Telomere length, stem cells and aging


Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Telomere structure.
Figure 2: Telomere elongation mechanisms.
Figure 3: The telomerase knockout mouse as a model for telomere-induced aging.
Figure 4: A stem cell theory for the role of telomeres and telomerase in cancer and aging.
Figure 5: Antagonistic effects of telomerase in cancer and aging.


  1. 1

    Chan, S.W. & Blackburn, E.H. New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21, 553–563 (2002).

    CAS  PubMed  Google Scholar 

  2. 2

    de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005).

    CAS  PubMed  Google Scholar 

  3. 3

    Liu, D., O'Connor, M.S., Qin, J. & Songyang, Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J. Biol. Chem. 279, 51338–51342 (2004).

    CAS  PubMed  Google Scholar 

  4. 4

    Harley, C.B., Futcher, A.B. & Greider, C.W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    CAS  Google Scholar 

  5. 5

    Collins, K. & Mitchell, J.R. Telomerase in the human organism. Oncogene 21, 564–579 (2002).

    CAS  PubMed  Google Scholar 

  6. 6

    Collado, M., Blasco, M.A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007).

    CAS  Google Scholar 

  7. 7

    Blasco, M.A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Herrera, E. et al. Disease states associated to telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950–2960 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Garcia-Cao, I. et al. Increased p53 activity does not accelerate telomere-driven ageing. EMBO Rep. 7, 546–552 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Flores, I., Benetti, R. & Blasco, M.A. Telomerase regulation and stem cell behaviour. Curr. Opin. Cell Biol. 18, 254–260 (2006).

    CAS  PubMed  Google Scholar 

  11. 11

    De Lange, T. Protection of mammalian telomeres. Oncogene 21, 532–540 (2002).

    CAS  Google Scholar 

  12. 12

    Bailey, S.M. et al. Strand-specific postreplicative processing of mammalian telomeres. Science 293, 2462–2465 (2001).

    CAS  Google Scholar 

  13. 13

    Griffith, J.D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).

    CAS  Google Scholar 

  14. 14

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

    CAS  PubMed  Google Scholar 

  15. 15

    Wang, R.C., Smogorzewska, A. & de Lange, T. Homologous recombination generates T-loop-sized deletions at human telomeres. Cell 119, 355–368 (2004).

    CAS  PubMed  Google Scholar 

  16. 16

    Ye, J.Z. et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18, 1649–1654 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Liu, D. et al. PTOP interacts with POT1 and regulates its localization to telomeres. Nat. Cell Biol. 6, 673–680 (2004).

    CAS  PubMed  Google Scholar 

  18. 18

    Smith, S., Giriat, I., Schmitt, A. & de Lange, T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282, 1484–1487 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Smogorzewska, A. et al. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20, 1659–1668 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).

    CAS  Google Scholar 

  21. 21

    Celli, G.B. & de Lange, T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat. Cell Biol. 7, 712–718 (2005).

    CAS  PubMed  Google Scholar 

  22. 22

    Hockemeyer, D., Daniela, J.P., Takai, H. & de Lange, T. Recent expansion of the telomeric complex in rodents: two distinct POT1 proteins protect mouse telomeres. Cell 126, 63–77 (2006).

    CAS  Google Scholar 

  23. 23

    Blasco, M.A. Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet. 6, 611–622 (2005).

    CAS  PubMed  Google Scholar 

  24. 24

    Zhu, X.D., Kuster, B., Mann, M., Petrini, J.H. & Lange, T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat. Genet. 25, 347–352 (2000).

    CAS  PubMed  Google Scholar 

  25. 25

    Zhu, X.D. et al. ERCC1/XPF removes the 3′-overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol. Cell 12, 1489–1498 (2003).

    CAS  PubMed  Google Scholar 

  26. 26

    van Overbeek, M. & de Lange, T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr. Biol. 16, 1295–1302 (2006).

    CAS  PubMed  Google Scholar 

  27. 27

    Lenain, C. et al. The Apollo 5′ exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr. Biol. 16, 1303–1310 (2006).

    CAS  PubMed  Google Scholar 

  28. 28

    Dimitrova, N. & de Lange, T. MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes Dev. 20, 3238–3243 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Karlseder, J. et al. The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol. 2, E240 (2004).

    PubMed  PubMed Central  Google Scholar 

  30. 30

    Bradshaw, P.S., Stavropoulos, D.J. & Meyn, M.S. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nat. Genet. 37, 193–197 (2005).

    CAS  PubMed  Google Scholar 

  31. 31

    Samper, E., Goytisolo, F.A., Slijepcevic, P., van Buul, P.P. & Blasco, M.A. Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep. 1, 244–252 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Tarsounas, M. et al. Telomere maintenance requires the RAD51D recombination/repair protein. Cell 117, 337–347 (2004).

