1Institute for Human Genetics, University of Münster, 48149 Münster, Germany 2Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University of Münster, 48149 Münster, Germany 3Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, 48149 Münster, Germany
Molecular aging markers provide the opportunity for biological age determination in humans and to study factors, such as genetic determinants, affecting the ageing process. In males with Klinefelter syndrome (KS, non-mosaic karyotype 47, XXY), which is the most common sex chromosome aneuploidy, age-related morbidity and mortality are increased, and a significantly reduced life span has been observed. The aim of this study was to investigate whether Klinefelter patients exhibit molecular signs of premature ageing. We studied, specifically, age-associated DNA methylation patterns (by pyrosequencing) and relative telomere length (TL; by quantitative polymerase chain reaction) in blood in a cohort of Klinefelter patients (n=178 and 266 for DNA methylation and TL, respectively) aged 18-71 years and compared them to the data of age-matched healthy male (n = 184 and 196 for DNA methylation and TL, respectively) and female controls (n = 50). Age-associated DNA methylation patterns were not indicative of accelerated ageing in Klinefelter men. Significantly longer telomeres were found in the young Klinefelter subjects aged 18-24 years (mean=1.51 vs. 1.09 and 1.26 in female and male controls, respectively). However, telomere length in subsequent age groups showed no difference to controls. Gonosomal aneuploidy in Klinefelter syndrome is associated with higher baseline TL at adolescent age, but comparable TL with progressive age in other age groups.
Table 1 Primer sequences used for pyrosequencing and relative telomere length determination.
Figure 1. Biological/epigenetic age was determined for individuals in the three groups and plotted against chronological age. There was a strong positive linear correlation between the two, regardless of the group.
N (Age determination)
Table 2 Number of samples per group and age group.
Figure 2. Changes in telomere length with age, according to group. Telomeres suffer attrition with age, regardless of genotype, however telomere shortening shows a steeper decrease in KS men (m = -0.02) compared to XY males (m = -0.007; p < 0.001) and XX females (m = -0.004; p < 0.01) probands.
Figure 3. Age-group associated changes in telomere length. Comparison of the average rTL in the three study groups reveals that KS patients present significantly longer telomeres than both XY males and XX females only in the youngest age group. * p < 0.05, *** p < 0.001.
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