Imagine the brain as a vast and intricate network, humming with activity. As we age, however, this network can start to show some wear and tear. But what if I told you that the aging process isn’t the same for everyone? Researchers have discovered that there are molecular differences in how male and female brains age. Using data from various brain regions, they identified specific vulnerabilities in both sexes. The hippocampus and hypothalamus are more at risk in males, while the cerebellar hemisphere and the anterior cingulate cortex are more vulnerable in females. Interestingly, immune response genes seem to increase with age, while neurogenesis-related genes decrease. Furthermore, they found that genes associated with Alzheimer’s disease were enriched in aging brains. In male brains, key synaptic signaling regulators were identified, while in female brains, neuron projection morphogenesis was a key factor. This groundbreaking research opens up new avenues for understanding gender differences in neurodegenerative diseases such as Alzheimer’s.

BackgroundAging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive.ResultsUsing the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer’s disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases.ConclusionsThis integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD.

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