Advertisement

Telomeres, Telomerase and Ageing

  • Gabriele SaretzkiEmail author
Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 90)

Abstract

Telomeres are specialised structures at the end of linear chromosomes. They consist of tandem repeats of the hexanucleotide sequence TTAGGG, as well as a protein complex called shelterin. Together, they form a protective loop structure against chromosome fusion and degradation. Shortening or damage to telomeres and opening of the loop induce an uncapped state that triggers a DNA damage response resulting in senescence or apoptosis.

Average telomere length, usually measured in human blood lymphocytes, was thought to be a biomarker for ageing, survival and mortality. However, it becomes obvious that regulation of telomere length is very complex and involves multiple processes. For example, the “end replication problem” during DNA replication as well as oxidative stress are responsible for the shortening of telomeres. In contrast, telomerase activity can potentially counteract telomere shortening when it is able to access and interact with telomeres. However, while highly active during development and in cancer cells, the enzyme is down-regulated in most human somatic cells with a few exceptions such as human lymphocytes. In addition, telomeres can be transcribed, and the transcription products called TERRA are involved in telomere length regulation.

Thus, telomere length and their integrity are regulated at many different levels, and we only start to understand this process under conditions of increased oxidative stress, inflammation and during diseases as well as the ageing process.

This chapter aims to describe our current state of knowledge on telomeres and telomerase and their regulation in order to better understand their role for the ageing process.

Keywords

Telomerase Telomere Senescence DNA damage Ageing 

References

  1. Abedin S, Michel JJ, Lemster B, Vallejo AN (2005) Diversity of NKR expression in aging T cells and in T cells of the aged: the new frontier into the exploration of protective immunity in the elderly. Exp Gerontol 40(7):537–548.  https://doi.org/10.1016/j.exger.2005.04.012 CrossRefPubMedGoogle Scholar
  2. Abreu E, Aritonovska E, Reichenbach P, Cristofari G, Culp B, Terns RM, Lingner J, Terns MP (2010) TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol 30:2971–2982.  https://doi.org/10.1128/MCB.00240-10 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adaikalakoteswari A, Balasubramanyam M, Ravikumar R, Deepa R, Mohan V (2007) Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis 195(1):83–89CrossRefPubMedGoogle Scholar
  4. Adams J, Martin-Ruiz C, Pearce MS, White M, Parker L, von Zglinicki T (2007) No association between socio-economic status and white blood cell telomere length. Aging Cell 6(1):125–128CrossRefPubMedGoogle Scholar
  5. Adler NE, Rehkopf DH (2008) U.S. disparities in health: descriptions, causes, and mechanisms. Annu Rev Public Health 29:235–252CrossRefPubMedGoogle Scholar
  6. Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H, Birch-Machin MA, von Zglinicki T, Saretzki G (2008) Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci 121:1046–1053CrossRefPubMedGoogle Scholar
  7. Akbar AN, Beverley PC, Salmon M (2004) Will telomere erosion lead to a loss of T cell memory? Nat Rev Immunol 4:737–743CrossRefPubMedGoogle Scholar
  8. Akbar AN, Vukmanovic-Stejic M (2007) Telomerase in T lymphocytes: use it and lose it? J Immunol 178(11):6689–6694Google Scholar
  9. Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, Mitsiades N, Chauhan D, Richardson P, Munshi NC, Anderson KC (2002) Cytokines modulate telomerase activity in a human multiple myeloma cell line Cancer Research 62:3876–3882Google Scholar
  10. Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, Mitsiades N, Chauhan D, Richardson P, Munshi NC, Anderson KC (2003) Nuclear factor kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Res 63:18–21PubMedGoogle Scholar
  11. Akiyama M, Yamada O, Hideshima T, Yanagisawa T, Yokoi K, Fujisawa K, Eto Y, Yamada H, Anderson KC (2004) TNFalpha induces rapid activation and nuclear translocation of telomerase in human lymphocytes. Biochem Biophys Res Commun 316:528–532CrossRefPubMedGoogle Scholar
