Berchtold Nicole C, Cribbs David H, Coleman Paul D, Rogers Joseph, Head Elizabeth, Kim Ronald, Beach Tom, Miller Carol, Troncoso Juan, Trojanowski John Q, Zielke H Ronald, Cotman Carl W
Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697-4540, USA.
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15605-10. doi: 10.1073/pnas.0806883105. Epub 2008 Oct 1.
Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20-99 years. Perspectives on 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 in the superior-frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh 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, 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 down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open 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 idea.
在55名年龄在20至99岁之间认知功能完好的个体的整个生命周期中，对海马体、内嗅皮质、额上回和中央后回的基因表达谱进行了评估。由此出现了与大脑衰老相关的全球基因变化的观点，揭示了两个总体概念。首先，前脑的不同区域随年龄表现出显著不同的基因谱变化。例如，比较同等样本量的组，额上回中有5029个探针集随年龄有显著变化，而内嗅皮质中为1110个。整个皮质区域在六七十岁时出现显著变化，表明这个时期是大脑衰老的关键转折点，尤其是在男性中。其次，大脑衰老中明显的性别差异很明显，这表明大脑不仅在发育过程中，而且在晚年生活中基因表达都会发生两性异形变化。在所有脑区中，总体而言男性比女性表现出更多的基因变化。此外，基因本体分析显示，不同类别的基因在男性和女性中受到的影响主要不同。值得注意的是，男性大脑的特征是随着年龄增长整体分解代谢和合成代谢能力下降，下调的基因在能量产生和蛋白质合成/运输类别中大量富集。免疫激活增加是两性衰老的一个突出特征，在女性大脑中的激活比例更大。这些数据为探索基因表达中与年龄相关的变化提供了机会，这些变化决定了大脑中神经退行性变和代偿机制之间的平衡，并表明这种平衡在男性和女性中设定方式不同，这是一个有趣的观点。
