Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype

Abstract

Cellular senescence, a state of irreversible cell-cycle arrest caused by a variety of cellular stresses, is critically involved in age-related tissue dysfunction in various organs. However, the features of cells in the central nervous system that undergo senescence and their role in neural impairment are not well understood as yet. Here, through comprehensive investigations utilising single-cell transcriptome analysis and various mouse models, we show that microglia, particularly in the white matter, undergo cellular senescence in the brain and spinal cord during ageing and in disease models involving demyelination. Microglial senescence is predominantly detected in disease-associated microglia, which appear in ageing and neurodegenerative diseases. We also find that commensal bacteria promote the accumulation of senescent microglia and disease-associated microglia during ageing. Furthermore, knockout of p16INK4a, a key senescence inducer, ameliorates the neuroinflammatory phenotype in damaged spinal cords in mice. These results advance our understanding of the role of cellular senescence in the central nervous system and open up possibilities for the treatment of age-related neural disorders.

Senescent and disease-associated microglia are modifiable features of aged brain white matter

“…Based on the observation that senescent DAM cells express Lgals3 /GAL3 20 , 32 , we investigated the abundance of GAL3+ cells across the hippocampus and adjacent white matter in young and old brain slices ( Extended Data Fig. 1 ).…”

Emerging role of senescent microglia in brain aging-related neurodegenerative diseases

“…This phenomenon can have profound implications for tissue and organismal aging [ 64 , 65 ]. Interestingly, an analysis of SASP reveals that many of its components are markers associated with the neuroinflammatory response, with a majority being substances secreted in high amounts by microglia [ 51 ]. The accumulation of local senescent microglia might induce paracrine senescence in neighboring cells (including other glial cells and neurons) through SASP-related secretory molecules, leading to the aging of the entire brain [ 52 , 66 ].…”

Molecular hallmarks of ageing in amyotrophic lateral sclerosis

“…Consequently, senescent cells can induce significant alterations in the cellular microenvironment through SASP, which can worsen inflammation [ 174 ]. Microglia in the white matter are thought to be the primary cell type undergoing senescence in the CNS during ageing [ 175 ].…”

“…ExRNAs and EVs are also implicated in ALS pathogenesis. Some exRNAs, including mRNA, microRNA and circular RNA, are present in exosomes and as they are dysregulated in ALS they have been proposed as potential biomarkers [ 174 , 175 ] [ 251 ] (RNA dysregulation in ALS is reviewed in more detail in the ' Defects in RNA dysfunction section). Transgenic SOD1 G93A mice release astrocyte-derived EVs containing mutant SOD1 G93A that transfer to spinal neurons and selectively trigger death [ 252 ].…”