Hasselholm Emma B, Just Jesper, Chang Simon, Skakkebæk Anne, Gravholt Claus Højbjerg
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Clin Epigenetics. 2025 Sep 1;17(1):147. doi: 10.1186/s13148-025-01963-4.
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.
性染色体非整倍体特纳综合征（45,X；TS）和克氏综合征（47,XXY；KS）与衰老相关的合并症、预期寿命缩短以及全基因组DNA甲基化变化有关。这表明在这两种综合征中，反映生理功能而非实际年龄的生物衰老有所增加。为了研究与生理衰退相关的DNA甲基化模式是否会导致TS和KS的合并症模式及寿命缩短，我们将所谓的表观遗传时钟应用于TS队列（n = 57）与女性对照（n = 33）以及KS队列（n = 65）与男性对照（n = 63）的DNA甲基化数据。此外，我们评估了表观遗传年龄与临床变量之间的相关性，旨在确定TS和KS中的临床衰老标志物。
将TS与女性对照进行比较，所有表观遗传时钟均表明生物衰老提前。将KS与男性对照进行比较，虽然一些表观遗传时钟表明生物衰老加速，但证据较少。考虑到TS中的雌激素替代疗法，一些表观遗传时钟发现该治疗可降低TS的生物年龄。将表观遗传时钟与临床变量相关联，一些不良结局——主要与身体组成相关——在对照组中与年龄相关。在TS中，以及在某些情况下在KS中，这些相关性减弱。在TS和KS中，我们反而发现身体组成与衰老速率之间存在相关性。
我们证明，在性染色体非整倍体中，尤其是TS中，生物衰老明显增加，这可能导致寿命大幅缩短。此外，TS和KS中常见的身体组成的不利变化，特别是在性腺功能减退的情况下，可能导致衰老加速——或者是衰老加速的结果。
