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We leveraged human sex chromosome aneuploidies to test whether X and Y chromosome dosage influences epigenetic aging, quantified with DNA methylation (DNAm) clocks. In whole blood from individuals with karyotypes 46,XX (female) and 46,XY, 47,XXY, 47,XYY (male), we measured epigenetic age and age acceleration using a first\u2010generation clock (Skin &amp; Blood) and two next\u2010generation clocks (GrimAge and DunedinPACE), and examined the components underlying GrimAge. Next\u2010generation clocks indicated lower epigenetic age acceleration and a slower pace of aging in 47,XXY versus 46,XY. In GrimAge, a weighted sum of DNAm surrogates, higher DNAmLeptin (negatively weighted) and lower DNAmPACKYRS (positively weighted smoking proxy) in 47,XXY jointly reduced GrimAge in comparison to 46,XY. DunedinPACE also indicated a slower pace of aging in 47,XXY. In contrast, the first\u2010generation Skin &amp; Blood clock indicated higher age acceleration in 47,XXY and 47,XYY than in 46,XY. Enrichment analyses of autosomal EWAS loci highlighted immune pathways and karyotype\u2010specific signatures, for example, metabolic\/cancer\u2010related processes in 47,XXY and renal\/amino acid transport processes in 47,XYY. Overall, X chromosome gain in 47,XXY was associated with lower GrimAge and slower DunedinPACE, whereas the Skin &amp; Blood clock diverged, suggesting that DNAm clocks capture partially distinct biological domains of aging differentially perturbed by sex\u2010chromosome dosage. These findings motivate larger, age\u2010spanning studies with direct phenotyping to define mechanisms.<\/jats:p>","DOI":"10.1111\/acel.70243","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T10:34:42Z","timestamp":1759228482000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Epigenetic Clock Analysis of Sex Chromosome Aneuploidies"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4488-1175","authenticated-orcid":false,"given":"Joshua","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Human Genetics, David Geffen School of Medicine at UCLA University of California Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Teoli","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Biologie Mol\u00e9culaire, Unit\u00e9 M\u00e9dicale de Biologie Endocrinienne, Centre de Biologie et Pathologie Est Hospices Civils de Lyon  Bron France"},{"name":"Universit\u00e9 Claude Bernard Lyon 1  Lyon France"},{"name":"Laboratoire de Biom\u00e9trie et Biologie Evolutive, UMR 5558, CNRS Universit\u00e9 Claude Bernard Lyon 1  Villeurbanne France"},{"name":"Institut Cellule Souche et Cerveau (SBRI), Unit\u00e9 INSERM 1208 Centre de Recherche INSERM  Bron France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Rey","sequence":"additional","affiliation":[{"name":"Laboratoire de Biom\u00e9trie et Biologie Evolutive, UMR 5558, CNRS Universit\u00e9 Claude Bernard Lyon 1  Villeurbanne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3414-3993","authenticated-orcid":false,"given":"Cristina","family":"Vieira","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Claude Bernard Lyon 1  Lyon France"},{"name":"Laboratoire de Biom\u00e9trie et Biologie Evolutive, UMR 5558, CNRS Universit\u00e9 Claude Bernard Lyon 1  Villeurbanne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-2353","authenticated-orcid":false,"given":"Jean\u2010Fran\u00e7ois","family":"Lemaitre","sequence":"additional","affiliation":[{"name":"Laboratoire de Biom\u00e9trie et Biologie Evolutive, UMR 5558, CNRS Universit\u00e9 Claude Bernard Lyon 1  Villeurbanne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Plotton","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Claude Bernard Lyon 1  Lyon France"},{"name":"Institut Cellule Souche et Cerveau (SBRI), Unit\u00e9 INSERM 1208 Centre de Recherche INSERM  Bron France"},{"name":"Service de m\u00e9decine de la reproduction H\u00f4pital Femme\u2010M\u00e8re\u2010Enfant, Hospices Civils de Lyon  Bron France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel A. 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