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During aging and in Alzheimer\u2019s disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age-related dysfunction represents a promising strategy to augment CNS waste clearance; however, the mechanisms underlying this decline remain elusive. Here, we demonstrate that age-related alterations in meningeal immunity underlie this lymphatic impairment. Single-cell RNA sequencing of meningeal lymphatic endothelial cells from aged mice revealed their response to IFN\u03b3, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFN\u03b3 in young mice via AAV-mediated overexpression attenuated CSF drainage\u2014comparable to the deficits observed in aged mice. Therapeutically, IFN\u03b3 neutralization alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal.<\/jats:p>","DOI":"10.1084\/jem.20221929","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T02:20:45Z","timestamp":1678933245000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":104,"title":["Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-7424","authenticated-orcid":true,"given":"Justin","family":"Rustenhoven","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Brain Immunology and Glia Center, School of Medicine, Washington University in St. Louis 1 , St. Louis, MO, 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