Telomere Abstracts 2

© 2010

Telomerase activity: a biomarker of cell proliferation, not malignant transformation

            (Belair, Yeager et al. 1997) Download

Telomerase activity is readily detected in most cancer biopsies, but not in premalignant lesions or in normal tissue samples with a few exceptions that include germ cells and hemopoietic stem cells. Telomerase activity may, therefore, be a useful biomarker for diagnosis of malignancies and a target for inactivation in chemotherapy or gene therapy. These observations have led to the hypothesis that activation of telomerase may be an important step in tumorigenesis. To test this hypothesis, we studied telomerase activity in isogeneic samples of uncultured and cultured specimens of normal human uroepithelial cells (HUCs) and in uncultured and cultured biopsies of superficial and myoinvasive transitional cell carcinoma (TCC) of the bladder. Our results demonstrated that four of four TCC biopsies, representing both superficial and myoinvasive TCCs, were positive for telomerase activity, but all samples of uncultured HUC were telomerase negative. However, when the same normal HUC samples were established as proliferating cultures in vitro, telomerase activity was readily detected but usually at lower levels than in TCCs. Consistent with the above observation of the telomerase activity in HUCs, telomeres did not shorten during the HUC in vitro lifespan. Demonstration of telomerase in proliferating human epithelial cells in vitro was not restricted to HUCs, because it was also present in prostate and mammary cell cultures. Notably, telomerase activity was relatively low or undetectable in nonproliferating HUC cultures. These data do not support a model in which telomerase is inactive in normal cells and activated during tumorigenic transformation. Rather, these data support a model in which the detection of telomerase in TCC biopsies, but not uncultured HUC samples, reflects differences in proliferation between tumor and normal cells in vivo.


Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells

            (Calado, Yewdell et al. 2009) Download

Androgens have been used in the treatment of bone marrow failure syndromes without a clear understanding of their mechanism of action. Blood counts of patients with dyskeratosis congenita or aplastic anemia with mutations in telomerase genes can improve with androgen therapy. Here we observed that exposure in vitro of normal peripheral blood lymphocytes and human bone marrow-derived CD34(+) cells to androgens increased telomerase activity, coincident with higher TERT mRNA levels. Cells from patients who were heterozygous for telomerase mutations had low baseline telomerase activity, which was restored to normal levels by exposure to androgens. Estradiol had an effect similar to androgens on TERT gene expression and telomerase enzymatic activity. Tamoxifen abolished the effects of both estradiol and androgens on telomerase function, and letrozole, an aromatase inhibitor, blocked androgen effects on telomerase activity. Conversely, flutamide, an androgen receptor antagonist, did not affect androgen stimulation of telomerase. Down-regulation by siRNA of estrogen receptor-alpha (ER alpha), but not ER beta, inhibited estrogen-stimulated telomerase function. Our results provide a mechanism for androgen therapy in bone marrow failure: androgens appear to regulate telomerase expression and activity mainly by aromatization and through ER alpha. These findings have potential implications for the choice of current androgenic compounds and the development of future agents for clinical use.

A prospective study of relative telomere length and postmenopausal breast cancer risk

            (De Vivo, Prescott et al. 2009) Download

During breast cancer progression, a substantial increase in chromosomal aberrations is observed in the transition from ductal hyperplasia to carcinoma in situ. Telomeres are essential structures to chromosomal integrity. Consequently, telomere dysfunction, which leads to genomic instability, is hypothesized to play a causal role in the progression of breast cancer. However, the few epidemiologic studies that have assessed the relationship between telomere length and breast cancer risk have been inconsistent. We used quantitative real-time PCR to measure relative telomere length in genomic DNA extracted from peripheral blood leukocytes and examined its association with postmenopausal breast cancer risk in 1,122 invasive breast cancer cases and 1,147 matched controls free of diagnosed cancer nested within the prospective Nurses' Health Study. Our data show that relative telomere length was not associated with a significant elevation in postmenopausal breast cancer risk [below versus above median; odds ratio, 1.23; 95% confidence interval, 0.94-1.60; P(trend) = 0.20]. Estrone and estradiol hormone levels were significantly inversely associated with relative telomere length (P = 0.02). Other established breast cancer risk factors such as family history of breast cancer and history of benign breast disease were not associated with relative telomere length in separate linear regression models each adjusted for age and disease status (P > or = 0.07). Our results provide little support for an important role of telomere length, as measured in peripheral blood leukocytes, as a biomarker of breast cancer risk.

Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study

            (Farzaneh-Far, Cawthon et al. 2008) Download

BACKGROUND: Telomere shortening has been proposed as a marker of biological aging. Whether leukocyte telomere length is associated with mortality among patients with stable coronary artery disease (CAD) is unknown. METHODS AND RESULTS: We measured leukocyte telomere length in 780 patients with stable CAD in a prospective cohort study. Participants were categorized by quartiles of telomere length. Hazard Ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure (HF) hospitalization, and cardiovascular (CV) events. After 4.4 years of follow-up there were 166 deaths. Compared with participants in the highest telomere length quartile, those in the lowest quartile were at increased risk of death (age-adjusted HR 1.8; 95% CI 1.2 to 2.9). After multivariate adjustment for clinical (HR 2.1; CI 1.3 to 3.3), inflammatory (HR 2.0; CI 1.2 to 3.2), and echocardiographic (HR 1.9; CI 1.0 to 3.5) risk factors, patients in the lowest quartile of telomere length remained at significantly increased risk of death compared to those in the highest quartile. Patients in the lowest quartile of telomere length were also at significantly increased risk of HF hospitalization (HR 2.6; CI 1.1 to 6.0) but not CV events (HR 1.7; CI 0.9 to 3.5). CONCLUSIONS: Reduced leukocyte telomere length is associated with all-cause mortality in patients with stable CAD. The prognostic value of short telomeres in predicting death is not completely captured by existing clinical, inflammatory, and echocardiographic markers of risk.

Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease

            (Farzaneh-Far, Lin et al. 2010) Download

CONTEXT: Increased dietary intake of marine omega-3 fatty acids is associated with prolonged survival in patients with coronary heart disease. However, the mechanisms underlying this protective effect are poorly understood. OBJECTIVE: To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years). MAIN OUTCOME MEASURES: We measured leukocyte telomere length at baseline and again after 5 years of follow-up. Multivariable linear and logistic regression models were used to investigate the association of baseline levels of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) with subsequent change in telomere length. RESULTS: Individuals in the lowest quartile of DHA+EPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17), whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08; P < .001 for linear trend across quartiles). Levels of DHA+EPA were associated with less telomere shortening before (unadjusted beta coefficient x 10(-3) = 0.06; 95% CI, 0.02-0.10) and after (adjusted beta coefficient x 10(-3) = 0.05; 95% CI, 0.01-0.08) sequential adjustment for established risk factors and potential confounders. Each 1-SD increase in DHA+EPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98). CONCLUSION: Among this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.

Telomerase activity in the testis of infertile patients with selected causes

            (Fujisawa, Tanaka et al. 1998) Download

In human testes, stem cells such as spermatogonia need to produce progeny cells continually. Telomere length is maintained throughout spermatogenesis, i.e. from spermatogonia to spermatozoon, and telomerase is reported to be present in the testes. In this study, we measured the activity of telomerase in the human testes of 16 cases of idiopathic azoospermia, 10 of obstructive azoospermia, and 17 of oligozoospermia in order to understand the role of telomerase in spermatogenesis. Telomerase activity in the testes with Sertoli cell-only and in testes with maturation arrest were 0.08 +/- 0.05 optical density (OD) (mean +/- SD) and 1.96 +/- 0.98 OD, respectively (P < 0.05). Classifying those testes with maturation arrest into two groups, the telomerase activity of those with early maturation arrest (arrest at spermatocyte) and of those with late maturation arrest (arrest at round spermatid) was 1.82 +/- 0.82 OD and 2.10 +/- 1.14 OD respectively. There was no significant difference between the two groups. The telomerase activity in the testes showing hypospermatogenesis in obstructive azoospermia and in those of oligozoospermia with hypospermatogenesis was 1.89 +/- 1.06 OD and 1.92 +/- 1.02 OD respectively. No difference in telomerase activity existed between the testes with maturation arrest and those with hypospermatogenesis in obstructive azoospermia or oligozoospermia. Sertoli cell-only testes without germ cells showed no telomerase activity. The source of the telomerase activity was likely to be germ cells. The telomerase activity in the testes (n = 63) was related to the histology of the testes. The activity of telomerase showed no significant correlation with the sperm concentration in each patient. Only serum oestradiol level significantly correlated with telomerase activity (P < 0.05). The concentrations of follicle stimulating hormone, luteinizing hormone, or testosterone had no significant relationship with the telomerase activity. Therefore similar levels of telomerase activity were detected in the testes of infertile men with azoospermia and oligozoospermia and in testes showing maturation arrest.

