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This Review integrates mechanistic advances in sex chromosome biology\u2014including escape from X chromosome inactivation, X reactivation, parent-of-X-origin, X-skew, X- and Y-linked gene functions, and Y loss\u2014with aging, neurologic disease, immunity, cancer, and cardiometabolic disease. We highlight insights from mouse models, human studies, and emerging technologies that disentangle hormone-driven effects from chromosome-mediated effects and discuss translational implications for diagnostics, biomarkers, therapeutics, and clinical trial design, emphasizing the integration of sex chromosome biology into precision medicine.<\/jats:p>","DOI":"10.1126\/science.aeh0145","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:00:47Z","timestamp":1790877647000},"page":"53-59","update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["X and Y chromosomes as determinants of aging and disease"],"prefix":"10.1126","volume":"394","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-4372","authenticated-orcid":true,"given":"Dena B.","family":"Dubal","sequence":"first","affiliation":[{"name":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA."},{"name":"Bakar Aging Research Institute, University of California, San Francisco, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5497-5968","authenticated-orcid":true,"given":"Fabrisia","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Discovery Center for Musculoskeletal Recovery, Spaulding Rehabilitation Hospital, Charlestown, MA, USA."},{"name":"Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9996-9123","authenticated-orcid":true,"given":"Michael B.","family":"Stout","sequence":"additional","affiliation":[{"name":"Aging &amp; Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA."},{"name":"Oklahoma City VA Medical Center, Oklahoma City, OK, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8708-8206","authenticated-orcid":true,"given":"Dan","family":"Theodorescu","sequence":"additional","affiliation":[{"name":"University of Arizona Comprehensive Cancer Center, Tucson, AZ, USA."},{"name":"Departments of Urology and Cell and Molecular Medicine, University of Arizona, Tucson, AZ, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-024-00805-y"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2815"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2023.07.003"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-00996-9"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3687"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13206"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-026-00935-x"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3231"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24265"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz5677"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ads8169"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-025-00856-8"},{"key":"e_1_3_1_14_2","doi-asserted-by":"crossref","unstructured":"C. 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