Aged brain multi-omic integration captures immunometabolic and sex variation

Whalley, J. P.; Hunsberger, H. C.; Bennett, D. A.; Lamar, M.; Peterson, D. A.; Stutzmann, G. E.

doi:10.1101/2025.10.10.681695

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bioRxiv · 10.1101/2025.10.10.681695

Aged brain multi-omic integration captures immunometabolic and sex variation

Whalley, J. P.·Hunsberger, H. C.·Bennett, D. A.·Lamar, M.·Peterson, D. A.·Stutzmann, G. E.

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Abstract

Resolving the molecular basis for heterogeneous ageing in the human brain requires integrating its diverse molecular layers. Here we applied a tensor-decomposition framework to jointly analyse single-nucleus RNA-seq, DNA methylation, H3K9ac histone acetylation and proteomic data from 276 post-mortem human cortices. The analysis uncovered two dominant, multi-omic themes. First, we identified an immunometabolic axis characterised by microglial activation, suppression of PI3K-Akt-mTOR signalling and epigenetic signatures that suggest repurposing of developmental transcription factors such as BARHL1. Second, we decomposed the effect of sex into a multi-omic program linked to cellular plasticity: although driven by canonical sex-chromosome genes, this axis was epigenetically enriched for pathways regulating stem-cell pluripotency and exhibited a female-biased shift toward precursor-like states in the oligodendrocyte lineage. Together, these findings deliver a high-resolution atlas of glial ageing and demonstrate that broad risk factors manifest as complex, cell-specific vulnerabilities; an insight critical for the development of targeted therapeutic strategies.

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Whalley, J. P., Hunsberger, H. C., Bennett, D. A., Lamar, M., Peterson, D. A., Stutzmann, G. E.. 2025-10-13. Aged brain multi-omic integration captures immunometabolic and sex variation. https://doi.org/10.1101/2025.10.10.681695

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