Telomere biology and cardiovascular disease

            (Fuster and Andres 2006) Download

Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease.

Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length

            (Hapangama, Turner et al. 2008) Download

BACKGROUND: In order to test our hypothesis that endometriosis is associated with abnormal expression of telomerase and telomere lengthening in endometrium, we assessed endometrial expression of the human telomerase enzyme and telomere length (TL). METHODS: This prospective pilot study, included 29 women with symptomatic, surgically diagnosed endometriosis (Group 1) and 27 healthy, fertile, symptom-free women without endometriosis (Group 2, confirmed by laparoscopy). Seventeen women in Group 1 and 15 women in Group 2 had endometrial biopsies taken on Day 21 +/- 2 of the cycle. A further 12 women in each group were biopsied on Day 26 +/- 2. Telomerase and estrogen receptor beta (ERbeta) expression was evaluated by immunohistochemistry. Mean TL was determined by quantitative PCR. RESULTS: The endometria of fertile healthy women showed either weak or no telomerase immunoreactivity throughout the luteal phase. Immunostaining for telomerase was significantly increased during the implantation window and the premenstrual endometria of women with endometriosis (P < 0.0001). This was associated with a loss of stromal and vascular ERbeta immunostaining (P < 0.05). The mean TL were significantly longer in endometria of women with endometriosis during the implantation window (P = 0.005), indicating the biological relevance of our novel finding of telomerase in benign endometrium. There was positive correlation of the circulating estradiol with peripheral blood TL in women. CONCLUSIONS: We speculate that aberrant endometrial expression of telomerase mediates alterations in cell fate that enhance proliferation, contributing to the pathogenesis of endometriosis.

Dietary restraint and telomere length in pre- and postmenopausal women

            (Kiefer, Lin et al. 2008) Download

BACKGROUND: Leukocyte telomere shortening can serve as a biomarker of aging, as telomere length (TL) can decline with age and shortening is positively associated with morbidity and mortality. It is therefore important to identify psychological and behavioral factors linked to accelerated telomere shortening. Stress and poorer metabolic health (greater adiposity, insulin resistance, and cortisol) correlate with shorter telomeres. Self-reported dietary restraint (DR), defined as chronic preoccupation with weight and attempts at restricting food intake, is linked to greater perceived stress, cortisol, and weight gain, when assessed in community studies (versus in weight loss programs). OBJECTIVE: To test for an association between DR and TL in healthy women across a range of ages. METHODS: We examined whether DR is linked to TL in two samples, one of premenopausal women (aged 20-50 years;N = 36) and one of postmenopausal women (aged 53-69 years; N = 20). RESULTS: In both samples, higher levels of DR were associated with shorter leukocyte TL, independent of body mass index, smoking, and age. CONCLUSIONS: Chronic DR, as assessed by self-report (i.e. not caloric restriction), may be a risk factor for premature telomere shortening. Potential mechanisms are discussed.


Role of melatonin in the epigenetic regulation of breast cancer

            (Korkmaz, Sanchez-Barcelo et al. 2009) Download

The oncostatic properties of melatonin as they directly or indirectly involve epigenetic mechanisms of cancer are reviewed with a special focus on breast cancer. Five lines of evidence suggest that melatonin works via epigenetic processes: (1) melatonin influences transcriptional activity of nuclear receptors (ERalpha, GR and RAR) involved in the regulation of breast cancer cell growth; (2) melatonin down-regulates the expression of genes responsible for the local synthesis or activation of estrogens including aromatase, an effect which may be mediated by methylation of the CYP19 gene or deacetylation of CYP19 histones; (3) melatonin inhibits telomerase activity and expression induced by either natural estrogens or xenoestrogens; (4) melatonin modulates the cell cycle through the inhibition of cyclin D1 expression; (5) melatonin influences circadian rhythm disturbances dependent on alterations of the light/dark cycle (i.e., light at night) with the subsequent deregulation of PER2 which acts as a tumor suppressor gene.

