Senescent-like microglia limit remyelination through the senescence associated secretory phenotype
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.
Authors
- Jeffrey K. Huang (ORCID: https://orcid.org/0000-0003-0996-9451)
- Jason R. Plemel (ORCID: https://orcid.org/0000-0003-1385-1464)
- Phillip S. Gross (ORCID: https://orcid.org/0000-0003-2642-6504)
- George S. Melchor (ORCID: https://orcid.org/0000-0001-5256-3647)
- Sean Selva
- Nataliia V. Shults (ORCID: https://orcid.org/0000-0002-8643-3389)
- Violeta Durán‐Laforet (ORCID: https://orcid.org/0000-0002-1679-4744)
- Sameera Zia (ORCID: https://orcid.org/0000-0002-2956-0584)
- Enrique Álvarez (ORCID: https://orcid.org/0000-0001-5854-9643)
- Dorothy P. Schafer (ORCID: https://orcid.org/0000-0003-2201-6276)
- Zeeba Manavi (ORCID: https://orcid.org/0000-0001-8704-6164)
- William E. Barclay (ORCID: https://orcid.org/0000-0002-6910-9157)
- Meng‐meng Fu (ORCID: https://orcid.org/0000-0003-4958-0424)
- Sung Hyun Lee (ORCID: https://orcid.org/0000-0003-3876-2564)
- Low Tone Ho (ORCID: https://orcid.org/0000-0002-6846-2127)
Institutions
- National Institutes of Health (US)
- University of Alberta (CA)
- University of Massachusetts Chan Medical School (US)
- Georgetown University (US)
- Neuropsychiatric Research Institute (US)
- National Institute of Neurological Disorders and Stroke (US)
- Women and Children’s Health Research Institute (CA)
- University of Colorado Anschutz Medical Campus (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1038/s41467-025-57632-w
- Citations
- 28
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 23.58
Funders
- National Multiple Sclerosis Society
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health
- National Institute on Aging
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke