The aging human orbitofrontal cortex: Decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-CoA desaturase activity

Abstract

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.

Introduction

Emerging evidence from lesion and imaging studies suggests that the human orbitofrontal cortex (OFC, Brodmann area 10) plays a critical role in both cognitive and affective regulation [1]. Among the different prefrontal cortex subregions, the OFC is particularly vulnerable to age-related reductions in gray matter volume [2], [3], [4], [5] and function [6], [7], [8] in otherwise healthy subjects. Moreover, reductions in OFC gray matter volume are observed in both young [9], [10] and geriatric [11], [12] patients with major depressive disorder (MDD) relative to age-matched healthy controls. Although postmortem histological studies suggest that reductions in OFC gray matter volume during normal aging and in MDD are due to neuronal shrinkage rather than neuronal loss [13], [14], [15], little is known about the environmental and/or genetic factors that contribute to reductions in OFC gray matter volume and associated affective dysregulation.

Emerging evidence from clinical and preclinical studies suggests that omega-3 polyunsaturated fatty acids (PUFA) play an important role in cortical maturation and function during perinatal development [16]. Dietary-induced deficits in the principal brain omega-3 fatty acid, docosahexaenoic acid (DHA, 22:6n-3), during perinatal development is associated with neuronal shrinkage in the adult rat brain [17], and aged rodents exhibit significant deficits in cortical DHA composition [18], [19], [20]. A recent imaging study found that dietary omega-3 fatty acid composition was positively correlated with cortical gray matter volume in healthy adult subjects [21], and we have recently found that adult patients with MDD exhibit significant and selective DHA deficits in the postmortem OFC relative to age-matched controls [22]. Collectively, these data support the hypothesis that the neuronal shrinkage and reductions in gray matter volume observed in the OFC during aging and in MDD may be due in part to reductions in DHA composition.

In the present study, we determined age-related changes in OFC gray matter fatty acid composition by gas chromatography in normal subjects aged 29–80 years (n=30). Our specific prediction was that increasing age would be associated with a progressive decline in DHA composition. Because aged rodents exhibit abnormalities in cortical fatty acid composition despite dietary precursor availability [18], [19], [20], we also determined the expression of the principal lipogenic genes that regulate fatty acid biosynthesis in the same tissues by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Principal lipogenic genes include delta-5 desaturase (FASD1) [23], delta-6 desaturase (FASD2) [24], elongase (HELO1 [ELOVL5]) [25], the peroxisome assembly gene PEX19 [26], and stearoyl-CoA desaturase (SCD) [27]. It was hypothesized that age-related alterations in fatty acid composition would be associated with parallel changes in lipogenic gene expression. We report that increasing age is associated with a progressive decline in PUFA composition, including DHA and arachidonic acid (AA, 20:4n-6), transient, apparently compensatory, elevations in elongase and desaturase gene expression, and associated elevations in SCD expression and activity.