  12. Akkad A, Hastings R, Konje JC, Bell SC, Thurston H, Williams B (2006) Telomere length in small-for-gestational-age babies. BJOG 113(3):318–323CrossRefPubMedGoogle Scholar
  13. Allsopp RC, Harley CB (1995) Evidence for a critical telomere length in senescent human fibroblasts. Exp Cell Res 219(1):130–136CrossRefPubMedGoogle Scholar
  14. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB (1992) Telomere length predicts replicative capacityof human fibroblasts. Proc Natl Acad Sci USA 89:10114–10118CrossRefPubMedGoogle Scholar
  15. Al-Mayah AH, Bright SJ, Bowler DA, Slijepcevic P, Goodwin E, Kadhim MA (2017) Exosome-mediated telomere instability in human breast epithelial cancer cells after X irradiation. Radiat Res 187:98–106.  https://doi.org/10.1667/RR14201.1 CrossRefPubMedGoogle Scholar
  16. Alonso-Arias R, Moro-García MA, López-Vázquez A, Rodrigo L, Baltar J, García FM, Jaurrieta JJ, López-Larrea C (2011) NKG2D expression in CD4+ T lymphocytes as a marker of senescence in the aged immune system. Age (Dordr.) 33(4):591–605.  https://doi.org/10.1007/s11357-010-9200-6 CrossRefGoogle Scholar
  17. Anderson R, Richardson GD, Passos JF (2017) Mechanisms driving the ageing heart. Exp Gerontol S0531-5565(17):30464–30463.  https://doi.org/10.1016/j.exger.2017.10.015 CrossRefGoogle Scholar
  18. Andrews NP, Fujii H, Goronzy JJ, Weyand CM (2010) Telomeres and immunological diseases of aging. Gerontology 56:390–403CrossRefPubMedGoogle Scholar
  19. Antunes DM, Kalmbach KH, Wang F, Dracxler RC, Seth-Smith ML, Kramer Y, Buldo-Licciardi J, Kohlrausch FB, Keefe DL (2015) A single-cell assay for telomere DNA content shows increasing telomere length heterogeneity, as well as increasing mean telomere length in human spermatozoa with advancing age. J Assist Reprod Genet 32(11):1685–1690.  https://doi.org/10.1007/s10815-015-0574-3 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, von Zglinicki T (2015) Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians. EBioMedicine 2:1549–1558.  https://doi.org/10.1016/j.ebiom.2015.07.029. eCollection 2015 Oct
  21. Arbeev KG, Hunt SC, Kimura M, Aviv A, Yashin AI (2011) Leukocyte telomere length, breast cancer risk in the offspring: the relations with father’s age at birth. Mech Ageing Dev 132(4):149–153.  https://doi.org/10.1016/j.mad.2011.02.004 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Arnoult N, Van Beneden A, Decottignies A (2012) Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 andHP1alpha. Nat Struct Mol Biol 19:948–956.  https://doi.org/10.1038/nsmb.2364 CrossRefPubMedGoogle Scholar
  23. Arora R, Azzalin CM (2015) Telomere elongation chooses TERRA ALTernatives. RNA Biol 12:938–941.  https://doi.org/10.1080/15476286.2015.1065374 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Arora R, Lee Y, Wischnewski H, Brun CM, Schwarz T, Azzalin CM (2014) RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenancein ALT tumour cells. Nat Commun 5:5220.  https://doi.org/10.1038/ncomms6220 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Aston KI, Hunt SC, Susser E, Kimura M, Factor-Litvak P, Carrell D, Aviv A (2012) Divergence of sperm and leukocyte age-dependent telomere dynamics: implications for male-driven evolution of telomere length in humans. Mol Hum Reprod 18(11):517–522.  https://doi.org/10.1093/molehr/gas028
  26. Astrup AS, Tarnow L, Jorsal A, Lajer M, Nzietchueng R, Benetos A, Rossing P, Parving HH (2010) Telomere length predicts all-cause mortality in patients with type 1 diabetes. Diabetologia 53(1):45–48.  https://doi.org/10.1007/s00125-009-1542-1 CrossRefPubMedGoogle Scholar
  27. Atkinson SP, Hoare SF, Glasspool RM, Keith WN (2005) Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters. Cancer Res 65(17):7585–7590Google Scholar
  28. Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Huffman DM, Schechter CB, Wright WE, Shay JW, Barzilai N, Govindaraju DR, Suh Y (2010) Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci USA 107(Suppl 1):1710–1717.  https://doi.org/10.1073/pnas.0906191106 CrossRefPubMedGoogle Scholar
