Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter

Lin Wang, Chang-Yi Cui, Christopher T. Lee, Monica Bodogai, Na Yang, Changyou Shi, Mustafa O. Irfanoglu, James R. Occean, Sadia Afrin, Nishat Sarker, Ross A. McDevitt, Elin Lehrmann, Shahroze Abbas, Nirad Banskota, Jinshui Fan, Supriyo De, Peter Rapp, Arya Biragyn, Dan Benjamini, Manolis Maragkakis and Payel Sen ()
Additional contact information
Lin Wang: NIH
Chang-Yi Cui: NIH
Christopher T. Lee: NIH
Monica Bodogai: NIH
Na Yang: NIH
Changyou Shi: NIH
Mustafa O. Irfanoglu: NIH
James R. Occean: NIH
Sadia Afrin: NIH
Nishat Sarker: NIH
Ross A. McDevitt: NIH
Elin Lehrmann: NIH
Shahroze Abbas: NIH
Nirad Banskota: NIH
Jinshui Fan: NIH
Supriyo De: NIH
Peter Rapp: NIH
Arya Biragyn: NIH
Dan Benjamini: NIH
Manolis Maragkakis: NIH
Payel Sen: NIH

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract To systematically understand age-induced molecular changes, we performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events: microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes. Our study provides a resourceful dataset of spatially resolved transcriptomic features in the naturally aging murine brain encompassing three age groups and both sexes. The results link previous disjointed findings and provide a comprehensive overview of brain aging identifying fiber tracts as a focal point of inflammation.

Date: 2025
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DOI: 10.1038/s41467-025-58466-2

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