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+<p>Gene expression profiles were assessed in the hippocampus (HC), entorhinal cortex (EC), superior frontal gyrus (SG), and postcentral gyrus (PCG) across the lifespan of 63 cognitively intact individuals from 20-99 years old. New perspectives on the global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age (20-59 vs. 60-99) in the superior frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the 6th-7th decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident across the lifespan, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with downregulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with more widespread activation in the female brain. These data open new opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain, and suggest that this balance is set differently in males and females, an intriguing and novel idea. HgU133plus2.0 microarray chips were used to profile gene expression in 4 brain regions of cognitively intact humans, across the adult lifespan (ages 20-99).</p>