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Aged brain multi-omic integration captures immunometabolic and sex variation
Justin P Whalley1, Holly C Hunsberger2, David A Bennett3
1Center for Cancer Cell Biology, Immunology, and Infection, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
This study reveals key molecular drivers of human brain aging, identifying an immunometabolic axis and a sex-based cellular plasticity program. These findings offer insights into cell-specific vulnerabilities and potential therapeutic targets for brain aging.
Area of Science:
- Neuroscience
- Genomics
- Epigenetics
Background:
- Human brain aging is complex and molecularly heterogeneous.
- Understanding glial cell aging is crucial for neurological health.
Purpose of the Study:
- To elucidate the multi-omic molecular basis of heterogeneous brain aging.
- To identify key biological axes and sex-specific differences in brain aging.
Main Methods:
- Applied a tensor-decomposition framework to integrate multi-omic data (scRNA-seq, DNA methylation, H3K9ac, proteomics).
- Analyzed data from 276 post-mortem human cortices.
Main Results:
- Identified an immunometabolic axis in aging brains involving microglial activation and suppressed PI3K-Akt-mTOR signaling.
- Uncovered a sex-based multi-omic program linked to cellular plasticity, with a female-biased shift in oligodendrocyte lineage towards precursor states.
- Discovered epigenetic signatures suggesting repurposing of developmental transcription factors like BARHL1.
Conclusions:
- Generated a high-resolution atlas of glial aging.
- Demonstrated that aging risk factors manifest as complex, cell-specific vulnerabilities.
- Provided insights critical for developing targeted therapeutic strategies for brain aging.
