Gene expression changes in the course of normal brain aging are sexually dimorphic

Abstract

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.

Fig. 1.

Differential gene responsiveness to aging across the brain in cognitively normal controls. The SFG shows the greatest number of gene changes with aging, followed by the PCG and HC. The EC showed the fewest responsive genes.

Fig. 2.

Brain regions show different patterns of change across the lifespan. Patterns of gene changes over 20-year increments were compared, with males and females combined. A notably large increase in gene change was observed in the shift from 40–59 to 60–79 years, occurring in all brain regions. The PCG additionally shows gene responses earlier in the fourth and fifth decades, a time period when other brain regions show relatively little gene change.

Fig. 3.

The male brain undergoes more global gene change than the female brain during aging [(20–59 yrs) vs. (60–99 yrs)]. (A) Gene change was assessed independently for males and females. Relative to females, males showed more than three times as many gene changes globally across the brain and more down-regulated than up-regulated genes. (B) Patterns of global gene changes over 20-year increments reveal that males underwent substantial gene change in the transition to the sixth and seventh decades of life, whereas females showed relatively few gene changes at this age range. In contrast, whereas gene expression appears to be stable after age 80 in the male brain, females show more gene changes with increasing age, with the largest numbers of genes responding across the brain in the eighth and ninth decades.

Fig. 4.

In aging, males show more gene changes than females in all brain regions except the HC. Numbers of genes showing differential expression between young (20–59 years) and aged (60–99 years) cases was assessed independently for males and females in each brain region.

Fig. 5.

Gene expression profiles across the lifespan undergo sexually dimorphic and region-specific changes. Patterns of global gene changes over 20-year increments were compared independently for males and females in each brain region. Pronounced sexually dimorphic patterns are apparent in the SFG and PCG, whereas the HC and EC show less dramatic differences between males and females.