  29. Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88(2):557–579.  https://doi.org/10.1152/physrev.00026.2007 CrossRefPubMedGoogle Scholar
  30. Avin BA, Umbricht CB, Zeiger MA (2016) Human telomerase reverse transcriptase regulation by DNA methylation, transcription factor binding and alternative splicing. Int J Oncol 49(6):2199–2205.  https://doi.org/10.3892/ijo.2016.3743 CrossRefPubMedGoogle Scholar
  31. Aviv A (2008) The epidemiology of human telomeres: faults and promises. J Gerontol A Biol Sci Med Sci 63(9):979–983CrossRefPubMedGoogle Scholar
  32. Aviv A, Chen W, Gardner JP, Kimura M, Brimacombe M, Cao X, Srinivasan SR, Berenson GS (2009) Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa Heart Study. Am J Epidemiol 169:323–329.  https://doi.org/10.1093/aje/kwn338 CrossRefPubMedGoogle Scholar
  33. Azhibek D, Skvortsov D, Andreeva A, Zatsepin T, Arutyunyan A, Zvereva M, Dontsova O (2016) TERRA mimicking ssRNAs prevail over the DNA substrate for telomerase in vitro due to interactions with the alternative binding site. J Mol Recognit 29(6):242–247.  https://doi.org/10.1002/jmr.2521 CrossRefPubMedGoogle Scholar
  34. Azzalin CM, Lingner J (2008) Telomeres: the silence is broken. Cell Cycle 7:1161–1165CrossRefPubMedGoogle Scholar
  35. Azzalin CM, Lingner J (2015) Telomere functions grounding on TERRA firma. Trends Cell Biol 25(1):29–36.  https://doi.org/10.1016/j.tcb.2014.08.007 CrossRefPubMedGoogle Scholar
  36. Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318:798–801CrossRefPubMedGoogle Scholar
  37. Bae NS, Baumann P (2007) A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol Cell 26(3):323–334CrossRefPubMedGoogle Scholar
  38. Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell. 87(1):13–20CrossRefPubMedGoogle Scholar
  39. Bailey SM, Cornforth MN, Kurimasa A, Chen DJ, Goodwin EH (2001) Strand-specific postreplicative processing of mammalian telomeres. Science 293:2462–2465CrossRefPubMedGoogle Scholar
  40. Baird DM, Britt-Compton B, Rowson J, Amso NN, Gregory L, Kipling D (2006) Telomere instability in the male germline. Hum Mol Genet 15(1):45–51CrossRefPubMedGoogle Scholar
  41. Bakaysa SL, Mucci LA, Slagboom PE, Boomsma DI, McClearn GE, Johansson B, Pedersen NL (2007) Telomere length predicts survival independent of genetic influences. Aging Cell 6:769–774CrossRefPubMedGoogle Scholar
  42. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageingassociated disorders. Nature 479:232–236.  https://doi.org/10.1038/nature10600 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530(7589):184–189.  https://doi.org/10.1038/nature16932 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Balcerczyk A, Gajewska A, Macierzynska-Piotrowska E, Pawelczyk T, Bartosz G, Szemraj J (2014) Enhanced antioxidant capacity and anti-ageing biomarkers after diet micronutrient supplementation. Molecules 19:14794–14808.  https://doi.org/10.3390/molecules190914794 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Bandres E, Merino J, Vazquez B, Inoges S, Moreno C, Subira ML, Sanchez-Ibarrola A (2000) The increase of IFN- production through aging correlates with the expanded CD8(+high)CD28(-)CD57(+) subpopulation. Clin Immunol 96:230–235CrossRefPubMedGoogle Scholar
  46. Banik SS, Counter CM (2004) Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. J Biol Chem 279(50):51745–51748CrossRefPubMedGoogle Scholar
  47. Batty GD, Wang Y, Brouilette SW, Shiels P, Packard C, Moore J, Samani NJ, Ford I (2009) Socioeconomic status and telomere length: the West of Scotland Coronary Prevention Study. J Epidemiol Community Health 63(10):839–841.  https://doi.org/10.1136/jech.2009.088427 CrossRefPubMedGoogle Scholar
  48. Baur JA, Zou Y, Shay JW, Wright WE (2001) Telomere position effect in human cells. Science 292:2075–2077CrossRefPubMedGoogle Scholar
  49. Bayne S, Liu JP (2005) Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol 240(1-2):11–22CrossRefPubMedGoogle Scholar
  50. Beery AK, Lin J, Biddle JS, Francis DD, Blackburn EH, Epel ES (2012) Chronic stress elevates telomerase activity in rats. Biol Lett 8(6):1063–1066.  https://doi.org/10.1098/rsbl.2012.0747 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Beier F, Balabanov S, Amberger CC, Hartmann U, Manger K, Dietz K, Kötter I, Brummendorf TH (2007) Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow-FISH. Lupus 16(12):955–962CrossRefPubMedGoogle Scholar
