Orbitofrontal cortex (OFC, Brodmann area 10) gray matter volume reductions and selective reductions in docosahexaenoic acid (DHA, 22:6n-3) are observed in adult patients with major depressive disorder (MDD). OFC gray matter volume also decreases with advancing age in healthy subjects. To examine if OFC gray matter DHA composition decreases during normal aging, we determined age-related changes in OFC gray matter fatty acid composition by gas chromatography in subjects aged 29-80 years (n=30). We additionally determined elongase (HELO1), delta-5 desaturase (FASD1), delta-6 desaturase (FASD2), peroxisomal (PEX19), and stearoyl-CoA desaturase (SCD) mRNA expression in the same tissues. Increasing age was associated with a progressive decline in polyunsaturated fatty acid (PUFA) composition, including DHA and arachidonic acid (AA, 20:4n-6), and transient, apparently compensatory, elevations in elongase and desaturase gene expression. The age-related reduction in PUFA composition was inversely correlated with SCD expression and activity resulting in elevations in monounsaturated fatty acid composition. These dynamic age-related changes in OFC gray matter fatty acid composition and biosynthetic gene expression may contribute to the progressive decline in OFC gray matter volume found with advancing age. The implications of age-related reductions in OFC PUFA composition for affective dysregulation in the elderly are discussed.