Aging-Related Changes in Telomeres and Telomerases and Implications for Heart Failure Therapy

  • Pim van der HarstEmail author
  • Dirk J. van Veldhuisen


Biological aging is an inevitable process affecting almost all organisms and species. Aging is associated with increased susceptibility to various chronic diseases, including the development of cancer, neurological diseases, and also heart failure. Telomere biology is attracting increasingly more attention as an important potentially modifiable player in the aging process and its associated conditions. Heart failure is characterized by apoptosis of cardiomyocytes and telomere erosion. Interventions aimed at modifying telomere biology might provide a promising strategy in the future prevention and treatment of heart failure.


Telomere Length Short Telomere Cardiac Stem Cell Leukocyte Telomere Length Dyskeratosis Congenita 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by Netherlands Heart Foundation (Grant 2006B140), the Innovational Research Incentives Scheme program of the Netherlands Organisation for Scientific Research (NWO VENI, grant 916.76.170 to P. van der Harst), and the Interuniversitair Cardiologisch Instituut Nederland (ICIN).


  1. 1.
    Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106:661–73.PubMedCrossRefGoogle Scholar
  2. 2.
    de Lange T. How telomeres solve the end-protection problem. Science. 2009;326:948–52.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Huzen J, van Veldhuisen DJ, van Gilst WH, van der Harst P. Telomeres and biological ageing in cardiovascular disease. Ned Tijdschr Geneeskd. 2008;152:1265–70.PubMedGoogle Scholar
  4. 4.
    de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100–10.PubMedCrossRefGoogle Scholar
  5. 5.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27:339–44.CrossRefGoogle Scholar
  6. 6.
    Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005;366:662–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Oikawa S, Tada-Oikawa S, Kawanishi S. Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening. Biochemistry. 2001;40:4763–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.PubMedCrossRefGoogle Scholar
  9. 9.
    Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470:359–65.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science. 2007;318:798–801.PubMedCrossRefGoogle Scholar
  11. 11.
    Schoeftner S, Blasco MA. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol. 2008;10:228–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Grobelny JV, Kulp-McEliece M, Broccoli D. Effects of reconstitution of telomerase activity on telomere maintenance by the alternative lengthening of telomeres (ALT) pathway. Hum Mol Genet. 2001;10:1953–61.PubMedCrossRefGoogle Scholar
  13. 13.
    Bryan TM, Reddel RR. Telomere dynamics and telomerase activity in in vitro immortalised human cells. Eur J Cancer. 1997;33:767–73.PubMedCrossRefGoogle Scholar
  14. 14.
    Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet. 1993;52:661–7.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature. 1999;402:551–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Hemann MT, Greider CW. Wild-derived inbred mouse strains have short telomeres. Nucleic Acids Res. 2000;28:4474–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Graakjaer J, Bischoff C, Korsholm L, Holstebroe S, Vach W, et al. The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life. Mech Ageing Dev. 2003;124:629–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, et al. Short telomeres on human chromosome 17p. Nat Genet. 1998;18:76–80.PubMedGoogle Scholar
  19. 19.
    Youngren K, Jeanclos E, Aviv H, Kimura M, Stock J, et al. Synchrony in telomere length of the human fetus. Hum Genet. 1998;102:640–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Okuda K, Bardeguez A, Gardner JP, Rodriguez P, Ganesh V, et al. Telomere length in the newborn. Pediatr Res. 2002;52:377–81.PubMedCrossRefGoogle Scholar
  21. 21.
    van der Harst P, de Boer RA, Samani NJ, Wong LS, Huzen J, et al. Telomere length and outcome in heart failure. Ann Med. 2010;42:36–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Njajou OT, Cawthon RM, Damcott CM, Wu SH, Ott S, et al. Telomere length is paternally inherited and is associated with parental lifespan. Proc Natl Acad Sci USA. 2007;104:12135–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Slagboom PE, Droog S, Boomsma DI. Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet. 1994;55:876–82.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Arbeev KG, Hunt SC, Kimura M, Aviv A, Yashin AI. Leukocyte telomere length, breast cancer risk in the offspring: the relations with father’s age at birth. Mech Ageing Dev. 2011;132:149–53.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Kimura M, Cherkas LF, Kato BS, Demissie S, Hjelmborg JB, et al. Offspring’s leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet. 2008;4:e37.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Aston KI, Hunt SC, Susser E, Kimura M, Factor-Litvak P, et al. Divergence of sperm and leukocyte age-dependent telomere dynamics: implications for male-driven evolution of telomere length in humans. Mol Hum Reprod. 2012;18(11):517–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, et al. Common variants near TERC are associated with mean telomere length. Nat Genet. 2010;42:197–9.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Mangino M, Richards JB, Soranzo N, Zhai G, Aviv A, et al. A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length. J Med Genet. 2009;46:451–4.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Levy D, Neuhausen SL, Hunt SC, Kimura M, Hwang SJ, et al. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci USA. 2010;107:9293–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Jones CH, Pepper C, Baird DM. Telomere dysfunction and its role in haematological cancer. Br J Haematol. 2012;156:573–87.PubMedCrossRefGoogle Scholar
