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On the occasion of Nobel Prize 2009: The Nobel Prize in Physiology and Medicine 2009 was given jointly to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for the discovery of "how chromosomes are protected by telomeres and the enzyme telomerase.

"Oxidative Stress, Oxygen Free Radicals and Telomere Shortening. A Biomarker of Ageing Determined by Environmental and Genetic Factors"

Prof. A. Valavanidis & Dr. Thomais Vlachogianni Department of Chemistry, University of Athens, University Campus Zografou, 15784 Athens, Greece E-mail: [email protected] & [email protected]

Abstract Telomeres are nucleoprotein structures located at the ends of chromosomes and are subjected to shortening at each cycle of cell division. Chromosome are the threat-like DNA molecules that carry the genes of living or organisms. Telomeres prevent chromosome ends from being recognized as double-strand breaks and protect them from end to end fusion and degradation. By contrast to stem cells and germ-line cells, telomeres in somatic cells shorten with each cell division leading to cellular senescence (ageing). The enzyme telomerase (cellular reverse transcriptase) is involved in telomere stability by synthesizing a new copy of the repeat by using its RNA template. Regulation of telomerase activity is an area of intense investigation, but its exact mechanisms are not yet elucidated. The contribution to telomere loss by oxidative DNA damage Senescence cells were found to contain 30% more oxidative modified guanine in their DNA. Since oxidative modifications and shortening by reactive oxygen species (ROS) leads to againg of the somatic cells, it is expected that antioxidants and reactive free radical scavengers may play a preventive role and possess anti-ageing properties. Additional evidence for the role of ROS in telomere shortening was associated with chronic oxidative stress and inflammation. Various models have been developed and applied to investigate the relationship between telomere length and oxidative stress. The studies reviewed in this report-review make the basis for a promising genetic marker for chronic oxidative stress, the role of antioxidants and their influence on telomere length and ageing. Future studies should investigate the genetic determinants of telomere shortening and stability and to assess the effects of environmental factors that increase oxidative stress and chronic inflammation. Keywords: telomere; telomerase; oxidative stress; chronic inflammation; ageing. .

Introduction: Telomeres and their role in biological systems Every nucleus of an eukaryotic cell is packed with chromosomes, the long, threat-like DNA molecules that carry the genes of living organisms. In the end of the chromosomes there is a region of repetitive nucleoprotein structure called telomeres, which prevent chromosomal ends from end to end fusion and degradation.1,2 Telomeres consist of stretches of repetitive DNA with high guanine and cytocine content. In humans, the telomere terminus consists of 4-15 kbp (bp = base pairs) of the hexanucleotides 5'-TTAGGG-3'. The G-rich DNA strand runs 5' to 3' toward the terminus and protrudes 100-150 nucleotides beyond the complementary C-rich strand. It is protected from degradation by intercalation into the double-stranded telomere DNA, forming a telomeric loop (t-loop).3-6

Figure 1. Telomeres at the end of chromosomes protecting from fusion and degradation. It has been observed that in most proliferating cells the telomere length was a dynamic factor and each time there is a cell division, the lengths of telomeres in human somatic cells decrease gradually by 20 to 200 base pairs. This loss of base pairs is a consequence of the so-called endreplication problem that intrigued molecular biologists for years. Thus, the enzyme that replicates chromosomes (DNA polymerase) is not able to replicate them completely. As a consequence, the replication machinery must leave a small region at the end of the telomere un-copied. The end-replication problem of shortening every time there is a cell division will lead eventually to the elimination of telomeres which in turn will lead to apoptosis or an irreversible growth arrest of the cells. These ageing cells (senescent) are irreversibly arrested in the G1 phase of the cell cycle. Except of the end-replication problem, there are also other factors contributing to the telomere shortening.7,8 The phenomenon of limited cellular division was first observed by Leonard Hayflick, and it was established as an important limit to how long a cell can remain active (Hayflick limit). It was found that the limit of human cell division in subcultures is around 40-60 times before dying out.9 As early as the 1930s Hermann Muller (Nobel Prize 1946) and Barbara McClintock (Nobel Prize 1983) had observed that the structures at the ends of the chromosomes, the so-called telomeres, seemed to prevent the chromosomes from attaching to each other. They suspected that the telomeres could have a protective role, but how they operate remained a mystery. Elizabeth Blackburn was studying the chromosome of Tetrahymena, a unicellular ciliate organism, when she identified a DNA sequence that was repeated several times at the ends of the chromosomes. At the same time Jack Szostak had made the observation that linear DNA molecule, a type of minichromosome, is rapidly degraded when introduced into yeast cells. From the Tetrahymena, Blackburn isolated the CCCCAA sequence, the function of this sequence was not clear. Szostak coupled it to the minichromosomes and put them back into yeast cells. The results were striking. The telomere DNA sequence protected the minichromosomes from degradation. As telomere DNA from one organism, Tetrahymena, protected chromosomes in an


