Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither?

Telomeres are nucleoprotein caps flanking DNA. They are shortened by cell division and oxidative stress and are lengthened by the enzyme telomerase and DNA exchange during mitosis. Short telomeres induce cellular senescence. As an indicator of oxidative stress and senescence (2 processes thought to be fundamental to aging), telomere length is hypothesized to be a biomarker of aging. This hypothesis has been tested for more than a decade with epidemiologic study methods. In cross-sectional studies, researchers have investigated whether leukocyte telomere length (LTL) is associated with demographic, behavioral, and health variables. In prospective studies, baseline LTL has been used to predict mortality and occasionally other adverse health outcomes. Conflicting data have generated heated debate about the value of LTL as a biomarker of overall aging. In this review, we address the epidemiologic data on LTL and demonstrate that shorter LTL is associated with older age, male gender, Caucasian race, and possibly atherosclerosis; associations with other markers of health are equivocal. We discuss the reasons for discrepancy across studies, including a detailed review of methods for measuring telomere length as they apply to epidemiology. Finally, we conclude with questions about LTL as a biomarker of aging and how epidemiology can be used to answer these questions.

[1]  D. Willcox,et al.  The Okinawan Diet: Health Implications of a Low-Calorie, Nutrient-Dense, Antioxidant-Rich Dietary Pattern Low in Glycemic Load , 2009, Journal of the American College of Nutrition.

[2]  A. Aviv,et al.  Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis , 2007, Osteoporosis International.

[3]  Igor Sidorov,et al.  Leukocyte telomere dynamics and human hematopoietic stem cell kinetics during somatic growth. , 2009, Experimental hematology.

[4]  T. Spector,et al.  Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. , 2007, The American journal of clinical nutrition.

[5]  T. Spector,et al.  Homocysteine levels and leukocyte telomere length. , 2008, Atherosclerosis.

[6]  Laura Scott,et al.  Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome , 2003, Nature.

[7]  E. Blackburn,et al.  Telomere states and cell fates , 2000, Nature.

[8]  D. Wynford‐Thomas,et al.  Extensive allelic variation and ultrashort telomeres in senescent human cells , 2003, Nature Genetics.

[9]  H. Christensen,et al.  Cognitive performance and leukocyte telomere length in two narrow age-range cohorts: a population study , 2010, BMC geriatrics.

[10]  Wei Han,et al.  Telomerase regulation, cell cycle, and telomere stability in primitive hematopoietic cells. , 1997, Blood.

[11]  S. Cummings,et al.  Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[12]  Tamara B Harris,et al.  A physiologic index of comorbidity: relationship to mortality and disability. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[13]  T. Spector,et al.  Common variants near TERC are associated with mean telomere length , 2010, Nature Genetics.

[14]  A. Aviv,et al.  Synchrony of telomere length among hematopoietic cells. , 2010, Experimental hematology.

[15]  D. Levy,et al.  Leukocyte Telomere Length and Carotid Artery Intimal Medial Thickness: The Framingham Heart Study , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[16]  A. Newman,et al.  Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study. , 2012, The journals of gerontology. Series A, Biological sciences and medical sciences.

[17]  G. Saretzki,et al.  Accelerated telomere shortening in fibroblasts after extended periods of confluency. , 1998, Free radical biology & medicine.

[18]  R. Kronmal,et al.  Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. , 2006, American journal of epidemiology.

[19]  P. Lansdorp,et al.  Flow cytometry and FISH to measure the average length of telomeres (flow FISH) , 2006, Nature Protocols.

[20]  G. De Backer,et al.  Paternal age at birth is an important determinant of offspring telomere length. , 2007, Human molecular genetics.

[21]  Andrew Steptoe,et al.  Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women , 2011, Brain, Behavior, and Immunity.

[22]  O. Melander,et al.  Telomere Length Is Associated With Obesity Parameters but With a Gender Difference , 2008, Obesity.

[23]  M. Fenech,et al.  A quantitative PCR method for measuring absolute telomere length , 2011, Biological Procedures Online.

