Background It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

SummaryEvidence assembled over the last decade shows that average telomere length (TL) acts as a biomarker for biological aging and cardiovascular disease (CVD) in particular. Although essential for a more profound understanding of the underlying mechanisms, little reference information is available on TL. We therefore sought to provide baseline TL information and assess the association of prevalent CVD risk factors with TL in subjects free of overt CVD within a small age range. We measured mean telomere restriction fragment length of peripheral blood leukocytes in a large, representative Asklepios study cohort of 2509 community-dwelling, Caucasian female and male volunteers aged approximately 35-55 years and free of overt CVD. We found a manifest age-dependent telomere attrition, at a significantly faster rate in men as compared to women. No significant associations were established with classical CVD risk factors such as cholesterol status and blood pressure, yet shorter TL was associated with increased levels of several inflammation and oxidative stress markers. Importantly, shorter telomere length was associated with an increasingly unhealthy lifestyle, particularly in men. All findings were age and gender adjusted where appropriate. With these cross-sectional results we show that TL of peripheral blood leukocytes primarily reflects the burden of increased oxidative stress and inflammation, whether or not determined by an increasingly unhealthy lifestyle, while the association with classical CVD risk factors is limited. This further clarifies the added value of TL as a biomarker for biological aging and might improve our understanding of how TL is associated with CVD.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

As with every -omics technology, metabolomics requires new methodologies for data processing. Due to the large spectral size, a standard approach in NMR-based metabolomics implies the division of spectra into equally sized bins, thereby simplifying subsequent data analysis. Yet, disadvantages are the loss of information and the occurrence of artifacts caused by peak shifts. Here, a new binning algorithm, Adaptive Intelligent Binning (AI-Binning), which largely circumvents these problems, is presented. AI-Binning recursively identifies bin edges in existing bins, requires only minimal user input, and avoids the use of arbitrary parameters or reference spectra. The performance of AI-Binning is demonstrated using serum spectra from 40 hypertensive and 40 matched normotensive subjects from the Asklepios study. Hypertension is a major cardiovascular risk factor characterized by a complex biochemistry and, in most cases, an unknown origin. The binning algorithm resulted in an improved classification of hypertensive status compared with that of standard binning and facilitated the identification of relevant metabolites. Moreover, since the occurrence of noise variables is largely avoided, AI-Binned spectra can be unit-variance scaled. This enables the detection of relevant, low-intensity metabolites. These results demonstrate the power of AI-Binning and suggest the involvement of alpha-1 acid glycoproteins and choline biochemistry in hypertension.

Although evidence supports the function of telomere length (TL) as a marker for biological aging, no major determinants of TL are known besides inheritance, age and gender. Here we validate and, more importantly, assess the impact of paternal age at birth as a determinant for the offspring's peripheral blood leukocyte TL within the Asklepios study population. Telomere restriction fragment length and paternal age information were available for 2433 volunteers (1176 men and 1257 women) aged approximately 35-55 years old. Paternal age at birth was positively associated with offspring TL (offspring age and gender adjusted, P < 10 (-14)). The increase in TL was estimated at 17 base pairs for each supplemental year at birth and was not statistically different between male and female offspring. The effect size of paternal age outweighed the classical TL determinant gender by a factor of 2, demonstrating the large impact. Maternal age at birth was not independently associated with offspring TL. The peculiar interaction between paternal age at birth and inheritance might explain a large part of the genetic component of TL variance on a population level. This finding also provides further proof for the theory that TL is not completely reset in the zygote. Furthermore, as paternal age is subject to demographic evolution, its association with TL might have a substantial impact on the results and comparability of TL within and between epidemiological studies. In conclusion, paternal age is an important determinant for TL, with substantial consequences for future studies.