  31. 31.
    Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol. 2011;21:349–53.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Honig LS, Kang MS, Schupf N, Lee JH, Mayeux R. Association of shorter leukocyte telomere repeat length with dementia and mortality. Arch Neurol. 2012;69(10):1332–9.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Cao Y, Li H, Mu FT, Ebisui O, Funder JW, et al. Telomerase activation causes vascular smooth muscle cell proliferation in genetic hypertension. FASEB J. 2002;16:96–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Perez-Rivero G, Ruiz-Torres MP, Rivas-Elena JV, Jerkic M, Diez-Marques ML, et al. Mice deficient in telomerase activity develop hypertension because of an excess of endothelin production. Circulation. 2006;114:309–17.PubMedCrossRefGoogle Scholar
  35. 35.
    Demissie S, Levy D, Benjamin EJ, Cupples LA, Gardner JP, et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell. 2006;5:325–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Bhupatiraju C, Saini D, Patkar S, Deepak P, Das B, et al. Association of shorter telomere length with essential hypertension in Indian population. Am J Hum Biol. 2012;24:573–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Yang Z, Huang X, Jiang H, Zhang Y, Liu H, et al. Short telomeres and prognosis of hypertension in a Chinese population. Hypertension. 2009;53:639–45.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Vasan RS, Demissie S, Kimura M, Cupples LA, Rifai N, et al. Association of leukocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the Framingham Heart Study. Circulation. 2008;117:1138–44.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Zee RY, Castonguay AJ, Barton NS, Germer S, Martin M. Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study. Transl Res. 2010;155:166–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Salpea KD, Talmud PJ, Cooper JA, Maubaret CG, Stephens JW, et al. Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis. 2010;209:42–50.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Uziel O, Singer JA, Danicek V, Sahar G, Berkov E, et al. Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control. Exp Gerontol. 2007;42:971–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Astrup AS, Tarnow L, Jorsal A, Lajer M, Nzietchueng R, et al. Telomere length predicts all-cause mortality in patients with type 1 diabetes. Diabetologia. 2010;53:45–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Adaikalakoteswari A, Balasubramanyam M, Ravikumar R, Deepa R, Mohan V. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis. 2007;195:83–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Kuhlow D, Florian S, von Figura G, Weimer S, Schulz N, et al. Telomerase deficiency impairs glucose metabolism and insulin secretion. Aging (Albany, NY). 2010;2:650–8.Google Scholar
  45. 45.
    Makino N, Sasaki M, Maeda T, Mimori K. Telomere biology in cardiovascular disease – role of insulin sensitivity in diabetic hearts. Exp Clin Cardiol. 2010;15:e128–33.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet. 2001;358:472–3.PubMedCrossRefGoogle Scholar
  47. 47.
    Brouilette S, Singh RK, Thompson JR, Goodall AH, Samani NJ. White cell telomere length and risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol. 2003;23:842–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Mukherjee M, Brouilette S, Stevens S, Shetty KR, Samani NJ. Association of shorter telomeres with coronary artery disease in Indian subjects. Heart. 2009;95:669–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, 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;369:107–14.PubMedCrossRefGoogle Scholar
  50. 50.
    Weischer M, Bojesen SE, Cawthon RM, Freiberg JJ, Tybjaerg-Hansen A, et al. Short telomere length, myocardial infarction, ischemic heart disease, and early death. Arterioscler Thromb Vasc Biol. 2012;32:822–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Brouilette SW, Whittaker A, Stevens SE, van der Harst P, Goodall AH, et al. Telomere length is shorter in healthy offspring of subjects with coronary artery disease: support for the telomere hypothesis. Heart. 2008;94:422–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Ogami M, Ikura Y, Ohsawa M, Matsuo T, Kayo S, et al. Telomere shortening in human coronary artery diseases. Arterioscler Thromb Vasc Biol. 2004;24:546–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Huzen J, Peeters W, de Boer RA, Moll FL, Wong LS, et al. Circulating leukocyte and carotid atherosclerotic plaque telomere length: interrelation, association with plaque characteristics, and restenosis after endarterectomy. Arterioscler Thromb Vasc Biol. 2011;31:1219–25.PubMedCrossRefGoogle Scholar
  54. 54.
