interplay of regional and cell-type-specific molecular events. Soreq et al. find that glial genes shift their regional expression patterns, while microglia-specific genes globally increase their expression upon aging. Moreover, immunohistochemistry reveals decreased numbers of oligodendrocytes and neuronal subpopulations in the aging neocortex.