[24]  J. Woo,et al.  Older men with higher self-rated socioeconomic status have shorter telomeres. , 2009, Age and ageing.

[25]  A. Risch,et al.  Short Telomeres in Patients with Vascular Dementia: An Indicator of Low Antioxidative Capacity and a Possible Risk Factor? , 2000, Laboratory Investigation.

[26]  Jean Adams,et al.  No association between socio‐economic status and white blood cell telomere length , 2007, Aging cell.

[27]  R. Kronmal,et al.  Leukocyte telomere length and mortality in the Cardiovascular Health Study. , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[28]  K. Krause,et al.  Telomere length is not predictive of dementia or MCI conversion in the oldest old , 2010, Neurobiology of Aging.

[29]  P. Lansdorp,et al.  Telomeres and Aging , 2008 .

[30]  M. Blasco,et al.  Telomere length, stem cells and aging. , 2007, Nature chemical biology.

[31]  N. Samani,et al.  Leukocyte telomere length and coronary artery calcification. , 2010, Atherosclerosis.

[32]  A. Aviv,et al.  Short Telomeres Are Associated With Increased Carotid Atherosclerosis in Hypertensive Subjects , 2004, Hypertension.

[33]  A. Aviv.  Leukocyte telomere length: the telomere tale continues. , 2009, The American journal of clinical nutrition.

[34]  U. Jensen,et al.  The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells , 2010, Aging cell.

[35]  J. Campisi,et al.  Four faces of cellular senescence , 2011, The Journal of cell biology.

[36]  L. Rudolph,et al.  Short Telomeres and Prognosis of Hypertension in a Chinese Population , 2009, Hypertension.

[37]  D I Boomsma,et al.  Genetic determination of telomere size in humans: a twin study of three age groups. , 1994, American journal of human genetics.

[38]  S. Petersen,et al.  Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. , 1998, Experimental cell research.

[39]  A. D. Diez Roux,et al.  Race/ethnicity and telomere length in the Multi‐Ethnic Study of Atherosclerosis , 2009, Aging cell.

[40]  I. Deary,et al.  The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people , 2006, Neuroscience Letters.

[41]  D. Levy,et al.  Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study , 2006, Aging cell.

[42]  S. Kritchevsky,et al.  Leukocyte Telomere Length Is Not Associated With BMD, Osteoporosis, or Fracture in Older Adults: Results From the Health, Aging and Body Composition Study , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[43]  N. Samani,et al.  Telomere shortening in atherosclerosis , 2001, The Lancet.

[44]  E. Hadley,et al.  Exceptional survival in human populations: National Institute on Aging perspectives and programs , 2005, Mechanisms of Ageing and Development.

[45]  A. Aviv.  Leukocyte telomere length, hypertension, and atherosclerosis: are there potential mechanistic explanations? , 2009, Hypertension.

[46]  Richard M. Cawthon,et al.  Telomere length measurement by a novel monochrome multiplex quantitative PCR method , 2009, Nucleic acids research.

[47]  J. Skurnick,et al.  Telomere length inversely correlates with pulse pressure and is highly familial. , 2000, Hypertension.

[48]  T. Spector,et al.  Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm , 2008, PLoS genetics.

[49]  J. Woo,et al.  The effect of telomere length, a marker of biological aging, on bone mineral density in elderly population , 2009, Osteoporosis International.

[50]  C B Harley,et al.  Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Carole J Proctor,et al.  Modelling telomere shortening and the role of oxidative stress , 2002, Mechanisms of Ageing and Development.

[52]  P. Kirkpatrick,et al.  Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis: Effects of Telomerase and Oxidative Stress , 2006, Circulation research.

[53]  R. Cawthon,et al.  Association between telomere length in blood and mortality in people aged 60 years or older , 2003, The Lancet.

[54]  Andrew D. Johnson,et al.  Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology , 2010, Proceedings of the National Academy of Sciences.

[55]  R. Westendorp,et al.  Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population‐based study , 2005, Aging cell.