Effect of long-term hormone therapy on telomere length in postmenopausal women

            (Lee, Im et al. 2005) Download

Telomeres undergo attrition with each cell division, and telomere length is associated with age-related diseases and mortality in the elderly. Estrogen can influence the attrition of telomeres by diverse mechanisms. This is a retrospective case control study that investigated the influence of long-term hormone therapy (HT) on telomere length in postmenopausal women. We recruited 130 postmenopausal women from 55 to 69 years of age for this study, and divided them into two groups. The first group included 65 women who had been on estrogen and progesterone therapy for more than five years (HT group). The other group was composed of 65 women matched in age to the HT group who had never had HT (non- HT group). The relative ratios of telomere length of study subjects to a reference DNA from a healthy young female were measured using quantitative PCR. Plasma levels of lipid profiles, total antioxidant status (TAS), C-reactive proteins (CRP), fasting glucose levels, and estradiol levels were measured. Age at menopause, vitamin use, and exercise, alcohol, and cigarette smoking histories were also assessed in a questionnaire. Mean duration (+/- SD) of HT was 8.4 +/- 2.3 years. Prevalence of vitamin use and regular exercise were higher in the HT group than in the non-HT group (p < 0.01). Relative telomere length ratios in the HT group were significantly greater than those in the non-HT group (p < 0.01). HT was significantly correlated with the relative telomere length ratio in multivariate analysis when potential confounding variables were controlled for (p < 0.05). In conclusion, telomere lengths were longer in postmenopausal women who had a history of long-term HT than in postmenopausal women without HT. Long-term HT in postmenopausal women may alleviate telomere attrition.

The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer

            (Mirabello, Huang et al. 2009) Download

Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age-matched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.

Arginine methylation regulates telomere length and stability

            (Mitchell, Glenfield et al. 2009) Download

TRF2, a component of the shelterin complex, functions to protect telomeres. TRF2 contains an N-terminal basic domain rich in glycines and arginines, similar to the GAR motif that is methylated by protein arginine methyltransferases. However, whether arginine methylation regulates TRF2 function has not been determined. Here we report that amino acid substitutions of arginines with lysines in the basic domain of TRF2 induce telomere dysfunction-induced focus formation, leading to induction of cellular senescence. We have demonstrated that cells overexpressing TRF2 lysine mutants accumulate telomere doublets, indicative of telomere instability. We uncovered that TRF2 interacts with PRMT1, and its arginines in the basic domain undergo PRMT1-mediated methylation both in vitro and in vivo. We have shown that loss of PRMT1 induces growth arrest in normal human cells but has no effect on cell proliferation in cancer cells, suggesting that PRMT1 may control cell proliferation in a cell type-specific manner. We found that depletion of PRMT1 in normal human cells results in accumulation of telomere doublets, indistinguishable from overexpression of TRF2 lysine mutants. PRMT1 knockdown in cancer cells upregulates TRF2 association with telomeres, promoting telomere shortening. Taken together, these results suggest that PRMT1 may control telomere length and stability in part through TRF2 methylation.

Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA)

            (Nettleton, Diez-Roux et al. 2008) Download

BACKGROUND: Telomere length reflects biological aging and may be influenced by environmental factors, including those that affect inflammatory processes. OBJECTIVE: With data from 840 white, black, and Hispanic adults from the Multi-Ethnic Study of Atherosclerosis, we studied cross-sectional associations between telomere length and dietary patterns and foods and beverages that were associated with markers of inflammation. DESIGN: Leukocyte telomere length was measured by quantitative polymerase chain reaction. Length was calculated as the amount of telomeric DNA (T) divided by the amount of a single-copy control DNA (S) (T/S ratio). Intake of whole grains, fruit and vegetables, low-fat dairy, nuts or seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, and sugar-sweetened soda were computed with responses to a 120-item food-frequency questionnaire completed at baseline. Scores on 2 previously defined empirical dietary patterns were also computed for each participant. RESULTS: After adjustment for age, other demographics, lifestyle factors, and intakes of other foods or beverages, only processed meat intake was associated with telomere length. For every 1 serving/d greater intake of processed meat, the T/S ratio was 0.07 smaller (beta +/- SE: -0.07 +/- 0.03, P = 0.006). Categorical analysis showed that participants consuming >or=1 serving of processed meat each week had 0.017 smaller T/S ratios than did nonconsumers. Other foods or beverages and the 2 dietary patterns were not associated with telomere length. CONCLUSIONS: Processed meat intake showed an expected inverse association with telomere length, but other diet features did not show their expected associations.