    Wilson WR, Herbert KE, Mistry Y, Stevens SE, Patel HR, et al. Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease. Eur Heart J. 2008;29:2689–94.PubMedCrossRefGoogle Scholar
  55. 55.
    Cafueri G, Parodi F, Pistorio A, Bertolotto M, Ventura F, et al. Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. PLoS One. 2012;7:e35312.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Samani NJ, van der Harst P. Biological ageing and cardiovascular disease. Heart. 2008;94:537–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Buja LM, Vela D. Cardiomyocyte death and renewal in the normal and diseased heart. Cardiovasc Pathol. 2008;17:349–74.PubMedCrossRefGoogle Scholar
  58. 58.
    Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Burgess ML, McCrea JC, Hedrick HL. Age-associated changes in cardiac matrix and integrins. Mech Ageing Dev. 2001;122:1739–56.PubMedCrossRefGoogle Scholar
  60. 60.
    Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc. 1988;63:552–64.PubMedCrossRefGoogle Scholar
  61. 61.
    Pandya K, Kim HS, Smithies O. Fibrosis, not cell size, delineates beta-myosin heavy chain reexpression during cardiac hypertrophy and normal aging in vivo. Proc Natl Acad Sci USA. 2006;103:16864–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993;73:413–67.PubMedGoogle Scholar
  63. 63.
    Collerton J, Martin-Ruiz C, Kenny A, Barrass K, von Zglinicki T, et al. Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study. Eur Heart J. 2007;28:172–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, et al. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res. 2003;93:604–13.PubMedCrossRefGoogle Scholar
  65. 65.
    Oh H, Wang SC, Prahash A, Sano M, Moravec CS, et al. Telomere attrition and Chk2 activation in human heart failure. Proc Natl Acad Sci USA. 2003;100:5378–83.PubMedCrossRefGoogle Scholar
  66. 66.
    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Cesselli D, Beltrami AP, D’Aurizio F, Marcon P, Bergamin N, et al. Effects of age and heart failure on human cardiac stem cell function. Am J Pathol. 2011;179:349–66.PubMedCrossRefGoogle Scholar
  68. 68.
    Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, et al. Human cardiac stem cells. Proc Natl Acad Sci USA. 2007;104:14068–73.PubMedCrossRefGoogle Scholar
  69. 69.
    Wong LS, Huzen J, de Boer RA, van Gilst WH, van Veldhuisen DJ, et al. Telomere length of circulating leukocyte subpopulations and buccal cells in patients with ischemic heart failure and their offspring. PLoS One. 2011;6:e23118.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49:2341–9.PubMedCrossRefGoogle Scholar
  71. 71.
    van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, et al. Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol. 2007;49:1459–64.PubMedCrossRefGoogle Scholar
  72. 72.
    Wong LS, Huzen J, van der Harst P, de Boer RA, Codd V, et al. Anaemia is associated with shorter leucocyte telomere length in patients with chronic heart failure. Eur J Heart Fail. 2010;12:348–53.PubMedCrossRefGoogle Scholar
  73. 73.
    Wong LS, van der Harst P, de Boer RA, Codd V, Huzen J, et al. Renal dysfunction is associated with shorter telomere length in heart failure. Clin Res Cardiol. 2009;98:629–34.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    van der Harst P, Wong LS, de Boer RA, Brouilette SW, van der Steege G, et al. Possible association between telomere length and renal dysfunction in patients with chronic heart failure. Am J Cardiol. 2008;102:207–10.PubMedCrossRefGoogle Scholar
  75. 75.
    Basel-Vanagaite L, Dokal I, Tamary H, Avigdor A, Garty BZ, et al. Expanding the clinical phenotype of autosomal dominant dyskeratosis congenita caused by TERT mutations. Haematologica. 2008;93:943–4.PubMedCrossRefGoogle Scholar
  76. 76.
    Leri A, Franco S, Zacheo A, Barlucchi L, Chimenti S, et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 2003;22:131–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Werner C, Hanhoun M, Widmann T, Kazakov A, Semenov A, et al. Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis. J Am Coll Cardiol. 2008;52:470–82.PubMedCrossRefGoogle Scholar
  78. 78.
    Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011;469:102–6.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Cottage CT, Neidig L, Sundararaman B, Din S, Joyo AY, et al. Increased mitotic rate coincident with transient telomere lengthening resulting from Pim-1 overexpression in cardiac progenitor cells. Stem Cells. 2012;30(11):2512–22.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Spyridopoulos I, Haendeler J, Urbich C, Brummendorf TH, Oh H, et al. Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation. 2004;110:3136–42.PubMedCrossRefGoogle Scholar
  81. 81.
    Werner C, Gensch C, Poss J, Haendeler J, Bohm M, et al. Pioglitazone activates aortic telomerase and prevents stress-induced endothelial apoptosis. Atherosclerosis. 2011;216:23–34.PubMedCrossRefGoogle Scholar
  82. 82.
    Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–61.PubMedCrossRefGoogle Scholar
  83. 83.
    Oyama J, Maeda T, Sasaki M, Higuchi Y, Node K, et al. Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats. Am J Physiol Heart Circ Physiol. 2012;302:H2092–101.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of CardiologyUniversity Medical Center Groningen, University of GroningenGroningenNetherlands

Personalised recommendations