[56]  G. Roos,et al.  The Individual Blood Cell Telomere Attrition Rate Is Telomere Length Dependent , 2009, PLoS genetics.

[57]  T. Spector,et al.  Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. , 2006, American journal of human genetics.

[58]  T. Zglinicki.  Role of oxidative stress in telomere length regulation and replicative senescence , 2006 .

[59]  H. Christensen,et al.  No associations between telomere length and age-sensitive indicators of physical function in mid and later life. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[60]  Andrea H. Mason,et al.  Mapping of a major locus that determines telomere length in humans. , 2005, American journal of human genetics.

[61]  Y. Ben-Shlomo,et al.  A life course approach to chronic disease epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives , 2002 .

[62]  Wei Chen,et al.  Leukocyte Telomere Dynamics: Longitudinal Findings Among Young Adults in the Bogalusa Heart Study , 2008, American journal of epidemiology.

[63]  Richard L. Sprott,et al.  Biomarkers of aging and disease: Introduction and definitions , 2010, Experimental Gerontology.

[64]  R. Wurm,et al.  Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments , 1999, Oncogene.

[65]  Richard Weindruch,et al.  Biomarkers of aging: from primitive organisms to humans. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[66]  T. Zglinicki.  Oxidative stress shortens telomeres , 2002 .

[67]  K. Riabowol,et al.  Paternal age is positively linked to telomere length of children , 2005, Aging cell.

[68]  D. Willcox,et al.  Siblings of Okinawan centenarians share lifelong mortality advantages. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[69]  References , 1971 .

[70]  N. Samani,et al.  A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans. , 2008, Human molecular genetics.

[71]  G. Saretzki,et al.  Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? , 1995, Experimental cell research.

[72]  A. Aviv,et al.  Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study , 2008, Aging cell.

[73]  I. Deary,et al.  Leukocyte telomere length is associated with cognitive performance in healthy women , 2010, Neurobiology of Aging.

[74]  E. Epel,et al.  Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study , 2010, PloS one.

[75]  Sudha Seshadri,et al.  A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[76]  A. Aviv,et al.  Longitudinal versus Cross-sectional Evaluations of Leukocyte Telomere Length Dynamics: Age-Dependent Telomere Shortening is the Rule , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[77]  B. Thiers.  Phenotype and Course of Hutchinson–Gilford Progeria Syndrome , 2009 .

[78]  M. Blasco,et al.  Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres , 2001, EMBO reports.

[79]  R. Mayeux,et al.  Shorter telomeres are associated with mortality in those with APOE ϵ4 and dementia , 2006 .

[80]  Jack W. Szostak,et al.  DNA sequences of telomeres maintained in yeast , 1984, Nature.

[81]  A. Aviv,et al.  Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study. , 2009, Atherosclerosis.

[82]  R. Cawthon,et al.  Association of longer telomeres with better health in centenarians. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[83]  Shan Jiang,et al.  Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice , 2010, Nature.

[84]  T. Spector,et al.  The association between physical activity in leisure time and leukocyte telomere length. , 2008, Archives of internal medicine.

[85]  B. Gersh.  Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study , 2008 .

[86]  George T. Baker,et al.  Biomarkers of aging , 1988, Experimental Gerontology.

[87]  G. Mcclearn,et al.  Telomere length predicts survival independent of genetic influences , 2007, Aging cell.

[88]  M. Nalls,et al.  The association of cataract with leukocyte telomere length in older adults: defining a new marker of aging. , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[89]  F. Kronenberg,et al.  Influences on the reduction of relative telomere length over 10 years in the population-based Bruneck Study: introduction of a well-controlled high-throughput assay. , 2009, International journal of epidemiology.

[90]  F. Grodstein,et al.  Shorter Telomeres May Mark Early Risk of Dementia: Preliminary Analysis of 62 Participants from the Nurses' Health Study , 2008, PloS one.

[91]  J. Kaufman,et al.  Telomere length versus hormonal and bone mineral status in healthy elderly men , 2005, Mechanisms of Ageing and Development.

[92]  T. von Zglinicki,et al.  Telomeres as biomarkers for ageing and age-related diseases. , 2005, Current molecular medicine.