  52. Bellon M, Nicot C (2017) Telomere dynamics in immune senescence and exhaustion triggered by chronic viral infection. Viruses 9(10):pii: E289.  https://doi.org/10.3390/v9100289 CrossRefGoogle Scholar
  53. Bendix L, Thinggaard M, Fenger M, Kolvraa S, Avlund K, Linneberg A, Osler M (2014) Longitudinal changes in leukocyte telomere length and mortality in humans. J Gerontol A Biol Sci Med Sci 69(2):231–239.  https://doi.org/10.1093/gerona/glt153 CrossRefPubMedGoogle Scholar
  54. Benetos A, Kimura M, Labat C, Buchoff GM, Huber S, Labat L, Lu X, Aviv A (2011) A model of canine leukocyte telomere dynamics. Aging Cell 10(6):991–995.  https://doi.org/10.1111/j.1474-9726.2011.00744.x CrossRefPubMedPubMedCentralGoogle Scholar
  55. Benetti R, García-Cao M, Blasco MA (2007) Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet 39:243–250CrossRefPubMedGoogle Scholar
  56. Bennaceur K, Atwill M, Al Zhrany N, Hoffmann J, Keavney B, Breault D, Richardson G, von Zglinicki T, Saretzki G, Spyridopoulos I (2014) Atorvastatin induces T cell proliferation by a telomerase reverse transcriptase (TERT) mediated mechanism. Atherosclerosis 236(2):312–320CrossRefPubMedGoogle Scholar
  57. Bernal A, Tusell L (2018) Telomeres: implications for cancer development. Int J Mol Sci 19(1):pii: E294.  https://doi.org/10.3390/ijms19010294
  58. Bernardes de Jesus B, Schneeberger K, Vera E, Tejera A, Harley CB, Blasco MA (2011) The telomerase activator ta-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 10:604–621.  https://doi.org/10.1111/j.1474-9726.2011.00700.x CrossRefPubMedGoogle Scholar
  59. Beyer AM, Freed JK, Durand MJ, Riedel M, Ait-Aissa K, Green P, Hockenberry JC, Morgan RG, Donato AJ, Peleg R, Gasparri M, Rokkas CK, Santos JH, Priel E, Gutterman DD (2016) Critical role for telomerase in the mechanism of flow-mediated dilation in the human microcirculation. Circ Res 118:856–866.  https://doi.org/10.1161/CIRCRESAHA.115.307918 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Bilsland AE, Stevenson K, Atkinson S, Kolch W, Keith WN (2006) Transcriptional repression of telomerase RNA gene expression by c-Jun-NH2-kinase and Sp1/Sp3. Cancer Res 66:1363–1370CrossRefPubMedGoogle Scholar
  61. Birch J, Anderson RK, Correia-Melo C, Jurk D, Hewitt G, Marques FM, Green NJ, Moisey E, Birrell MA, Belvisi M, Black F, Taylor JJ, Fisher AJ, De Soyza A, Passos JF (2015) DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 309:L1124–L1137.  https://doi.org/10.1152/ajplung.00293.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Birch J, Victorelli S, Rahmatika D, Anderson RK, Jiwa K, Moisey E, Ward C, Fisher AJ, De Soyza A, Passos JF (2016) Telomere dysfunction and senescence-associated pathways in bronchiectasis. AM J Respir Crit Care Med 193(8):929–932.  https://doi.org/10.1164/rccm.201510-2035LE CrossRefPubMedPubMedCentralGoogle Scholar
  63. Birch J, Barnes PJ, Passos JF (2018) Mitochondria, telomeres and cell senescence: implications for lung ageing and disease. Pharmacol Ther 183:34–49.  https://doi.org/10.1016/jpharmthera.2017.10.005
  64. Bischoff C, Petersen HC, Graakjaer J, Andersen-Ranberg K, Vaupel JW, Bohr VA, Kølvraa S, Christensen K (2006) No association between telomere length and survival among the elderly and oldest old. Epidemiology 17:190–194CrossRefPubMedPubMedCentralGoogle Scholar
  65. Blackburn EH (1994) Telomeres: no end in sight. Cell 77(5):621–623CrossRefPubMedGoogle Scholar
  66. Blackburn EH (2000) Telomere states and cell fates. Nature 408:53–56CrossRefPubMedGoogle Scholar
  67. Blackburn EH (2001) Switching and ignalling at the telomere. Cell 106:661–673CrossRefPubMedPubMedCentralGoogle Scholar
  68. Blackburn EH (2005) Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett 579:859–862CrossRefPubMedGoogle Scholar
  69. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:25–34CrossRefPubMedPubMedCentralGoogle Scholar
  70. Boccardi V, Esposito A, Rizzo MR, Marfella R, Barbieri M, Paolisso G (2013) Mediterranean diet, telomere maintenance and health status among elderly. PLoS ONE 8:e62781CrossRefPubMedPubMedCentralGoogle Scholar
