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A Metabolome Atlas of the Aging Mouse Brain (Study part II)

ABSTRACT: The mammalian brain relies on neurochemistry to fulfill its functions. Yet, the complexity of the brain metabolome and its changes during diseases or aging remains poorly understood. To start bridging this gap, we generated a metabolome atlas of the aging wildtype male and female mouse brain from 10 anatomical regions spanning from adolescence to old age. We combined data from three chromatography-based mass spectrometry assays and structurally annotated 1,547 metabolites to reveal the underlying architecture of aging-induced changes in the brain metabolome. Overall differences between sexes were minimal. We found 99% of all metabolites to significantly differ between brain regions in at least one age group. We also discovered that 97% of the metabolome showed significant changes with respect to age groups. For example, we identified a shift in sphingolipid patterns during aging that is related to myelin remodeling in the transition from adolescent to aging brains. This shift was accompanied by large changes in overall signature in a range of other metabolic pathways. We found clear metabolic similarities in brain regions that were functionally related such as brain stem, cerebrum and cerebellum. In cerebrum, metabolic correlation patterns got markedly weaker in the transition from adolescent to adulthood, whereas the overall correlation patterns between all regions reflected a decreased brain segregation at old age. We were also able to map metabolic changes to gene and protein brain atlases to link molecular changes to metabolic brain phenotypes. Metabolic profiles can be investigated via https://mouse.atlas.metabolomics.us/. This new resource enables brain researchers to link new metabolomic studies to a foundation data set.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Brain

SUBMITTER: Jun Ding

PROVIDER: ST001888 | MetabolomicsWorkbench | Sun Jul 25 00:00:00 BST 2021

REPOSITORIES: MetabolomicsWorkbench

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Project description:Gene expression profiles were assessed in the hippocampus (HC), entorhinal cortex (EC), superior frontal gyrus (SG), and postcentral gyrus (PCG) across the lifespan of 63 cognitively intact individuals from 20-99 years old. New perspectives on the 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 (20-59 vs. 60-99) in the superior frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the 6th-7th 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 across the lifespan, 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 downregulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with more widespread activation in the female brain. These data open new 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 and novel idea. HgU133plus2.0 microarray chips were used to profile gene expression in 4 brain regions of cognitively intact humans, across the adult lifespan (ages 20-99). Experiment Overall Design: Postmortem brain tissue was collected from ADRC brain banks. Cases were preferentially selected where 3 or more brain regions were available.

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A Metabolome Atlas of the Aging Mouse Brain (Study part II)

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