Abstract
Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [18F]fluoro-D-glucose (18FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22–55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R−, n = 53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r = −0.52), temporal (r = −0.51) and striatal regions (r = −0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R− groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism.
Highlights
Aging of the human brain is associated with decreases in brain glucose metabolism [1]
Several studies have corroborated that healthy individuals carriers of the e4 allele, which increases the risk of Alzheimer’s disease (AD), have lower regional cerebral glucose metabolism than noncarriers in brain regions where glucose metabolism is markedly reduced in AD patients [3,4,5,6]
These results are consistent with our recent findings showing that in humans the 7R+ is associated with longevity and with increased physical activity and that dopamine receptor D4 (DRD4) knockout mice do not show the increases in longevity observed in wild type mice when they are exposed to enriched environments [15]
Summary
Aging of the human brain is associated with decreases in brain glucose metabolism [1]. There is significant interindividual variability in the age associated decreases in regional brain glucose metabolism [2]. This variability is likely to reflect both genetic and environmental factors and their interactions. The effects of aging on brain glucose metabolism have been mostly investigated with respect to the apolipoprotein E gene (APOE e4). Since heritability studies clearly point to a strong genetic component underlying human personality [9], it is reasonable to expect that genes influencing personality are likely to contribute to the effects of aging in the human brain
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