    CAS  PubMed  Google Scholar 

  33. 33

    Jaco, I. et al. Role of mammalian Rad54 in telomere length maintenance. Mol. Cell. Biol. 23, 5572–5580 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    de Lange, T. et al. Structure and variability of human chromosome ends. Mol. Cell. Biol. 10, 518–527 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Makarov, V.L., Lejnine, S., Bedoyan, J. & Langmore, J.P. Nucleosomal organization of telomere-specific chromatin in rat. Cell 73, 775–787 (1993).

    CAS  PubMed  Google Scholar 

  36. 36

    Garcia-Cao, M., O'Sullivan, R., Peters, A.H., Jenuwein, T. & Blasco, M.A. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat. Genet. 36, 94–99 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Gonzalo, S. et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat. Cell Biol. 8, 416–424 (2006).

    CAS  PubMed  Google Scholar 

  38. 38

    Gonzalo, S. et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat. Cell Biol. 7, 420–428 (2005).

    CAS  PubMed  Google Scholar 

  39. 39

    Peters, A.H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    CAS  Google Scholar 

  40. 40

    Schotta, G. et al. A silencing pathway to induce H3–K9 and H4–K20 trimethylation at constitutive heterochromatin. Genes Dev. 18, 1251–1262 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Kourmouli, N. et al. Heterochromatin and tri-methylated lysine 20 of histone 4 in mammals. J. Cell Sci. 117, 2491–2501 (2004).

    CAS  PubMed  Google Scholar 

  42. 42

    Benetti, R., Garcia-Cao, M. & Blasco, M.A. Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat. Genet. 39, 243–250 (2007).

    CAS  PubMed  Google Scholar 

  43. 43

    Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    CAS  Google Scholar 

  44. 44

    Steinert, S., Shay, J.W. & Wright, W.E. Modification of subtelomeric DNA. Mol. Cell. Biol. 24, 4571–4580 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Cohen, S.B. et al. Protein composition of catalytically active human telomerase from immortal cells. Science 315, 1850–1853 (2007).

    CAS  PubMed  Google Scholar 

  46. 46

    Muntoni, A. & Reddel, R.R. The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14, R191–196 (2005).

    CAS  PubMed  Google Scholar 

  47. 47

    Dunham, M.A., Neumann, A.A., Fasching, C.L. & Reddel, R.R. Telomere maintenance by recombination in human cells. Nat. Genet. 26, 447–450 (2000).

    CAS  PubMed  Google Scholar 

  48. 48

    Lundblad, V. Telomere maintenance without telomerase. Oncogene 21, 522–531 (2002).

    CAS  PubMed  Google Scholar 

  49. 49

    Hande, M.P., Samper, E., Lansdorp, P. & Blasco, M.A. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol. 144, 589–601 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Chang, S., Khoo, C.M., Naylor, M.L., Maser, R.S. & DePinho, R.A. Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes Dev. 17, 88–100 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Niida, H. et al. Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA. Mol. Cell. Biol. 20, 4115–4127 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Herrera, E., Martinez, A.C. & Blasco, M.A. Impaired germinal center reaction in mice with short telomeres. EMBO J. 19, 472–481 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Blanco, R., Muñoz, P., Klatt, P., Flores, J.M. & Blasco, M.A. Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev. 21, 206–220 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Wu, L. et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 126, 49–62 (2006).

    CAS  Google Scholar 

  55. 55

    Laud, P.R. et al. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 19, 2560–2570 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Benetti, R. et al. Suv4–20h deficiency results in telomere elongation and de-repression of telomere recombination. J. Cell Biol. (in the press).

  57. 57

    Blasco, M.A., Funk, W.D., Villeponteau, B. & Greider, C.W. Functional characterization and developmental regulation of mouse telomerase RNA. Science 269, 1267–1270 (1995).

    CAS  PubMed  Google Scholar 

  58. 58

    Lee, H.-W., Blasco, M.A., Gottlieb, G.J., Greider, C.W. & DePinho, R.A. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).

    CAS  PubMed  Google Scholar 

  59. 59

    Franco, S., Segura, I., Riese, H., Blasco, M.A. & Decreased, B. 16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res. 62, 552–559 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    Leri, A. et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22, 131–139 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Samper, E. et al. Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood 99, 2767–2775 (2002).

    CAS  PubMed  Google Scholar 

  62. 62

    Gonzalez-Suarez, E., Samper, E., Flores, J.M. & Blasco, M.A. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat. Genet. 26, 114–117 (2000).

    CAS  PubMed  Google Scholar 

  63. 63

    d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).

