Abstract
The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM) volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female) with a mean age of 56.2±22.0 years (range: 21–92). Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P<.001). Moreover, the downward slope was steeper among the Bcl-2 rs956572 A-allele carriers than in the G-homozygous participants. Our data provide convergent evidence for the genetic effect of the Bcl-2 functional allelic variant in brain aging. The rs956572 G-allele, which is associated with significantly higher Bcl-2 protein expression and diminished cellular sensitivity to stress-induced apoptosis, conferred a protective effect against age-related changes in brain GM volume, particularly in the cerebellum.
Highlights
Aging strongly affects brain morphology, which may contribute to cognitive change over time [1,2]
For gray matter (GM) volume, the B-cell CLL/lymphoma 2 (Bcl-2) genotype was significantly associated with age-related changes in several brain regions
The association of the Bcl-2 rs956572 polymorphism with age was a predictor of regional GM volumes in the right cerebellum [F(1,328) = 13.77; P,.0001], the right lingual gyrus
Summary
Aging strongly affects brain morphology, which may contribute to cognitive change over time [1,2]. Good et al [1] reported that aging predominantly and substantially affects gray matter (GM), and that GM volume decreased linearly with age. Others have reported that several of the age-associated changes in brain volume are probably nonlinear. In a 5-year MRI follow-up study, Van Haren et al [4] assessed 113 participants, and observed essentially no decrease until the age of 30 years. Studies of healthy volunteers reported significant trends in age-related volume reduction in certain regions of the brain, including the hippocampus [5], the cerebellum [1], and the prefrontal [2], temporal [2], and occipital lobes [5]
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