  71. Bodnar AG, Kim NW, Effros RB, Chiu CP (1996) Mechanism of telomerase induction during T cell activation. Exp Cell Res 228:58CrossRefPubMedGoogle Scholar
  72. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279(5349):349–352CrossRefPubMedGoogle Scholar
  73. Boggess JF, Zhou C, Bae-Jump VL, Gehrig PA, Whang YE (2006) Estrogen-receptor-dependent regulation of telomerase activity in human endometrial cancer cell lines. Gynecol Oncol 103:417–424CrossRefPubMedGoogle Scholar
  74. Boonekamp JJ, Simons MJ, Hemerik L, Verhulst S (2013) Telomere length behaves as biomarker of somatic redundancy rather than biological age. Aging Cell 12(2):330–332.  https://doi.org/10.1111/acel.12050 CrossRefPubMedGoogle Scholar
  75. Broer L, Codd V, Nyholt DR, Deelen J, Mangino M, Willemsen G, Albrecht E, Amin N, Beekman M, de Geus EJ, Henders A, Nelson CP, Steves CJ, Wright MJ, de Craen AJ, Isaacs A, Matthews M, Moayyeri A, Montgomery GW, Oostra BA, Vink JM, Spector TD, Slagboom PE, Martin NG, Samani NJ, van Duijn CM, Boomsma DI (2013) Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and apaternal age effect. Eur J Hum Genet EJHG 21:1163–1168CrossRefPubMedGoogle Scholar
  76. Büchner N, Zschauer TC, Lukosz M, Altschmied J, Haendeler J (2010) Downregulation of mitochondrial telomerase reverse transcriptase induced by H2O2 is Src kinase dependent. Exp Gerontol 45(7-8):558–562.  https://doi.org/10.1016/j.exger.2010.03.003 CrossRefPubMedGoogle Scholar
  77. Butler MG, Tilburt J, Devries A, Muralidhar B, Aue G, Hedges L, Atkinson J, Schwartz H (1998) Comparison of chromosome telomere integrity in multiple tissues from subjects at different ages. Cancer Genet Cytogenet 105(2):138–144Google Scholar
  78. Cairney CJ, Keith WN (2008) Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity. Biochimie 90(1):13–23CrossRefPubMedGoogle Scholar
  79. Campisi J, Kim SH, Lim CS, Rubio M (2001) Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol 36(10):1619–1637CrossRefPubMedGoogle Scholar
  80. Carneiro T, Khair L, Reis CC, Borges V, Moser BA, Nakamura TM, Ferreira MG (2010) Telomeres avoid end detection by severing the checkpoint signal transduction pathway. Nature 467(7312):228–232.  https://doi.org/10.1038/nature09353 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Caslini C, Connelly JA, Serna A, Broccoli D, Hess JL (2009) MLL associates with telomeres and regulates telomeric repeat-containing RNA transcription. Mol Cell Biol 29:4519–4526.  https://doi.org/10.1128/MCB.00195-09 CrossRefPubMedPubMedCentralGoogle Scholar
  82. 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 361:393–395CrossRefPubMedPubMedCentralGoogle Scholar
  83. Cesare AJ, Kaul Z, Cohen SB, Napier CE, Pickett HA, Neumann AA, Reddel RR (2009) Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions. Nat Struct Mol Biol 16(12):1244–1251.  https://doi.org/10.1038/nsmb.1725 CrossRefPubMedGoogle Scholar
  84. Chai W, Sfeir AJ, Hoshiyama H, Shay JW, Wright WE (2006) The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G-overhangs at human telomeres. EMBO Rep 7(2):225–230CrossRefPubMedGoogle Scholar
  85. Chan R, Woo J, Suen E, Leung J, Tang N (2010) Chinese tea consumption is associated with longer telomere length in elderly Chinese men. Br J Nutr 103(1):107–113.  https://doi.org/10.1017/S0007114509991383 CrossRefPubMedGoogle Scholar
  86. Chang AC, Ong SG, LaGory EL, Kraft PE, Giaccia AJ, Wu JC, Blau HM (2016a) Telomere shortening and metabolic compromise underlie dystrophic cardiomyopathy. Proc Natl Acad Sci USA 113(46):13120–13125CrossRefPubMedGoogle Scholar
  87. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2016b) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22(1):78–83.  https://doi.org/10.1038/nm.4010 CrossRefPubMedGoogle Scholar
  88. Chen JL, Greider CW (2003) Determinants in mammalian telomerase RNA that mediate enzyme processivity and cross-species incompatibility. EMBO J 22(2):304–314Google Scholar
  89. Chen LY, Liu D, Songyang Z (2007) Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol 27:5898–5909CrossRefPubMedPubMedCentralGoogle Scholar