[93]  G. De Backer,et al.  Systemic telomere length and preclinical atherosclerosis: the Asklepios Study. , 2009, European heart journal.

[94]  G. De Backer,et al.  Telomere length and cardiovascular risk factors in a middle‐aged population free of overt cardiovascular disease , 2007, Aging cell.

[95]  Rongling Li,et al.  Telomere length and cognitive function in community-dwelling elders: Findings from the Health ABC Study , 2011, Neurobiology of Aging.

[96]  G. Fraser,et al.  Ten years of life: Is it a matter of choice? , 2001, Archives of internal medicine.

[97]  L. Niedernhofer.  Tissue-specific accelerated aging in nucleotide excision repair deficiency , 2008, Mechanisms of Ageing and Development.

[98]  Lieu Tl,et al.  Obesity, cigarette smoking, and telomere length in women , 2005 .

[99]  J. Vaupel,et al.  No Association Between Telomere Length and Survival Among the Elderly and Oldest Old , 2006, Epidemiology.

[100]  T. Zglinicki,et al.  Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. , 2000, Free radical biology & medicine.

[101]  C. Harley,et al.  Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths , 2010, Nature Protocols.

[102]  J. Shay,et al.  Human diseases of telomerase dysfunction: insights into tissue aging , 2007, Nucleic acids research.

[103]  R. Cawthon.  Telomere measurement by quantitative PCR. , 2002, Nucleic acids research.

[104]  P. Klatt,et al.  High-throughput telomere length quantification by FISH and its application to human population studies , 2007, Proceedings of the National Academy of Sciences.

[105]  I. Komuro,et al.  Endothelial Cell Senescence in Human Atherosclerosis: Role of Telomere in Endothelial Dysfunction , 2002, Circulation.

[106]  Nancy E. Adler,et al.  The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men , 2008, Aging.

[107]  M. Blasco.  Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging , 2005, The EMBO journal.

[108]  Paola Sebastiani,et al.  Health and function of participants in the Long Life Family Study: A comparison with other cohorts , 2011, Aging.

[109]  N. Samani,et al.  Socioeconomic status and telomere length: the West of Scotland Coronary Prevention Study , 2009, Journal of Epidemiology & Community Health.

[110]  E. Giltay,et al.  Telomere length and mortality in elderly men: the Zutphen Elderly Study. , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[111]  Y. Ben-Shlomo,et al.  Life course epidemiology , 2003, Journal of epidemiology and community health.

[112]  J. Skurnick,et al.  Telomere Length as an Indicator of Biological Aging: The Gender Effect and Relation With Pulse Pressure and Pulse Wave Velocity , 2001, Hypertension.

[113]  V. Bohr,et al.  The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis , 2008, Human Genetics.

[114]  E. Blackburn,et al.  Telomere length is paternally inherited and is associated with parental lifespan , 2007, Proceedings of the National Academy of Sciences.

[115]  V. Bohr,et al.  Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: Molecules to patients , 2011, Mechanisms of Ageing and Development.

[116]  J. Vaupel,et al.  Telomere length and mortality: a study of leukocytes in elderly Danish twins. , 2008, American journal of epidemiology.

[117]  M. Blasco,et al.  Functional characterization and developmental regulation of mouse telomerase RNA , 1995, Science.

[118]  T. Spector,et al.  Human telomere biology: pitfalls of moving from the laboratory to epidemiology. , 2006, International journal of epidemiology.

[119]  T. Spector,et al.  A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length , 2009, Journal of Medical Genetics.

[120]  R. Sprott.  Biomarkers of aging. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[121]  Mary A Whooley,et al.  Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. , 2010, JAMA.

[122]  N. Samani,et al.  White Cell Telomere Length and Risk of Premature Myocardial Infarction , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[123]  Helen Christensen,et al.  Is telomere length a biomarker of aging? A review. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[124]  E. Giltay,et al.  Spurious association between telomere length reduction over time and baseline telomere length. , 2011, International journal of epidemiology.