{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:16:43Z","timestamp":1791415003655,"version":"4.3.3"},"reference-count":66,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000381","name":"Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000381","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The neurodegenerative processes driving the build\u2010up of disability in progressive multiple sclerosis (P\u2010MS) have not been fully elucidated. Recent data link cellular senescence (CS) to neurodegeneration. We investigated for evidence of CS in P\u2010MS and sought to determine its pattern.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used 53BP1, p16, and lipofuscin as markers of CS in white matter lesions (WMLs), normal appearing white matter (NAWM), normal appearing cortical gray matter (NAGM), control white matter (CWM), and control gray matter (CGM) on autopsy material from patient with P\u2010MS and healthy controls. Senescence\u2010associated secretory phenotype (SASP) factors were quantified in cerebrospinal fluid (CSF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>P16<jats:sup>+<\/jats:sup> cell counts were significantly increased in WMLs and GMLs, compared with NAWM, CWM, NAGM, and CGM and lipofuscin<jats:sup>+<\/jats:sup> cells were significantly increased in WMLs, compared with NAWM and CWM, indicating more abundant CS in demyelinated lesions. The 53BP1<jats:sup>+<\/jats:sup> cells in WMLs were significantly increased compared with NAWM and CWM. The 53BP1<jats:sup>+<\/jats:sup> and p16<jats:sup>+<\/jats:sup> cells were found significantly more abundant in acute active WMLs and GMLs, compared with chronic inactive lesions. Co\u2010localization studies showed evidence of CS in neurons, astrocytes, oligodendrocytes, microglia, and macrophages. Among the quantified CSF SASP factors, IL\u20106, MIF, and MIP1a levels correlated with 53BP1<jats:sup>+<\/jats:sup> cell counts in NAGM, whereas IL\u201010 levels correlated with p16<jats:sup>+<\/jats:sup> cell counts in NAWM. P16<jats:sup>+<\/jats:sup> cell counts in WMLs exhibited an inverse correlation with time to requiring a wheelchair and with age at death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our data indicates that CS primarily affects actively demyelinating gray and WMLs. A higher senescent cell load in P\u2010MS is associated with faster disability progression and death. 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