Skip to main content

Telomere shortening and ageing

Telomerverkürzung und Alterung

Zeitschrift für Gerontologie und Geriatrie volume 40, pages 314–324 (2007)Cite this article

Abstract

Telomeres form the ends of human chromosomes. Telomeres shorten with each round of cell division and this mechanism limits proliferation of human cells to a finite number of cell divisions by inducing replicative senescence, differentiation, or apoptosis. Telomere shortening can act as a tumor suppressor. However, as a downside, there is growing evidence indicating that telomere shortening also limits stem cell function, regeneration, and organ maintenance during ageing. Moreover, telomere shortening during ageing and disease is associated with increasing cancer risk. In this review we summarize our current knowledge on the role of telomere shortening in human ageing, chronic diseases, and cancer.

Zusammenfassung

Telomere bilden die Endstücke menschlicher Chromosomen und sind für den Erhalt der Chromosomenstabilität essentiell. Telomere verkürzen sich aber mit jeder Zellteilung, wodurch die proliferative Lebesspanne menschlicher Zellen limitiert wird, da bei einer kritischen Verkürzung der Telomere Seneszenz, Stammzelldifferenzierung oder Apoptose induziert wird. Diese Telomer-abhängige Begrenzung der Lebensspanne menschlicher Zellen wird allgemein als Tumorsuppressormechanismus angesehen. Es gibt aber zunehmend Hinweise, dass die Verkürzung der Telomere auch nachteilige Auswirkungen im Rahmen der Alterung haben kann, da hierdurch die Funktion von Stammzellen und die regenerative Reserve der Organe beschränkt wird. Darüber hinaus ist die Verkürzung der Telomere im Rahmen der menschlichen Alterung und bei chronischen Erkrankungen mit einem erhöhten Tumorrisiko assoziiert. In dieser Übersicht fassen wir unser aktuelles Wissen über die Rolle von Telomeren in der Alterung, bei chronischen Erkrankungen und hinsichtlich der Krebsentstehung zusammen.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Blackburn EH (2001) Switching and signaling at the telomere. Cell 106:661–673

    PubMed  Article  CAS  Google Scholar 

  2. de Lange T (2004) T-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5(4):323–329

    PubMed  Article  CAS  Google Scholar 

  3. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB (1992) Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89(21):10114–10118

    PubMed  Article  CAS  Google Scholar 

  4. Lingner J, Cooper JP, Cech TR (1995) Telomerase and DNA end replication: no longer a lagging strand problem? Science 269(5230):1533–1534

    PubMed  Article  CAS  Google Scholar 

  5. Saretzki G, Von Zglinicki T (2002) Replicative aging, telomeres, and oxidative stress. Ann NY Acad Sci 959:24–29

    PubMed  CAS  Article  Google Scholar 

  6. Greider CW (1996) Telomere length regulation. Annu Rev Biochem 65:337–365

    PubMed  Article  CAS  Google Scholar 

  7. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426 (6963):194–198

    PubMed  Article  CAS  Google Scholar 

  8. Wright WE, Shay JW (1992) The twostage mechanism controlling cellular senescence and immortalization. Exp Gerontol 27:383–389

    PubMed  Article  CAS  Google Scholar 

  9. Djojosubroto MW, Choi YS, Lee HW, Rudolph KL (2003) Telomeres and telomerase in aging, regeneration and cancer. Mol Cells 15:164–175

    PubMed  CAS  Google Scholar 

  10. Allsopp RC, Chang E, Kashefi-Aazam M, Rogaev EI, Piatyszek MA, Shay JW, Harley CB (1995) Telomere shortening is associated with cell division in vitro and in vivo. Exp Cell Res 220(1):194–200

    PubMed  Article  CAS  Google Scholar 

  11. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, Cummings JL, Effros RB (2003) Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol Aging 24(1):77–84

    PubMed  Article  CAS  Google Scholar 

  12. Martin-Ruiz C, Dickinson HO, Keys B, Rowan E, Kenny RA, Von Zglinicki T (2006) Telomere length predicts poststroke mortality, dementia, and cognitive decline. Ann Neurol 60(2):174–180

    PubMed  Article  Google Scholar 

  13. Boukamp P (2005) Skin aging: a role for telomerase and telomere dynamics? Curr Mol Med 5(2):171–177

    PubMed  Article  CAS  Google Scholar 

  14. Nakamura K, Izumiyama-Shimomura N, Sawabe M, Arai T, Aoyagi Y, Fujiwara M, Tsuchiya E, Kobayashi Y, Kato M, Oshimura M, Sasajima K, Nakachi K, Takubo K (2002) Aomparative analysis of telomere lengths and erosion with age in human epidermis and lingual epithelium. J Invest Dermatol 119(5):1014–1019

    PubMed  Article  CAS  Google Scholar 

  15. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92(20):9363–9367

    PubMed  Article  CAS  Google Scholar 

  16. de Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM, Varmus HE (1990) Structure andvariability of human chromosome ends. Mol Cell Biol 10(2):518–527

    PubMed  CAS  Google Scholar 

  17. Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 91(21):9857–9860

    PubMed  Article  CAS  Google Scholar 

  18. Zimmermann S, Martens UM (2005) Telomere dynamics in hematopoietic stem cells. Curr Mol Med 5(2):179–185

    PubMed  Article  CAS  Google Scholar 

  19. Gutierrez L, Ju Z (2007) Telomere shortening induces cell intrinsic checkpoints and environmental alterations limiting adult stem cell function. In: Rudolph KL. Telomeres and Telomerase in Aging, Disease, and Cancer. Springer Publishing 2007 (In press)

