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. 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]Szostak J.W. Blackburn E.H. Cloning yeast telomeres on linear plasmid vectors.Cell. 1982; 29: 245-255Abstract Full Text PDF PubMed Scopus (414) Google Scholar]. In 1984 Carol Greider working with Elizabeth Blackburn discovered the enzyme which forms telomeric sequences [2Greider C.W. Blackburn E.H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.Cell. 1985; 43: 405-413Abstract Full Text PDF PubMed Scopus (2707) Google Scholar, 3Greider C.W. Blackburn E.H. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis.Nature. 1989; 337: 331-337Crossref PubMed Scopus (1363) Google Scholar]. 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]Olovnikov A.M. Principle of marginotomy in template synthesis of polynucleotides.Doklady Akademii nauk SSSR. 1971; 201: 1496-1499PubMed Google Scholar]. 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). 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]Blackburn E.H. Greider C.W. Szostak J.W. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging.Nature Medicine. 2006; 12: 1133-1138Crossref PubMed Scopus (717) Google Scholar]. The length of telomeres serves as a mechanism of normal cell senescence [[6]Allsopp R.C. Harley C.B. Evidence for a critical telomere length in senescent human fibroblasts.Experimental Cell Research. 1995; 219: 130-136Crossref PubMed Scopus (354) Google Scholar]. 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]Sozou P.D. Kirkwood T.B. A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA.Journal of Theoretical Biology. 2001; 213: 573-586Crossref PubMed Scopus (85) Google Scholar]. 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 [8Petersen S Saretzki G. von Zglinicki T. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts.Experimental Cell Research. 1998; 239: 152-160Crossref PubMed Scopus (354) Google Scholar, 9Serra V. Grune T. Sitte N. Saretzki G. von Zglinicki T. Telomere length as a marker of oxidative stress in primary human fibroblast cultures.Annals of the New York Academy of Sciences. 2000; 908: 327-330Crossref PubMed Scopus (81) Google Scholar]. 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]Adaikalakoteswari A. Balasubramanyam M. Ravikumar R. Deepa R. Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.Atherosclerosis. 2007; 195: 83-89Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. 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]Satoh M. Ishikawa Y. Takahashi Y. Itoh T. Minami Y. Nakamura M. Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease.Atherosclerosis. 2008; 198: 347-353Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar]. Following this, LTL was shown to negatively correlate with homocysteine levels by Richards et al. [[12]Richards J.B. Valdes A.M. Gardner J.P. et al.Homocysteine levels and leukocyte telomere length.Atherosclerosis. 2008; 200: 271-277Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar] and to positively correlate with HDL in the study of Chen et al. [[13]Chen W. Gardner J.P. Kimura M. et al.Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study.Atherosclerosis. 2009; 205: 620-625Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. In a recent issue of Atherosclerosis, Olivieri et al. [[14]Olivieri F. Lorenzi M. Antonicelli R. et al.Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.Atherosclerosis. 2009; 206: 588-593Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar] 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]Salpea K.D. Talmud P.J. Cooper J.A. et al.Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation.Atherosclerosis. 2009; https://doi.org/10.1016/j.atherosclerosis.2009.09.070Abstract Full Text Full Text PDF Scopus (226) Google Scholar] 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. The association of telomere length with atherosclerosis and CVD has been supported by a large number of studies over the last few years [16Samani N.J. Boultby R. Butler R. Thompson J.R. Goodall A.H. Telomere shortening in atherosclerosis.Lancet. 2001; 358: 472-473Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar, 17Minamino T. Miyauchi H. Yoshida T. Ishida Y. Yoshida H. Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction.Circulation. 2002; 105: 1541-1544Crossref PubMed Scopus (836) Google Scholar, 18Matthews C. Gorenne I. Scott S. et al.Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress.Circulation Research. 2006; 99: 156-164Crossref PubMed Scopus (482) Google Scholar, 19Brouilette S. Singh R.K. Thompson J.R. Goodall A.H. Samani N.J. White cell telomere length and risk of premature myocardial infarction.Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23: 842-846Crossref PubMed Scopus (502) Google Scholar, 20Brouilette S.W. Moore J.S. McMahon A.D. et al.Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case–control study.Lancet. 2007; 369: 107-114Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar, 21Fitzpatrick A.L Kronmal R.A. Gardner J.P. et al.Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.American Journal of Epidemiology. 2007; 165: 14-21Crossref PubMed Scopus (654) Google Scholar]. Indicative of this effect is that CHD patients have mean LTL equivalent to that of 11 years older healthy subjects, as shown in the study of Brouilette et al. [[19]Brouilette S. Singh R.K. Thompson J.R. Goodall A.H. Samani N.J. White cell telomere length and risk of premature myocardial infarction.Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23: 842-846Crossref PubMed Scopus (502) Google Scholar], which reflects the biological ageing of the vascular wall (Fig. 3). The evidence so far, suggests that in atherosclerosis telomere length probably contributes as a primary abnormality. In support of this are studies showing that family history of CHD is in part inherited through short LTL [22Salpea K.D. Nicaud V. Tiret L. Talmud P.J. Humphries S.E. The association of telomere length with paternal history of premature myocardial infarction in the European Atherosclerosis Research Study II.Journal of Molecular Medicine (Berlin, Germany). 2008; 86: 815-824Crossref PubMed Scopus (53) Google Scholar, 23Brouilette S.W. Whittaker A. Stevens S.E. van der Harst P. Goodall A.H. Samani N.J. Telomere length is shorter in healthy offspring of subjects with coronary artery disease: support for the telomere hypothesis.Heart. 2008; 94: 422-425Crossref PubMed Scopus (81) Google Scholar], most importantly the prospective studies associating baseline LTL with the risk to develop CVD [20Brouilette S.W. Moore J.S. McMahon A.D. et al.Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case–control study.Lancet. 2007; 369: 107-114Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar, 21Fitzpatrick A.L Kronmal R.A. Gardner J.P. et al.Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.American Journal of Epidemiology. 2007; 165: 14-21Crossref PubMed Scopus (654) Google Scholar, 24Zee R.Y. Michaud S.E. Ridker P.M. Mean telomere length and risk of incident venous thromboembolism: a prospective, nested case–control approach.Clinica Chimica Acta: International Journal of Clinical Chemistry. 2009; 406: 148-150Crossref PubMed Scopus (7) Google Scholar], as well as the association of LTL with markers of subclinical CVD, such as intima-media thickness [10Adaikalakoteswari A. Balasubramanyam M. Ravikumar R. Deepa R. Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.Atherosclerosis. 2007; 195: 83-89Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 21Fitzpatrick A.L Kronmal R.A. Gardner J.P. et al.Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.American Journal of Epidemiology. 2007; 165: 14-21Crossref PubMed Scopus (654) Google Scholar]. For pragmatic reasons, most of the studies have used LTL instead of vascular wall cell telomere length. However, Wilson et al. [[25]Wilson W.R Herbert K.E. Mistry Y. et al.Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease.European Heart Journal. 2008; 29: 2689-2694Crossref PubMed Scopus (154) Google Scholar] have shown that LTL is a good predictor of vascular wall telomere length. Nonetheless, as LTL is only a surrogate of the telomere length in the cells contributing to atherosclerosis, it is likely that the real effect on CHD risk is greater than the observed when using LTL. It is now becoming apparent that type 2 diabetes (T2D) is also characterised by shorter telomeres [10Adaikalakoteswari A. Balasubramanyam M. Ravikumar R. Deepa R. Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.Atherosclerosis. 2007; 195: 83-89Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 26Sampson M.J. Winterbone M.S. Hughes J.C. Dozio N. Hughes D.A. Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes.Diabetes Care. 2006; 29: 283-289Crossref PubMed Scopus (275) Google Scholar, 14Olivieri F. Lorenzi M. Antonicelli R. et al.Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.Atherosclerosis. 2009; 206: 588-593Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 15Salpea K.D. Talmud P.J. Cooper J.A. et al.Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation.Atherosclerosis. 2009; https://doi.org/10.1016/j.atherosclerosis.2009.09.070Abstract Full Text Full Text PDF Scopus (226) Google Scholar]. It is not clear though, from the cross-sectional data available so far, whether the observed shorter telomeres in diabetes are a cause or consequence of the disease. Although the data are scarce, shorter telomeres have also been observed in type 1 diabetes patients [[27]Uziel O. Singer J.A. Danicek V. et al.Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control.Experimental Gerontology. 2007; 42: 971-978Crossref PubMed Scopus (105) Google Scholar]. The etiology of the disease in type 1 diabetes is in part different with that in type 2, although in both cases beta cell failure is the final trigger. Thus, one could speculate that critically short telomeres contribute to the onset of diabetes by eliciting senescent phenotypes in beta cells. However, in the case of type 1 diabetes again the data are cross-sectional, so the possibility that short telomeres are a result of the disease cannot be excluded. There is a need for a prospective study of the risk for diabetes in respect to telomere length in order to address this question. Nevertheless, telomere length seems like a useful marker for T2D since it is associated with its progression. In the study of Adaikalakoteswari et al. telomeres were shorter in patients with only impaired glucose tolerance compared to controls and even shorter in T2D patients [[10]Adaikalakoteswari A. Balasubramanyam M. Ravikumar R. Deepa R. Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.Atherosclerosis. 2007; 195: 83-89Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. In addition, telomere shortening has been linked to diabetes complications, such as diabetic nephropathy [[28]Verzola D. Gandolfo M.T. Gaetani G. et al.Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy.American Journal of Physiology. 2008; 295: F1563-1573Crossref PubMed Scopus (201) Google Scholar], microalbuminuria [[29]Tentolouris N. Nzietchueng R. Cattan V. et al.White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria.Diabetes Care. 2007; 30: 2909-2915Crossref PubMed Scopus (89) Google Scholar] and epithelial cancers [[30]Sampson M.J. Hughes D.A. Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes.Diabetologia. 2006; 49: 1726-1731Crossref PubMed Scopus (41) Google Scholar], while telomere shortening seems to be attenuated in patients with well-controlled diabetes [[27]Uziel O. Singer J.A. Danicek V. et al.Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control.Experimental Gerontology. 2007; 42: 971-978Crossref PubMed Scopus (105) Google Scholar]. A very interesting finding, confirmed in independent studies, is that patients with diabetes or prediabetes exhibiting atherosclerotic manifestations have the shortest telomeres compared to patients with diabetes or CVD alone. Adaikalakoteswari et al. found that among T2D patients those with atherosclerotic plaques had the shorter telomeres [[10]Adaikalakoteswari A. Balasubramanyam M. Ravikumar R. Deepa R. Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.Atherosclerosis. 2007; 195: 83-89Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. The study of Olivieri et al. [[14]Olivieri F. Lorenzi M. Antonicelli R. et al.Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.Atherosclerosis. 2009; 206: 588-593Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar] showed that T2D patients with MI had shorter telomeres than T2D subjects free of MI and in our study [[15]Salpea K.D. Talmud P.J. Cooper J.A. et al.Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation.Atherosclerosis. 2009; https://doi.org/10.1016/j.atherosclerosis.2009.09.070Abstract Full Text Full Text PDF Scopus (226) Google Scholar], among the T2D subjects those with CHD had the shorter telomeres. Finally, Satoh et al. showed that CHD patients with metabolic syndrome had shorter telomeres than CHD patients without metabolic syndrome [[11]Satoh M. Ishikawa Y. Takahashi Y. Itoh T. Minami Y. Nakamura M. Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease.Atherosclerosis. 2008; 198: 347-353Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar]. These observations suggest that substantially decreased telomere length, either caused by the common risk factors between CVD and diabetes and/or inherited short telomeres, possibly reflects greater tissue ageing and greater prevalence of senescent phenotypes in various tissues, including the vascular wall and pancreatic islets. Therefore, LTL might be a very useful marker of tissue ageing and progression of both CVD and diabetes. As to what determines telomere length, the data so far suggest a contribution of oxidative stress to the observed shorter LTLs in patients. Adaikalakoteswari et al. [[10]Adaikalakoteswari A. Balasubramanyam M. Ravikumar R. Deepa R. Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy.Atherosclerosis. 2007; 195: 83-89Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar] found a negative correlation with a lipid peroxidation marker, Satoh et al. [[11]Satoh M. Ishikawa Y. Takahashi Y. Itoh T. Minami Y. Nakamura M. Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease.Atherosclerosis. 2008; 198: 347-353Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar] with oxidative DNA damage and our study [[15]Salpea K.D. Talmud P.J. Cooper J.A. et al.Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation.Atherosclerosis. 2009; https://doi.org/10.1016/j.atherosclerosis.2009.09.070Abstract Full Text Full Text PDF Scopus (226) Google Scholar] showed a negative correlation with plasma oxidative stress and association with variation in a gene regulating mitochondrial reactive oxygen species production. The oxidative-induced telomere shortening has been established with in vitro experiments [8Petersen S Saretzki G. von Zglinicki T. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts.Experimental Cell Research. 1998; 239: 152-160Crossref PubMed Scopus (354) Google Scholar, 9Serra V. Grune T. Sitte N. Saretzki G. von Zglinicki T. Telomere length as a marker of oxidative stress in primary human fibroblast cultures.Annals of the New York Academy of Sciences. 2000; 908: 327-330Crossref PubMed Scopus (81) Google Scholar]. What is not clear yet is which factors, and to what extent contribute to the high levels of oxidative stress. The inverse correlation of LTL with variables reflecting the glycaemic state of patients in the study of Olivieri et al. [[14]Olivieri F. Lorenzi M. Antonicelli R. et al.Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.Atherosclerosis. 2009; 206: 588-593Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar] and the attenuation of telomere shortening in patients with good glycaemic control, as showed by Uziel et al. [[27]Uziel O. Singer J.A. Danicek V. et al.Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control.Experimental Gerontology. 2007; 42: 971-978Crossref PubMed Scopus (105) Google Scholar], suggest that hyperglycaemia might be driving the oxidative-induced telomere loss in diabetes. To this end the contribution of inflammation cannot be excluded, although many studies, including Oliveiri's et al. and ours, have failed to detect an association with inflammatory markers [14Olivieri F. Lorenzi M. Antonicelli R. et al.Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.Atherosclerosis. 2009; 206: 588-593Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 15Salpea K.D. Talmud P.J. Cooper J.A. et al.Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation.Atherosclerosis. 2009; https://doi.org/10.1016/j.atherosclerosis.2009.09.070Abstract Full Text Full Text PDF Scopus (226) Google Scholar]. On the other hand, the rate of telomere shortening was associated with longitudinal cumulative HDL in the study of Chen et al. This suggests that LTL probably reflects the of increased oxidative stress and markers of these are not as [[13]Chen W. Gardner J.P. Kimura M. et al.Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study.Atherosclerosis. 2009; 205: 620-625Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. What is the rate of oxidative telomere shortening and inflammation contributes to this effect to be with in vitro of is that in the study of Chen et al. [[13]Chen W. Gardner J.P. Kimura M. et al.Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study.Atherosclerosis. 2009; 205: 620-625Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar] the rate of telomere shortening was dependent on the baseline telomere length, which is also supported by the of et al. R. P. G. The blood cell telomere attrition rate is telomere length 2009; PubMed Scopus Google Scholar]. Thus, it is that in telomeres, greater loss cell is more likely to with the high in telomere length shown by studies S. of telomere in a study of Journal of Google Scholar, L. H. et of telomeres are in the and during PubMed Scopus Google Scholar], the that telomere length to a large It also the that to CVD and/or diabetes might be through inherited short telomeres. Telomere length to be very useful in the and possibly the of CVD and diabetes, the contribution of tissue ageing to their pathology. In order to explore this studies are to in more what is the role of telomeres in the of these and whether it is important or is a need for prospective studies to whether telomere shortening is and the of LTL in disease for diabetes, since is previous In addition, it to be confirmed LTL is a good surrogate of beta telomere length, as it has been shown for the vascular wall cells, whether it is a useful marker in More is a need to shed light on the basic biological of telomeres, like the mechanism in the of cell senescence by telomere length or how this is and the of telomeres with other chromosome We the Heart for D. and Humphries