  90. Chen W, Kimura M, Kim S, Cao X, Srinivasan SR, Berenson GS, Kark JD, Aviv A (2011) Longitudinal versus cross-sectional evaluations of leukocyte telomere length dynamics: age-dependent telomere shortening is the rule. J Gerontol A Biol Sci Med Sci 66:312–319.  https://doi.org/10.1093/gerona/glq223 CrossRefPubMedGoogle Scholar
  91. Chen LY, Zhang Y, Zhang Q, Li H, Luo Z, Fang H, Kim SH, Qin L, Yotnda P, Xu J, Tu BP, Bai Y, Songyang Z (2012a) Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Mol Cell 47:839–850.  https://doi.org/10.1016/j.molcel.2012.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  92. Chen LY, Redon S, Lingner J (2012b) The human CST complex is a terminator of telomerase activity. Nature 488:540–544.  https://doi.org/10.1038/nature11269 CrossRefPubMedGoogle Scholar
  93. Chen SH, Epel ES, Mellon SH, Lin J, Reus VI, Rosser R, Kupferman E, Burke H, Mahan L, Blackburn EH, Wolkowitz OM (2014) Adverse childhood experiences and leukocyte telomere maintenance in depressed and healthy adults. J Affect Disord 169:86–90.  https://doi.org/10.1016/j.jad.2014.07.035 CrossRefPubMedPubMedCentralGoogle Scholar
  94. Cherkas LF, Aviv A, Valdes AM, Hunkin JL, Gardner JP, Surdulescu GL, Kimura M, Spector TD (2006) The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell 5(5):361–365CrossRefPubMedGoogle Scholar
  95. Cherkas LF, Hunkin JL, Kato BS, Richards JB, Gardner JP, Surdulescu GL, Kimura M, Lu X, Spector TD, Aviv A (2008) The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med 168(2):154–158.  https://doi.org/10.1001/archinternmed.2007.39 CrossRefPubMedGoogle Scholar
  96. Chiarugi A, Moskowitz MA (2003) Poly(ADP-ribose) polymerase-1 activitypromotes NF-kappaB-driven transcription and microglial activation:implication for neurodegenerative disorders. J Neurochem 85:306–317CrossRefPubMedGoogle Scholar
  97. Choi J, Fauce SR, Effros RB (2008) Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun 22(4):600–605.  https://doi.org/10.1016/j.bbi.2007.12.004
  98. Chu HP, Cifuentes-Rojas C, Kesner B, Aeby E, Lee HG, Wei C, Oh HJ, Boukhali M, Haas W, Lee JT (2017) TERRA RNA antagonizes ATRX and protects telomeres. Cell 170(1):86–101.e16.  https://doi.org/10.1016/j.cell.2017.06.017
  99. Chung J, Khadka P, Chung IK (2012) Nuclear import of hTERT requires a bipartite nuclear localization signal and Akt-mediated phosphorylation. J Cell Sci 125:2684–2697CrossRefPubMedGoogle Scholar
  100. Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, Hottenga JJ, Fischer K, Esko T, Surakka I, Broer L, Nyholt DR, Mateo Leach I, Salo P, Hägg S, Matthews MK, Palmen J, Norata GD, O’Reilly PF, Saleheen D, Amin N, Balmforth AJ, Beekman M, de Boer RA, Böhringer S, Braund PS, Burton PR, de Craen AJ, Denniff M, Dong Y, Douroudis K, Dubinina E, Eriksson JG, Garlaschelli K, Guo D, Hartikainen AL, Henders AK, Houwing-Duistermaat JJ, Kananen L, Karssen LC, Kettunen J, Klopp N, Lagou V, van Leeuwen EM, Madden PA, Mägi R, Magnusson PK, Männistö S, McCarthy MI, Medland SE, Mihailov E, Montgomery GW, Oostra BA, Palotie A, Peters A, Pollard H, Pouta A, Prokopenko I, Ripatti S, Salomaa V, Suchiman HE, Valdes AM, Verweij N, Viñuela A, Wang X, Wichmann HE, Widen E, Willemsen G, Wright MJ, Xia K, Xiao X, van Veldhuisen DJ, Catapano AL, Tobin MD, Hall AS, Blakemore AI, van Gilst WH, Zhu H, CARDIoGRAM consortium, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Talmud PJ, Pedersen NL, Perola M, Ouwehand W, Kaprio J, Martin NG, van Duijn CM, Hovatta I, Gieger C, Metspalu A, Boomsma DI, Jarvelin MR, Slagboom PE, Thompson JR, Spector TD, van der Harst P, Samani NJ (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45:422–427.  https://doi.org/10.1038/ng.2528 CrossRefPubMedPubMedCentralGoogle Scholar
  101. Colgin LM, Wilkinson C, Englezou A, Kilian A, Robinson MO, Reddel RR (2000) The hTERTα splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia 2:426–432Google Scholar
  102. Colmegna I, Diaz-Borjon A, Fujii H, Schaefer L, Goronzy JJ, Weyand CM (2008) Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum 58:990–1000.  https://doi.org/10.1002/art.23287 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Cook BD, Dynek JN, Chang W, Shostak G, Smith S (2002) Role for the related poly(ADP-ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol 22(1):332–342Google Scholar