Telomere shortening in human coronary artery diseases

            (Ogami, Ikura et al. 2004) Download

BACKGROUND: Increased cell turnover in response to injury is considered to be important in the development of atherosclerotic plaques. Telomere shortening has been shown to be associated with cell turnover. We assessed the telomere length of human coronary endothelial cells to clarify whether there is a relationship between telomere shortening and coronary artery disease (CAD). METHODS AND RESULTS: Coronary endothelial cells were obtained from 11 patients with CAD who underwent autopsy and 22 patients without CAD who underwent autopsy by scraping off the luminal surface of coronary arteries. DNA extracted from the endothelial cells were blotted and hybridized with telomere-specific oligonucleotide ([TTAGGG]4). The hybridization signal intensity, which represented telomeric DNA content, was standardized with centromeric DNA content (T/C ratio) to estimate telomere length. The T/C ratios were significantly smaller (P<0.0001) in CAD patients than in age-matched non-CAD patients (CAD patients, 0.462+/-0.135; non-CAD patients, 1.002+/-0.212). In 6 individual CAD patients, the T/C ratio at the atherosclerotic lesion was significantly smaller (P<0.05) than that at the non-atherosclerotic portion. CONCLUSIONS: These findings suggest that focal replicative senescence and telomere shortening of endothelial cells may play a critical role in coronary atherogenesis and CAD.


References

Belair, C. D., T. R. Yeager, et al. (1997). "Telomerase activity: a biomarker of cell proliferation, not malignant transformation." Proc Natl Acad Sci U S A 94(25): 13677-82.

Calado, R. T., W. T. Yewdell, et al. (2009). "Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells." Blood 114(11): 2236-43.

De Vivo, I., J. Prescott, et al. (2009). "A prospective study of relative telomere length and postmenopausal breast cancer risk." Cancer Epidemiol Biomarkers Prev 18(4): 1152-6.

Farzaneh-Far, R., R. M. Cawthon, et al. (2008). "Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study." Arterioscler Thromb Vasc Biol 28(7): 1379-84.

Farzaneh-Far, R., J. Lin, et al. (2010). "Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease." JAMA 303(3): 250-7.

Fujisawa, M., H. Tanaka, et al. (1998). "Telomerase activity in the testis of infertile patients with selected causes." Hum Reprod 13(6): 1476-9.

Fuster, J. J. and V. Andres (2006). "Telomere biology and cardiovascular disease." Circ Res 99(11): 1167-80.

Hapangama, D. K., M. A. Turner, et al. (2008). "Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length." Hum Reprod 23(7): 1511-9.

Kiefer, A., J. Lin, et al. (2008). "Dietary restraint and telomere length in pre- and postmenopausal women." Psychosom Med 70(8): 845-9.

Korkmaz, A., E. J. Sanchez-Barcelo, et al. (2009). "Role of melatonin in the epigenetic regulation of breast cancer." Breast Cancer Res Treat 115(1): 13-27.

Lee, D. C., J. A. Im, et al. (2005). "Effect of long-term hormone therapy on telomere length in postmenopausal women." Yonsei Med J 46(4): 471-9.

Mirabello, L., W. Y. Huang, et al. (2009). "The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer." Aging Cell 8(4): 405-13.

Mitchell, T. R., K. Glenfield, et al. (2009). "Arginine methylation regulates telomere length and stability." Mol Cell Biol 29(18): 4918-34.

Nettleton, J. A., A. Diez-Roux, et al. (2008). "Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA)." Am J Clin Nutr 88(5): 1405-12.

Ogami, M., Y. Ikura, et al. (2004). "Telomere shortening in human coronary artery diseases." Arterioscler Thromb Vasc Biol 24(3): 546-50.