Epigenetic age acceleration in Turner and Klinefelter syndrome: Correlations with clinical aging markers

The sex chromosome aneuploidies Turner syndrome (45,X; TS) and Klinefelter syndrome (47,XXY; KS) are associated with aging-related comorbidities, reduced life expectancy and genome-wide DNA methylation changes. This indicates that biological aging, reflecting physiological function rather than chronological age, is increased in both syndromes. To investigate whether DNA methylation patterns linked to physiological decline could contribute to the comorbidity patterns and reduced lifespan in TS and KS, we applied so-called epigenetic clocks to DNA methylation data from cohorts of TS (n = 57) compared to female controls (n = 33) and KS (n = 65) compared to male controls (n = 63). Additionally, we evaluated correlations between epigenetic age and clinical variables, aiming to identify clinical aging markers in TS and KS.

Comparing TS to female controls, all epigenetic clocks indicated advanced biological aging. Comparing KS to male controls, less evidence was observed although some epigenetic clocks indicated accelerated biological aging. Considering estrogen replacement therapy in TS, some epigenetic clocks found that treatment reduced biological age in TS. Correlating epigenetic clocks to clinical variables, several unfavorable outcomes-mainly related to body composition-correlated with age in controls. In TS, and in some cases KS, these correlations were diminished. In TS and KS, we instead found correlations between body composition and the rate of aging.

We demonstrated that biological aging was clearly increased in sex chromosome aneuploidies, especially TS, potentially contributing to the severely reduced lifespan. Additionally, unfavorable changes in body composition, common in both TS and KS, and in particular in the presence of hypogonadism, could result in accelerated aging-or be the result thereof.