    CAS  PubMed  Google Scholar 

  65. 65

    Poch, E. et al. Short telomeres protect from diet-induced atherosclerosis in apolipoprotein E-null mice. FASEB J. 18, 418–420 (2004).

    CAS  PubMed  Google Scholar 

  66. 66

    Shay, J.W. & Wright, W.E. Telomerase therapeutics for cancer: challenges and new directions. Nat. Rev. Drug Discov. 5, 577–584 (2006).

    CAS  PubMed  Google Scholar 

  67. 67

    Greenberg, R.A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97, 515–525 (1999).

    CAS  PubMed  Google Scholar 

  68. 68

    Rudolph, K.L., Millard, M., Bosenberg, M.W. & DePinho, R.A. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 28, 155–159 (2001).

    CAS  PubMed  Google Scholar 

  69. 69

    Choudhury, A.R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat. Genet. 39, 99–105 (2007).

    CAS  PubMed  Google Scholar 

  70. 70

    Siegl-Cachedernier, I., Muñoz, P., Flores, J.M., Klatt, P. & Blasco, M.A. Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres. Genes Dev. (in the press).

  71. 71

    Espejel, S. et al. Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs. J. Cell Biol. 167, 627–638 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Khoo, C.M., Carrasco, D.R., Bosenberg, M.W., Paik, J.H. & Depinho, R.A. Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse. Proc. Natl. Acad. Sci. USA 104, 3931–3936 (2007).

    CAS  PubMed  Google Scholar 

  73. 73

    Wong, K.K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).

    CAS  Google Scholar 

  75. 75

    Maser, R.S. et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447, 966–971 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Oh, B.-K., Kim, Y.-J., Park, C. & Park, Y.N. Up-regulation fo telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am. J. Pathol. 166, 73–80 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Matsutani, N. et al. Expression of telomeric repeat binding factor 1 and 2 and TRF1-interacting nuclear protein 2 in human gastric carcinomas. Int. J. Oncol. 19, 507–512 (2001).

    CAS  PubMed  Google Scholar 

  78. 78

    Muñz, P., Blanco, R., Flores, J.M. & Blasco, M.A. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat. Genet. 37, 1063–1071 (2005).

    Google Scholar 

  79. 79

    Nakanishi, K. et al. Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Clin. Cancer Res. 9, 1105–1111 (2003).

    CAS  PubMed  Google Scholar 

  80. 80

    Bellon, M. et al. Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia. Int. J. Cancer 119, 2090–2097 (2006).

    CAS  PubMed  Google Scholar 

  81. 81

    de Laat, W.L., Jaspers, N.G. & Hoeijmakers, J.H. Molecular mechanism of nucleotide excision repair. Genes Dev. 13, 768–785 (1999).

    CAS  PubMed  Google Scholar 

  82. 82

    Lazzerini Denchi, E., Celli, G. & de Lange, T. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication. Genes Dev. 20, 2648–2653 (2006).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Karlseder, J. et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol. Cell. Biol. 23, 6533–6541 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Dynek, J.N. & Smith, S. Resolution of sister telomere association is required for progression through mitosis. Science 304, 97–100 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Chiang, Y.J., Kim, S.H., Tessarollo, L., Campisi, J. & Hodes, R.J. Telomere-associated protein TIN2 is essential for early embryonic development through a telomerase-independent pathway. Mol. Cell Biol. 24, 6631–6634 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Kaminker, P. et al. Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2. J. Cell Sci. 118, 1321–1330 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Epel, E.S. et al. Accelerated telomere shortening in response to life stress. Proc. Natl. Acad. Sci. USA 101, 17312–17315 (2004).

    CAS  Google Scholar 

  88. 88

    Valdes, A.M. et al. Obesity, cigarette smoking, and telomere length in women. Lancet 366, 662–664 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Canela, A., Vera, E., Klatt, P. & Blasco, M.A. High-thoughput telomere length quantification by FISH and its application to human population studies. Proc. Natl. Acad. Sci. USA 104, 5300–5305 (2007).

    CAS  Google Scholar 

  90. 90

    Cherkas, L.F. et al. The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell 5, 361–365 (2006).

    CAS  PubMed  Google Scholar 

  91. 91

    Oh, H. et al. Telomere attrition and Chk2 activation in human heart failure. Proc. Natl. Acad. Sci. USA 100, 5378–5383 (2003).

    CAS  PubMed  Google Scholar 

  92. 92

    O'Sullivan, J.N. et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat. Genet. 32, 280–284 (2002).

    CAS  PubMed  Google Scholar 

  93. 93

    Wiemann, S.U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002).