entirely different one, yeast, this demonstrated the existence of a previously unrecognized fundamental mechanism. Later it became evident that telomere DNA with its characteristic sequence is present in most plants and animals, from amoeba to man.10 Then, Carol Greider (graduate student) and her supervisor Blackburn started to investigate if the formation of telomere DNA could be due to an unknown enzyme. In 1984 they discovered signs of an enzymatic activity in a cell extract. They named the enzyme telomerase. After purification, they showed that it consists of RNA as well as protein. The RNA component turned out to contain the CCCCAA sequence and serves as a template when the telomere is built, while the protein component is required for the construction work (enzymatic activity). Telomerase extends telomere DNA, providing a platform that enables DNA polymerases to copy the entire length of the chromosome without missing the very end portion. Scientists began to investigate the role of telomeres might play in the ageing of cells, but also in the organisms as a whole. Although the ageing process turned out to be more complex and depending on genetic and several other different factors, telomere shortening is one of them. Professors Blackburn E, Szostak J and Greider C, for their discoveries and the importance of telomeres and telomerase in cell biochemistry and molecular biology, received the Nobel Prize for Physiology or Medicine in 2009.10


The discovery of teleomeres and telomerase had a major impact within the scientific community. Many scientists started to speculate on the role of shortening of telomeres in ageing of human and other aerobic organisms. Most normal cells do not divide frequently, therefore their chromosomes are not at risk of telomere shortening and they do not require high telomerase activity. In contrast, cancerous cells have the ability to divide infinitely and preserve their telomeres by increasing their telomerase activity. Several studies investigated the role of telomerase and tried to eradicate or stop the growth of cancer cells. Clinical trials evaluated vaccines directed against cells with elevated telomerase activity. Some inherited diseases are known to be caused by telomerase defects (congenital aplastic anemia, skin and lungs diseases). The discovery of telomere and telomerase and their role stimulated the development of potential new therapies.

The Influence of Certain Biochemical Factors in Telomere Regulation In contrast to stem cells and germ-line cells, telomeres in somatic cells shorten with each cell division. Cell proliferation is therefore considered to be one of the most important causes of telomere shortening. Human diploid fibroblasts have a limited replicative life span in vitro due to telomere attrition, leading eventually to ageing (senescence).11 Telomerase is a cellular reverse transcriptase that consists of two components, a reverse transcriptase subunit (hTERT) and a telomerase RNA component (hTERC).12 The telomerase enzyme recognizes the tip of a Grich strand of a telomeric DNA repeat sequence and elongates the telomere in the 5'3'direction, then synthesizes a new copy of the repeat by using its RNA template. The exact mechanims of regulation of telomerase activity, despite of intense scientific investigation, is not yet elucidated. Human telomerase ribonucleproteins pass through several stages before they start with telomere elongation.13,14 In most human somatic cells telomerase activity is absent or very low, in contrast to stem cells and germ-line cells which express sufficient telomerase to maintain the length and function of telomeres for infinite time.15,16 Oxidative Stress and Telomere Shortening Telomeres demonstrated high sensitivity to damage by oxidative stress due to their high content of guanines.17,18 In adition, oxidative damage to nucleobases has been reported to accumulate over the life span of a cell or an organism, contributing significantly to senescence (ageing). Senescet cells were found to contain 30% more oxidative modified guanine in their DNA and four times as many free 8-oxodG bases (8-oxo-deoxyguanosine).15 Furthermore, oxygen free radicals and ROS, especially hydroxyl radicals (HO·) , produce single-strand breaks, either directly or as an intermediate step in the repair of oxidative base modifications. In contrast to the majority of genomic DNA, telomere DNA was reported to be deficient in the repair of single-strand breaks.19 Evidence for this increased sensitivity to ROS-induced was observed from two studies in the calf thymus DNA , when H2O2 reacted with Cu2+ , measured by HPLC (High-performance liquid chromatography) with an electrochemical detector (HPLC-ECD) and in W1-38 fibroblasts which were irradiated with UVA.20,21. Oxidative lesions on telomeric DNA by ROS makes also repair less efficient than the rest of the genome. Exposed human fibroblasts to hydrogen peroxide (H2O2), a prominent ROS contributing to metabolism of aerobic cells, was shown to increase the frequency of single-strand breaks in telomeres and the repair was slow or incomplete, compared to minisatellites. There are various explanations to the repair deficiency of telomeres, one assumes that the binding of TRF2 (telomeric repeat binding factor) to telomere blocks the access of DNA repair enzymes to telomere strand breaks, or that TRF2 inhibits the phosphorylation of the ATM kinase (ataxia telangiectasia mutated gene), which leads to an impaired DNA damage response.23,24 It is well known that ROS produce oxidative stress through inflammatory conditions. Oxidative stress is associated with increased pro-inflammatory cytokines.25 Studies showed that telomerase activity was negatively correlated with pro-inflammatory cytokine tumor necrosis