  104. Cong Y, Shay JW (2008) Actions of human telomerase beyond telomeres. Cell Res 18(7):725–732CrossRefPubMedGoogle Scholar
  105. Cong YS, Wen J, Bacchetti S (1999) The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet 8:137–142CrossRefPubMedGoogle Scholar
  106. Cong YS, Wright WE, Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev 66:407–425CrossRefPubMedPubMedCentralGoogle Scholar
  107. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypesreveal cell-nonautonomous functions of oncogenic RAS and the p53 tumorsuppressor. PLoS Biol 6:2853–2868.  https://doi.org/10.1371/journal.pbio.0060301 CrossRefPubMedGoogle Scholar
  108. Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118.  https://doi.org/10.1146/annurev-pathol-121808-102144 CrossRefPubMedPubMedCentralGoogle Scholar
  109. Counter CM, Hahn WC, Wei W et al (1998) Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci USA 95(25):14723–14728CrossRefPubMedGoogle Scholar
  110. Counter CM, Press W, Compton CC (2003) Telomere shortening in cultured autografts of patients with burns. Lancet 361(9366):1345–1346CrossRefPubMedGoogle Scholar
  111. Crous-Bou M, Fung TT, Prescott J, Julin B, Du M, Sun Q, Rexrode KM, Hu FB, de Vivo I (2014) Mediterranean diet and telomere length in Nurses’ Health Study: population based cohort study. BMJ 349:g6674.  https://doi.org/10.1136/bmj.g6674 CrossRefPubMedPubMedCentralGoogle Scholar
  112. Czesnikiewicz-Guzik M, Lee WW, Cui D, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ (2007) T cell subset-specific susceptibility to aging. Clin Immunol 127(1):107–118.  https://doi.org/10.1016/j.clim.2007.12.002 CrossRefGoogle Scholar
  113. 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 damagecheckpoint response in telomere-initiated senescence. Nature 426:194–198CrossRefPubMedGoogle Scholar
  114. Dagarag M, Evazyan T, Rao N, Effros RB (2004) Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J Immunol 173(10):6303–6311.  https://doi.org/10.4049/jimmunol.173.10.6303 CrossRefPubMedGoogle Scholar
  115. Damjanovic AK, Yang Y, Glaser R, Kiecolt-Glaser JK, Nguyen H, Laskowski B, Zou Y, Beversdorf DQ, Weng NP (2007) Accelerated telomere erosion isassociated with a declining immune function of caregivers of Alzheimer’sdisease patients. J. Immunol 179:4249–4254CrossRefPubMedPubMedCentralGoogle Scholar
  116. Dantzer B, Fletcher QE (2015) Telomeres shorten more slowly in slow-aging wild animals than in fast-aging ones. Exp Gerontol 71:38–47.  https://doi.org/10.1016/j.exger.2015.08.012 CrossRefPubMedGoogle Scholar
  117. Daubenmier J, Lin J, Blackburn E, Hecht FM, Kristeller J, Maninger N, Kuwata M, Bacchetti P, Havel PJ, Epel E (2012) Changes in stress, eating, andmetabolic factors are related to changes in telomerase activity in a randomizedmindfulness intervention pilot study. Psychoneuroendocrinology 37:917–928.  https://doi.org/10.1016/j.psyneuen.2011.10.008 CrossRefPubMedGoogle Scholar
  118. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC (2009) Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol 217(3):327–344.  https://doi.org/10.1002/path.2500 CrossRefPubMedGoogle Scholar
  119. de Lange T (2002) Protection of mammalian telomeres. Oncogene 21:532–540CrossRefPubMedGoogle Scholar
  120. de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110CrossRefPubMedGoogle Scholar
  121. de Lange T (2009) How telomeres solve the end-protection problem. Science 326:948–952.  https://doi.org/10.1126/science.1170633 CrossRefPubMedPubMedCentralGoogle Scholar
  122. De Meyer T, Rietzschel ER, De Buyzere ML, De Bacquer D, Van Criekinge W, De Backer GG, Gillebert TC, Van Oostveldt P, Bekaert S, Asklepios investigators (2007) Paternal age at birth is an important determinant of offspring telomere length. Hum Mol Genet 16:3097–3102CrossRefPubMedGoogle Scholar
  123. de Rooij SR, van Pelt AM, Ozanne SE, Korver CM, van Daalen SK, Painter RC, Schwab M, Viegas MH, Roseboom TJ (2015) Prenatal undernutrition and leukocyte telomere length in late adulthood: the Dutch famine birth cohort study. Am J Clin Nutr 102(3):655–660.  https://doi.org/10.3945/ajcn.115.112326 CrossRefPubMedGoogle Scholar
