Researchers here show that a few different senolytic approaches improve the state of the population of microglia in the white matter of the brain in aged mice. This is much as one might expect, given past work into the effects of clearing senescent cells on cognitive function and neurodegeneration in various mouse models. Microglia are innate immune cells of the brain. The presence of senescent and inflammatory microglia is important in the age-related disruption of normal function in the brain, and removing them is beneficial. Sadly, little progress has been made to date in assessing established low-cost senolytic drugs in patients with neurodegenerative conditions; one small clinical trial was conducted for Alzheimer's disease, and that is about it.
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, GeoMx immunolabeling, 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+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.
Link: https://doi.org/10.1038/s43587-026-01154-7
View the full article at FightAging
