Support for leucocyte telomere length as a proxy for telomere length in vascular tissues

Telomere length is regarded as a potential biomarker of aging; there is a growing body of evidence indicating that shorter telomeres are associated with various diseases, including cancer, infectious disease, psychological stress, and cardiovascular disease. In cardiovascular disease in particular this had led to the hypothesis that premature, or accelerated, aging of the vasculature is a major contributing factor.

While a handful of papers have estimated telomere length in specific vascular tissues, the numbers and sizes of samples in these studies are usually small, due to the limitations in obtaining the tissues and cells of interest. Thus, telomere length in genomic DNA obtained from circulating leucocytes is routinely used as a proxy for telomere length in other tissues. However, the inflammatory processes involved in disorders such as cardiovascular disease can result in increased white cell turnover, raising the possibility that the shorter telomeres measured simply reflect recent replicative activity. As many telomere researchers (myself included) believe that shorter telomere length is a primary abnormality that contributes to increased risk of cardiovascular disease, evidence demonstrating a correlation in telomere length between matched samples (leucocyte and vascular DNA from the same individual) is always welcome. A recent paper presented at the European Society of Cardiology and published in European Heart Journal by Wilson et al. provides just such evidence:

Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease

Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease. Aims. Previous studies have suggested that reduced telomere length in circulating leucocytes in humans is associated with premature vascular disease and by implication, accelerated vascular ageing. Importantly, a link between telomere length in circulating leucocytes and the blood vessel wall has never been established. We, thus, investigated the relationship between vascular wall and circulating leucocyte telomere length in humans with and without overt vascular disease. Methods and results. Aortic biopsies and paired blood leucocytes were obtained from 20 patients with asymptomatic abdominal aortic aneurysms (AAAs), undergoing elective open repair, and 12 morphologically normal aortas from a group of cadaveric organ donors of similar mean age. Telomere content was compared by quantitative PCR and expressed as telomere:genomic DNA ratio. The telomere:genomic DNA content was significantly reduced in wall biopsies of AAA vs. normal aorta, and this difference remained after adjusting for age and gender. There were strong correlations between leucocyte and vascular telomere content when the AAA and control groups were analysed either separately or grouped irrespective of the presence of vascular disease (r = 0.62, P < 0.001). Conclusion. The findings demonstrate that leucocyte DNA content is predictive of vascular telomere content and is an accurate surrogate for human vascular age.

The authors showed that subjects with abdominal aortic aneurysms (AAA) had decreased telomere content in their vascular tissues, relative to tissues from subjects free of aortic disease, supporting the link between dysfunctional telomeres and dysfunctional vasculature. However, the difference in telomere content between healthy and diseased vascular tissue appears to be smaller than the difference between leucocytes from healthy and diseased subjects. Shorter telomeres in the vasculature may predispose to developing cardiovascular disease, but has increased white cell turnover in the systemic circulation of subjects with aortic disease led to the larger observed difference? If so, perhaps the differences in leucocyte telomere length between cases and controls in previous association studies of cardiovascular disease have resulted in a slight over-estimate of the differences in telomere length within the vasculature. Nevertheless, after adjusting for age there was a strong and highly significant positive correlation between tissue and leucocyte telomere length. This is the first study of its kind to demonstrate that “telomere attrition in blood leucocytes is indicative of similar changes in the vascular wall”.

So, is leucocyte telomere length a suitable proxy? The issue of increased white cell turnover in subjects with cardiovascular disease remains critical; adjustments for markers of inflammation (something that was not performed in the present study) are crucial in downstream analysis and interpretation of results if the impact of cell turnover (and the associated telomere attrition) is to be assessed. However, the data presented certainly indicate that differences in telomere length observed in circulating blood cells are reflected in the vasculature, providing support for the validity of previous association studies.