Gene mRNA expression, DNA methylation, and microRNA expression vary dramatically during the human lifespan, but the vast majority of studies mapping genetic variants affecting these traits have either ignored age, or treated it as a confounding variable. Given that age is the main risk factor for many diseases, the identification of genetic loci that affect how these traits change with age could shed light on mechanisms for disease pathogenesis. Performing a genome-wide analysis of age-by-genotype interactions across over 300 individuals, we identify and cross validate over 100 genomic loci that control gene expression, DNA methylation, and microRNA expression in the aging human brain. Furthermore, we applied our analysis across 44 human tissues and found striking enrichment of temporal genetic regulation in the brain. Overlapping our temporal control loci with genome-wide association study results we also see a striking enrichment for SNPs involved in neurological diseases including Alzheimer’s disease, schizophrenia, and Parkinson’s disease. Together, these results indicate that genetic loci that exhibit temporal control of mRNA, DNA methylation, and microRNA over human aging are an important class of genetic variants that may shed light on the pathogenesis of age related human disease. More broadly, this study emphasizes the importance of gene-by-environment interactions in the understanding of how natural genetic variation affects gene expression in the human brain.