factor alpha (TNF-).24, 26 The TNF- activates nuclear factor kappa B (NF-B) and activator protein-1 (AP-1) transcription factors, thus enhancing the expression of pro-inflammatory genes, leading to an inflammatory response.27 The autosomal recessive disorder Ataxia telengiectasia (A-T). Ataxia-telangiectasia is a rare, childhood neurological disorder that causes degeneration in the part of the brain that controls motor movements and speech. Its most unusual symptom is an acute sensitivity to ionizing radiation, such as X-rays or gamma-rays. The disease has a strong association with chronic oxidative stress and telomere shortening. In most cases mutations of the ataxia telangiectasia mutated gene (ATM) account for this disease, because ATM encodes a protein kinase that is activated in response to DNA strand breaks and is thought to be essential for maintaining chromosomal stability and telomere integrity. Experimental results suggest that A-T cells are in a chronic state of oxidative stress and have a defective maintenance or repair of telomeric DNA, contributing to their enhanced telomere shortening.28 More evidence for the role of oxidative stress in A-T was obtained from a study in which markers of the redox status in brains of ATM-deficient mice were analysed. These mice showed a significant increase in the activity of thioredoxin and MnSOD (Mn-Superoxide dismutase) and a significant decrease in Catalase activity in the cerebella, a good indication of increased levels of free radicals and ROS.29 Can Antioxidants Vitamins Reduce Telomere Shortening? These results and the role of oxidative stress in telomere shortening, inevitably directed biological experiments to the use of antioxidant vitamins in the prevention of telomere shortening.30 Some studies supported this suggestion. It was found that age-dependent telomere shortening in human vascular endothelial cells, in vitro, could be slowed down by an ascorbic acid derivative (ascorbate-2-O-phosphate). It led to an extension of the cellular life span and prevented cell-size enlargement (cellular indication of senescence).31 The same treatment of human embryonic cells with ascorbic acid phosphoric ester magnesium salt decreased the level of oxidative stress, prevented telomere attrition and extended the replicative life span of cells.32 Another study in vitro used chondrocyte senescence (risk for cartilage degeneration). These cells, chondrocytes, cultured in the presence of the oxidant H2O2 showed that oxidative stress induced telomere shortening and replicative senescence, but in the presence of ascorbate-2-O-phosphate the shortening was reduced.33 Although in vitro experiments showed positive results with antioxidants, in vivo experiments are considered more important because other biological factor might influence the telomere shortening. Male and female rats were used for these type of experiments. Several oxidative stress markers were studied and the results showed that female rats exhibited longer telomeres than male rats. Expression levels of certain antioxidant enzymes, such as MnSOD, GPx I, (glutathione peroxidase I) and GRx (glutathione reductase), in the renal cortex and medulla were found to be higher in female than in male rats. The explanation is that female rats have higher levels of estrogens, which enhance gene expression of MnSOD. The decreased antioxidant levels may be partially responsible for the age-related kidney telomere shortening.34,35 Proliferating fibroblasts exposed to buthionine sulfoximine, which depletes the antioxidant enzyme reduced glutathione (GSH, reduced Glutathione is a linear tripeptide, the molecule has a sulfhydryl (SH) group on the cysteinyl portion, which accounts for its strong electron-donating character), decreased telomerase activity, whereas repletion of cells with glutathione increased telomerase activity in a dose-dependent manner.36 The Role of Oxidative Stress, Chronic Inflammatory Diseases, Prolonged Exercise, Obesity and Smoking in Telomere Length Studies investigated the association between telomere length and diseases in which inflammation and oxidative stress play an important role. In vitro study which investigated the relationship of homocysteine (excerts atherogenic effects because of increased H2O2 generation)


