Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.

Chase M Carver, Paul T Gomez, Sonia L Rodriguez, James T Redden, Amanda S Latham, Yooree Ha, Jennifer M Kachergus, Yi Liu, Ji Shi, Tommy Tran, Liguo Wang, Simon Melov, E A Thompson, Marissa J Schafer

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. · pubmed

Paper

Abstract

Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3). Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3

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Research summary

The study identifies a specific senescent microglial population in aged mouse white matter driven by GAL3 and demonstrates that targeting this pathway reduces senescence markers. This work is relevant because it targets cellular senescence, a root cause of aging, rather than just treating downstream symptoms, but the impact is limited by its focus on a specific mouse model and a single biomarker without evidence of lifespan extension or comprehensive functional recovery.

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