    CAS  PubMed  Google Scholar 

  94. 94

    Samani, N.J. et al. Telomere shortening in atherosclerosis. Lancet 358, 472–473 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Wolthers, K.C. et al. T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 274, 1543–1547 (1996).

    CAS  PubMed  Google Scholar 

  96. 96

    Cawthon, R.M., Smith, K.R., O'Brien, E., Sivatchenko, A. & Kerber, R.A. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–395 (2003).

    CAS  PubMed  Google Scholar 

  97. 97

    Honig, L.S., Schupf, N., Lee, J.H., Tang, M.X. & Mayeux, R. Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann. Neurol. 60, 181–187 (2006).

    PubMed  Google Scholar 

  98. 98

    Mitchell, J.R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001).

    CAS  Google Scholar 

  100. 100

    Vulliamy, T. et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat. Genet. 36, 447–449 (2004).

    CAS  PubMed  Google Scholar 

  101. 101

    Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005).

    CAS  PubMed  Google Scholar 

  102. 102

    Marrone, A., Stevens, D., Vulliamy, T., Dokal, I. & Mason, P.J. Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood 104, 3936–3942 (2004).

    CAS  PubMed  Google Scholar 

  103. 103

    Tsakiri, K.D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl. Acad. Sci. USA 104, 7552–7557 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Armanios, M.Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat. Genet. 36, 877–882 (2004).

    CAS  PubMed  Google Scholar 

  106. 106

    Du, X. et al. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes. Mol. Cell. Biol. 24, 8437–8446 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Mochizuki, Y., He, J., Kulkarni, S., Bessler, M. & Mason, P.J. Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc. Natl. Acad. Sci. USA 101, 10756–10761 (2004).

    CAS  PubMed  Google Scholar 

  108. 108

    Bell, D.R. & Van Zant, G. Stem cells, aging, and cancer: inevitabilities and outcomes. Oncogene 23, 7290–7296 (2004).

    CAS  PubMed  Google Scholar 

  109. 109

    Vaziri, H. et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc. Natl. Acad. Sci. USA 91, 9857–9860 (1994).

    CAS  PubMed  Google Scholar 

  110. 110

    Allsopp, R.C., Cheshier, S. & Weissman, I.L. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J. Exp. Med. 193, 917–924 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Allsopp, R.C., Morin, G.B., DePinho, R., Harley, C.B. & Weissman, I.L. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102, 517–520 (2003).

    CAS  PubMed  Google Scholar 

  112. 112

    Allsopp, R.C. et al. Effect of TERT over-expression on the long-term transplantation capacity of hematopoietic stem cells. Nat. Med. 9, 369–371 (2003).

    CAS  PubMed  Google Scholar 

  113. 113

    Flores, I., Cayuela, M.L. & Blasco, M.A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253–1256 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Ferron, S. et al. Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131, 4059–4070 (2004).

    CAS  PubMed  Google Scholar 

  115. 115

    Sarin, K.Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Cayuela, M.L., Flores, J.M. & Blasco, M.A. The telomerase RNA component Terc is required for the tumour-promoting effects of Tert overexpression. EMBO Rep. 6, 268–274 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Levy, V., Lindon, C., Harfe, B.D. & Morgan, B.A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005).

    CAS  PubMed  Google Scholar 

  118. 118

    Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat. Med. 11, 1351–1354 (2005).

    CAS  PubMed  Google Scholar 

  119. 119

    Ju, Z. et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat. Med. 13, 742–747 (2007).

    CAS  PubMed  Google Scholar 

  120. 120

    Samper, E., Flores, J.M. & Blasco, M.A. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep. 2, 800–807 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Bodnar, A.G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).

    CAS  PubMed  Google Scholar 

  122. 122

    Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Gonzalez-Suarez, E., Geserick, C., Flores, J.M. & Blasco, M.A. Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene 24, 2256–2270 (2005).

    CAS  PubMed  Google Scholar 

  124. 124

    Artandi, S.E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl. Acad. Sci. USA 99, 8191–8196 (2002).

    CAS  PubMed  Google Scholar 

  125. 125

    Canela, A., Martín-Caballero, J., Flores, J.M. & Blasco, M.A. Constitutive expression of Tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice. Mol. Cell. Biol. 24, 4275–4293 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


M.A. Blasco's laboratory is funded by the MCyT (SAF2005-00277, GEN2001 4856-C13-08), the Regional Government of Madrid (GR/SAL/0597/2004), the European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003 506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842, MOL CANCER MED LSHC-CT-2004-502943) and the Josef Steiner Cancer Research Award 2003.

Author information



Corresponding author

Correspondence to Maria A Blasco.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Blasco, M. Telomere length, stem cells and aging. Nat Chem Biol 3, 640–649 (2007).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing