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Senescent-like microglia limit remyelination through the senescence associated secretory phenotype

Author

Listed:
  • Phillip S. Gross

    (Georgetown University
    Georgetown University)

  • Violeta Durán-Laforet

    (University of Massachusetts Chan Medical School)

  • Lana T. Ho

    (University of California Berkeley)

  • George S. Melchor

    (Georgetown University
    Georgetown University)

  • Sameera Zia

    (University of Alberta)

  • Zeeba Manavi

    (Georgetown University)

  • William E. Barclay

    (National Institutes of Health)

  • Sung Hyun Lee

    (Georgetown University)

  • Nataliia Shults

    (Georgetown University)

  • Sean Selva

    (University of Colorado Anschutz Medical Campus)

  • Enrique Alvarez

    (University of Colorado Anschutz Medical Campus)

  • Jason R. Plemel

    (University of Alberta)

  • Meng-meng Fu

    (University of California Berkeley
    National Institutes of Health)

  • Dorothy P. Schafer

    (University of Massachusetts Chan Medical School)

  • Jeffrey K. Huang

    (Georgetown University
    Georgetown University)

Abstract

The capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

Suggested Citation

  • Phillip S. Gross & Violeta Durán-Laforet & Lana T. Ho & George S. Melchor & Sameera Zia & Zeeba Manavi & William E. Barclay & Sung Hyun Lee & Nataliia Shults & Sean Selva & Enrique Alvarez & Jason R. , 2025. "Senescent-like microglia limit remyelination through the senescence associated secretory phenotype," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57632-w
    DOI: 10.1038/s41467-025-57632-w
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