and ageing, found that the rate of telomere shortening was increased in homocysteine-treated cells. It was observed that homocysteine treatment resulted in a threefold increase in the rate of telomere shortening. This effect wad attenuated by the addition of the antioxidant enzyme Catalase (CAT).37 It was hypothesized that vascular pathology might be connected with telomere shortening. Circulating leukocytes have been investigated and it was found that coronary and carotid atherosclerosis, premature myocardial infraction and hypertension are associated with telomere shortening.38-40 Other studies with animals showed a link between telomere length and oxidative stress and atherosclerosis. Hypertensive rats showed telomere attrition in their kidney.41 Diabetes has also been associated with telomere shortening. Patients with diabetes type 2 are known to suffer from proinflammatory state with oxidative stress.42,43 Telomere shortening was not evident in patients with ulcerative colitis or Crohn's disease and patients with inflammatory bowel disease. 44,45 Muscle biopsies from athletes with exercise-associated fatigue were compared with those from controls. Subject were matched for age, gender, height, weight and training history. It was demonstrated that these athletes had significant shorter telomeres than their controls.46 Psychlological pathologies (schizophrenic and bipolar disorder patients, psychological stress) were found also to contribute to shortening of telomeres.47,48 Women with obesity (higher body mass index), who were also smokers and had lower vitamin use, were found to have shorter telomeres.49 Smoking and obesity have been shown through clinical studies that are important factors in many age-related diseases and are associated among other things with oxidative stress and inflammation. But lately it was observed that have also shorter telomeres.50,51 All these diseases, in which inflammation plays a major role, cause telomere shortening.52 Telomere Length as a Biomarker of Oxidative Stress, Disease Progression and Ageing In the last decade scientists worked extensively to promote various models of in vitro studies with different cell lines to investigate the association between telomere length and oxidative stress, but also progression of diseases and ageing.53,54 In contrast to humans, rodent telomeres are generally much longer and express telomerase in many tissues. Telomere shortening is broadly studied in mice, especially in telomerase knockout mice.55,56 However, it is only after 4-6 generations that telomere shortening becomes a critical issue in these mice, indicating mechanisms of carcinogenesis and ageing.57 Scientists noticed that rat telomeres do not have to be modulated to detect shortening, so the rat model might be more feasible in studying the effect of oxidative stress and ageing. Telomere length assessed in Wistar rats in the kidney, liver, lung and brain may determine life span (longevity). It was found that male rats have shortened life span compared to females.58,59 Dogs is another animal that has been used in experiments for telomere biology. It has been observed that dos share more similarities in telomere and telomerase biology with humans.60 Telomere length has been investigated in chickens, bird species and cattle, as models for applicability of the research to human telomere and telomerase activity.61,62 These studies indicate that telomere length and telomerase activity is a promising genetic biomarker for chronic oxidative stress, but there is a need for more experimental investigation to establish the role of the various factors, such as heredity and other ageing.63,64 Also, there is a need for more research on the role of telomere shortening on inflammatory diseases progression, cancer and ageing.65,66 Although there is a long way to be able to assess the effects of environmental factors in telomere attrition, future studies should aim to investigate also genetic determinants of telomere stability and other intrinsic and extrinsic factors leading to cell senescennce.67-70


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46. Collins M, Renault V, Grober LA, St Clair Gibson A, Lambert MI, et al. Athletes with exerciseassociated fatigue have abnarmall short muscle DNA telomeres. Med Sci Sports Exerc 35: 1524-1528, 2003. 47. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 101: 17312-17315, 2004. 48. Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkline N. Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct 20: 171-175, 2002. 49. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, et al. Obesity, cigarette smoking, and telomere length in women. Lancet 366: 662-664, 2005. 50. Morla M, Busquets X, Pons J, Sauleda J, MacNee W, Agusti AG. Telomere shortening in smokers with and without COPD. Eur Respir J 27: 525-528, 2006. 51. Burke A. Fitzgerald GA. Oxidative stress and smoking-induced vascular injury. Prog Cardiovasc Dis 46: 79-90, 2003. 52. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 117: 2417-2426, 2004. 53. Duan J, Zhang Z, Tong T. Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening. Int J Biochem Cell Biol 37: 1407-1420, 2005. 54. Serra V, Grune T, Sitte N, Saretzki T, von Zglinicki G. Telomere length as a marker of oxidative stress in primary human fibroblast cultures. Ann N.Y. Acad Sci 908: 327-330, 2000. 55. Blasco MA. Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging. EMBO J 24: 1095-1103, 2005. 56. Xin Z, Broccoli D. Manipulating mouse telomeres: models of tumorigenesis and aging. Cytogenet Genome Res 105: 471-478, 2004. 57. Cherif H, Tarry JL, Ozanne SE, Hales CN. Ageing and telomeres: a study into organ- and gender-speciifc telomere shortening. Nucleic Acid Res 31: 1576-1583, 2003. 58. Hastings R, Li NC, Lacy PS, Patel H, Herbert KE, Stanley AG, Williams B. Rapid telomere attrition in cardiac tissue of the ageing Wistar rat. Exp Gerontol 39: 855-857, 2004. 59. Jennings BJ, Ozanne SE, Dorling MW, Hales CN. Early growth determines the longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett 448: 4-8, 1999. 60. Nasir L, Devlin P, McKevitt T, Rutteman G, Argyle DJ. Telomere lengths and telomerase activity in dog tissues: a potential model system to study human telomere and telomerase biology. Neoplasia 3: 351-359, 2001. 61. Venkatesan RN, Price C. Telomerase expression in chickens: constitutive activity in somatic tisues and down-regulation in culture. Proc Natl Acad Sci USA 95: 14763-14768, 1998. 62. Haussmann MF, Winkler DW, O'Reilly KM, Huntington CE, Nisbet LC, Vleck CM. Telomeres shorten more slowly in long-lived birds and mammals than in short-lived ones. Proc Biol Biol Sci 270: 1387-1392, 2003. 63. Nordfjall K, Larefalk A, Lindgren P, Holmberg D, Roos G. Telomere length and heredity: indications of paternal inheritance. Proc Natl Acad Sci USA 102: 16374-16378, 2005. 64. Lin KW, Yan J. The telomere length dynamic and methods of its assessment. J Cell Mol Med 9: 977-989, 2005. 65. Hahn WC. Role of telomeres and telomerase in the pathogenesis of human cancer. J Clin Oncol 21: 2034-2043, 2003. 66. Raynaud CM, Sabatier L, Phillipot O, Olaussen KA, Soria JC. Telomere length, telomere proteins and genomic stability during the multistep carcinogenic process. Review. Crit Rev Oncol Hematol 66: 99-117, 2008. 67. Houben JMJ, Moonen HJJ, van Schooten FJ, Hageman GJ. Telomere length assessment: Biomarker of chronic oxidative stress? Review. Free Radic Biol Med 44: 235-246, 2008. 68. Aviv A. The epidemiology of human telomeres: faults and promises. Review. J Gerontol A Biol Sci Med Sci 63: 979-983, 2008. 69. von Figura G, Hartmann D, Song Z, Rudolph KL. Role of telomere dysfuction in aging and its detection by biomarkers. Review. J Mol Med 87: 1165-1171, 2009. 70. Lansdorp PM. Telomeres and disease. Review. EMBO J 28: 2532-2540, 2009.



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