Epigenetic Clock Analysis of Sex Chromosome Aneuploidies

Sex differences in lifespan are pervasive in nature and in humans, yet the contribution of sex chromosomes to DNA methylation-linked aging remains incompletely defined. 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-generation clock (Skin & Blood) and two next-generation clocks (GrimAge and DunedinPACE), and examined the components underlying GrimAge. Next-generation 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-generation Skin & 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-specific signatures, for example, metabolic/cancer-related 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 & Blood clock diverged, suggesting that DNAm clocks capture partially distinct biological domains of aging differentially perturbed by sex-chromosome dosage. These findings motivate larger, age-spanning studies with direct phenotyping to define mechanisms.