Telomere length in atherosclerosis and diabetes

Abstract

The Nobel Prize in Medicine in 2009 was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak for discovering the molecular structure of the far ends of chromosomes, called telomeres (Fig. 1), and how these protect chromosomes from degradation. Their discoveries shed light on a basic biological mechanism which stimulated research in a new exciting field aiming to explore the role of telomeres in normal ageing, cancer and age-related disease pathology. Fig. 1 Schematic presentation of telomeres. Elizabeth Blackburn first announced the identification of the repeated sequence of DNA in telomeres at a conference in 1980 and together with Jack Szostak in 1982 revealed that telomeres constitute a fundamental mechanism offering protection to chromosomes from degradation throughout different species [1]. In 1984 Carol Greider working with Elizabeth Blackburn discovered the enzyme which forms telomeric sequences [2,3]. This enzyme prevents telomere shortening with cell division, which otherwise takes place due to the incapability of DNA polymerase to fully copy the very end sequences of chromosomes during DNA replication, the so-called end-replication problem [4]. The impact of Blackburn's, Greider's and Szostak's work during the early 1980s is indicated by the increasing rate of publications in the field of telomeres thereafter (Fig. 2). Fig. 2 The rate of publications in the field of telomeres over the last 40 years, using data from the “Web of Science”. We now know that telomeres’ biological function goes beyond the protection of chromosome ends from degradation or fusion, playing an important role in the cell's ageing process [5]. The length of telomeres serves as a mechanism of normal cell senescence [6]. In somatic cells, where the enzyme telomerase is not expressed, telomeres become shorter with each cell division, due to the end-replication problem. Once the length reduces below a critical value replicative senescence, also called the Hayflick limit, is induced [7]. The rate of telomere shortening in telomerase negative cells is not only dependent on the number of cell divisions, but also on DNA damage. The ends of telomeres constitute 3′ single-strand overhangs which are prone to single-strand breaks, particularly those caused by oxidative damage, due to their G-rich content. The accumulation of such breaks along the telomeres leads to additional loss during replication [8,9]. Therefore, the length of telomeres indicates the replicative capacity and cumulative genomic damage of somatic cells, reflecting in this way the tissue's “biological age”. In recent years, the role of telomere length in the pathology of cardiovascular disease (CVD) and diabetes, where tissue ageing and senescence play major roles, has attracted a continuously growing research interest, and in the last two years alone six articles on telomere length have been published in Atherosclerosis. An article by Adaikalakoteswari et al. in the November 2007 issue associated shorter leukocyte telomere length (LTL) with impaired glucose tolerance, type 2 diabetes (T2D) and atherosclerotic plaques in T2D patients [10]. In June 2008, Satoh et al. showed that telomere length was shorter and telomerase activity lower in endothelial progenitor cells from patients with coronary heart disease (CHD) and even more reduced in CHD patients with metabolic syndrome. At the same time, oxidative DNA damage in these subjects displayed the opposite trend [11]. Following this, LTL was shown to negatively correlate with homocysteine levels by Richards et al. [12] and to positively correlate with HDL in the study of Chen et al. [13]. In a recent issue of Atherosclerosis, Olivieri et al. [14] showed that LTL is shorter in T2D patients compared to healthy subjects and even shorter in T2D patients with CHD. More recently, in this issue, our study [15] confirms the shorter LTL in T2D patients and also correlates LTL with plasma oxidative stress and variation in a gene regulating mitochondrial production of reactive oxygen species.