Aging is one of the most complex biological processes we know of, and the human brain the most complex biological system. Unsurprisingly, that makes figuring out how aging affects our brains – affects those processes we really care about like learning, behaviour, and memory – enormously difficult.

A whole host of gross-level neuroanatomical changes take place as we get older, but it’s unclear to what extent these can explain the cognitive deficits that characterize normal aging and diseases of age like Alzheimer’s. For example, while some parts of the hippocampus (a brain structure crucial for the formation of new memories, and linked to dementia) lose neurons as we age, other parts only grow more and more synaptic connections.

To get the complete picture, we need more detail – we need to know what is going at the level of individual genes. In recent years, two groups (Lu et al. and Erraji-Benchekroun et al.) have published microarray expression studies of the aging human brain. However, in both studies there is no control for gender – female and male brains are all lumped into one group –  and this adds substantial noise to their results. Male and female brains are known to develop differently, and even to age differently at the neuroanatomical level – for instance, men experience more (and earlier-onset) brain atrophy and a greater increase in cerebrospinal fluid.

Last month, Berchtold et al. published a gene expression study of aging in four areas of the human brain, and for the first time looked at gender differences in brain aging:

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

Before controlling for gender, Berchtold et al. examined the entire set of brain samples to see if there were any general trends across brain regions. Surprisingly, they found that the superior-frontal gyrus and the postcentral gyrus consistently showed the most aging-related changes. This is unexpected, because it’s the other two brain regions – the hippocampus and the entorhinal cortex – that are most associated with age-related brain diseases and cognitive decline.

Berchtold et al. then sorted brain samples by gender. They found that between young (20-59yrs) and old age (60-99yrs), the male brain undergoes three times as many changes in gene expression as the female brain. Also, men exhibit significantly higher levels of change in all areas save the hippocampus, where men and women experience roughly the same number of gene changes.

To get a more detailed picture, Berchtold et al. classified brains into four age groups: 20-39yrs, 40-59yrs, 60-79yrs and 80-99yrs. For men, the largest number of gene expression changes (about 5000) was observed between the age categories of 40-59yrs and 60-79yrs, and there were few changes in subsequent decades, i.e., the male brain seemed to stabilize. In contrast, the female brain showed substantially fewer changes (about 1000) between those age categories, and showed the most changes (about 3500) between later age categories 60-79yrs and 80-99yrs. The authors take this as evidence that the aging female brain never stabilizes in the way that the aging male brain does; it would be interesting to divide the final female age category into two finer categories (80-89yrs and 90-99yrs) to verify that stabilization never happens. They also point out that this trend is consistent with what we know about the incidence of dementia: dementia risk stabilizes for men around age 85, but increases for women from ages 77 to 95.

Because women and men have different life expectancies (women live on average 5-10 years longer), Berchtold et al. were concerned that the differences in aging between men and women might just be reflecting the difference in longevity – i.e., that women might show almost the same sequence of aging events as men, only drawn out over a longer scale. To test this idea, they compared lists of significantly differentially expressed genes from the most critical aging period for men and women. They found that more than 75% of gene expression changes for each sex were unique to that sex – i.e., most gene change differences can’t be ascribed to simple differences in longevity.

Finally, Berchtold et al. used Gene Ontology annotations to determine whether any functional categories of genes were significantly differentially regulated with age between young (20-59yrs) and old (60-99yrs) brains. In males (but not females), they found a general decreasing capacity for energy production with age (e.g., several relevant Gene Ontology categories were downregulated, including electron transport, oxidative phosphorylation, ATP metabolism, mitochondrial transport, etc.). In females (but not males), categories for neuronal morphogenesis and intracellular signalling were significantly downregulated. In both sexes, genes associated with synaptic transmission were downregulated, and genes associated with cell death and angiogenesis were upregulated. Interestingly, for both sexes many genes associated with inflammation and the immune system were upregulated (while a bit of inflammation can be neuroprotective, too much is undesirable, and a general feature of aging in many tissues).

…….So what do all these results mean? Can we immediately conclude that male brains change for the worse at a relatively young age – but then stabilize – and that female brains just keep on getting worse with increasing age? While evolutionary theory predicts that many of the observed gene expression changes are deleterious, others could be adaptive damage-control responses, beneficial, or even just plain neutral. Also, to interpret this data properly, we need to be able to disentangle cause from effect – some gene expression changes matter a lot more than others. Berchtold et al. have given us a wonderful resource to study how aging affects the brain at the gene level, but we still need to do a lot of work before we can connect this vast catalogue of gene expression values to the higher-level biological and cognitive phenomena that we are most interested in.