  20. Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, Rudolph KL (2002) Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 16(9):935–942

    PubMed  Article  CAS  Google Scholar 

  21. Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, Lee HW, von Zglinicki T, Ganser A, Schirmacher P, Nakauchi H, Rudolph KL (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39(1):99–105

    PubMed  Article  CAS  Google Scholar 

  22. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ, Mu D, Lucito R, Powers S, Lowe SW (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125(7):1253–1267

    PubMed  Article  CAS  Google Scholar 

  23. Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA (2003) Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361(9355):393–395

    PubMed  Article  CAS  Google Scholar 

  24. Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shepherd J, Packard CJ, Samani NJ; West of Scotland Coronary Prevention Study Group (2007) Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 369(9556):107–114

    PubMed  Article  CAS  Google Scholar 

  25. van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ, van Gilst WH, van Veldhuisen DJ; MERIT-HF Study Group (2007) Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol 49(13):1459–1464

    PubMed  Article  CAS  Google Scholar 

  26. Martin-Ruiz CM, Gussekloo J, van Heemst D, von Zglinicki T, Westendorp RG (2005) Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Aging Cell 4(6):287–290

    PubMed  Article  CAS  Google Scholar 

  27. Ganser A, Hoelzer D (1992) Clinical course of myelodysplastic syndromes. Hematol Oncol Clin North Am 6(3):607–618

    PubMed  CAS  Google Scholar 

  28. Ju Z, Rudolph KL (2006) Telomeres and telomerase in cancer stem cells. Eur J Cancer 42(9):1197–1203

    PubMed  Article  CAS  Google Scholar 

  29. Blasco, MA, Lee HW, Hande MP, Samper E, Lansdorp PM, dePinho RA, Greider CW (1997) Telomere shortening and tumour formation by mouse cells lacking telomerase RNA. Cell 91:25–34

    PubMed  Article  CAS  Google Scholar 

  30. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in ageing telomerase-deficient mice. Cell 96:701–712

    PubMed  Article  CAS  Google Scholar 

  31. Satyanarayana A, Wiemann SU, Buer J, Lauber J, Dittmar KE, Wustefeld T, Blasco MA, Manns MP, Rudolph KL (2003) Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells. EMBO J 22(15):4003–4013

    PubMed  Article  CAS  Google Scholar 

  32. Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL (2007) Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13(6):742–747

    PubMed  Article  CAS  Google Scholar 

  33. Brown JP, Wei W, Sedivy JM (1997) Bypasss of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277(5327):831–834

    PubMed  Article  CAS  Google Scholar 

  34. Mason PJ, Wilson DB, Bessler M (2005) Dyskeratosis congenita – a disease of dysfunctional telomere maintenance. Curr Mol Med 5(2):159–170

    PubMed  Article  CAS  Google Scholar 

  35. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402(6761):551–555

    PubMed  Article  CAS  Google Scholar 

  36. Young NS (2006) Pathophysiologic mechanisms in acquired aplastic anemia. Hematology Am Soc Hematol Educ Program, pp 72–77

  37. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356(13):1317–1326

    PubMed  Article  CAS  Google Scholar 

  38. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK (2007) Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA 104(18):7552–7557

    PubMed  Article  CAS  Google Scholar 

  39. Smogorzewska A, Karlseder J, Holtgreve- Grez H, Jauch A, de Lange T (2002) DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol 12(19):1635–1644

    PubMed  Article  CAS  Google Scholar 

  40. Maser RS, Wong KK, Sahin E, Xia H, Naylor M, Hedberg HM, Artandi SE, DePinho RA (2007) DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol Cell Biol 27(6):2253–2265

    PubMed  Article  CAS  Google Scholar 

  41. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA (2000) Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406(6796):641–645

    PubMed  Article  CAS  Google Scholar 

  42. Lechel A, Holstege H, Begus Y, Schienke A, Kamino K, Lehmann U, Kubicka S, Schirmacher P, Janker J, Rudolph KL (2007) Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132(4):1465–1475

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. H. Jiang

    Present address: Kidney Disease Center, The 1st Affiliated Hospital of Zhe Jiang University, Zhejiang, China

Affiliations

  1. Institute and Max-Planck-Research Group for Molecular Medicine, Ulm University, Ulm, Germany

    Z. Ju & K. L. Rudolph

  2. Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS), Beijing, China

    Z. Ju

  3. Max-Planck-Research-Group on Stem Cell Aging and Institute of Molecular Medicine, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    K. L. Rudolph

Authors
  1. H. Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z. Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. L. Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. L. Rudolph.

Additional information

Hong Jiang Formerly: Institute and Max-Planck-Research Group of Molecular Medicine Ulm University Ulm, Germany

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jiang, H., Ju, Z. & Rudolph, K.L. Telomere shortening and ageing. Z Gerontol Geriat 40, 314–324 (2007). https://doi.org/10.1007/s00391-007-0480-0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00391-007-0480-0

Key words

  • telomeres
  • ageing
  • cancer
  • chronic disease
  • replicative senescence

Schlüsselwörter

  • Telomere
  • Altern
  • Krebs
  • Chronische Erkrankungen
  • Replikative Seneszenz