  124. Deeks SG (2011) HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 62:141–155.  https://doi.org/10.1146/annurev-med-042909-093756 CrossRefPubMedPubMedCentralGoogle Scholar
  125. Deelen J, Uh HW, Monajemi R, Thijssen PE, Böhringer S, van den Akker EB, de Craen AJ, Rivadeneira F, Uitterlinden AG, Westendorp RG, Goeman JJ, Slagboom PE, Houwing-Duistermaat JJ, Beekman M (2013a) Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 ignalling and telomere maintenance pathways. Age (Dordr.) 35(1):235–249.  https://doi.org/10.1007/s11357-011-9340-3 CrossRefGoogle Scholar
  126. Deelen J, Beekman M, Capri M, Franceschi C, Slagboom PE (2013b) Identifying the genomic determinants of aging and longevity in human population studies: progress and challenges. BioEssays 35:386–396.  https://doi.org/10.1002/bies.201200148 CrossRefPubMedPubMedCentralGoogle Scholar
  127. Deelen J, Beekman M, Codd V, Trompet S, Broer L, Hägg S, Fischer K, Thijssen PE, Suchiman HE, Postmus I, Uitterlinden AG, Hofman A, de Craen AJ, Metspalu A, Pedersen NL, van Duijn CM, Jukema JW, Houwing-Duistermaat JJ, Samani NJ, Slagboom PE (2014) Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers. Int J Epidemiol 43(3):878–886.  https://doi.org/10.1093/ije/dyt267 CrossRefPubMedPubMedCentralGoogle Scholar
  128. Demissie S, Levy D, Benjamin EJ, Cupples LA, Gardner JP, Herbert A, Kimura M, Larson MG, Meigs JB, Keaney JF, Aviv A (2006) Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell 5:325–330CrossRefPubMedGoogle Scholar
  129. Denchi E, de Lange T (2007) Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448:1068–1071CrossRefPubMedGoogle Scholar
  130. Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman PM (2009) TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell 35:403–413.  https://doi.org/10.1016/j.molcel.2009.06.025 CrossRefPubMedPubMedCentralGoogle Scholar
  131. Deng Z, Kim ET, Vladimirova O, Dheekollu J, Wang Z, Newhart A, Liu D, Myers JL, Hensley SE, Moffat J, Janicki SM, Fraser NW, Knipe DM, Weitzman MD, Lieberman PM (2014) HSV-1 remodels host telomeres to facilitate viral replication. Cell Rep 9:2263–2278.  https://doi.org/10.1016/j.celrep.2014.11.019 CrossRefPubMedPubMedCentralGoogle Scholar
  132. Devereux TR, Horikawa I, Anna CH, Annab LA, Afshari CA, Barrett JC (1999) DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res 59(24):6087–6090PubMedGoogle Scholar
  133. Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8(21):2540–2551CrossRefPubMedGoogle Scholar
  134. Dimauro I, Sgura A, Pittaluga M, Magi F, Fantini C, Mancinelli R, Sgadari A, Fulle S, Caporossi D (2017) Regular exercise participation improves genomic stability in diabetic patients: an exploratory study to analyse telomere length and DNA damage. Sci Rep 7(1):4137.  https://doi.org/10.1038/s41598-017-04448-4 CrossRefPubMedPubMedCentralGoogle Scholar
  135. D’Mello NP, Jazwinski SM (1991) Telomere length constancy during aging of Saccharomyces cerevisiae. J Bacteriol 173(21):6709–6713Google Scholar
  136. Doksani Y, de Lange T (2016) Telomere-internal double-strand breaks are repaired by homologous recombination and PARP1/Lig3-dependent end-joining. Cell Rep 17(6):1646–1656.  https://doi.org/10.1016/j.celrep.2016.10.008 CrossRefPubMedPubMedCentralGoogle Scholar
  137. Doksani Y, Wu JY, de Lange T, Zhuang X (2013) Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 155:345–356.  https://doi.org/10.1016/j.cell.2013.09.048 CrossRefPubMedPubMedCentralGoogle Scholar
  138. Dow CT, Harley CB (2016) Evaluation of an oral telomerase activator for early age-related macular degeneration – a pilot study. Clin Ophthalmol 10:243–249.  https://doi.org/10.2147/OPTH.S100042. eCollection 2016
  139. Du M, Prescott J, Kraft P, Han J, Giovannucci E, Hankinson SE, De Vivo I (2012) Physical activity, sedentary behavior, and leukocyte telomere length in women. Am J Epidemiol 175(5):414–422.  https://doi.org/10.1093/aje/kwr330 CrossRefPubMedPubMedCentralGoogle Scholar
  140. Dunham MA, Neumann AA, Fasching CL, Reddel RR (2000) Telomere maintenance by recombination in human cells. Nat Genet 26:447–450CrossRefPubMedGoogle Scholar
  141. Effros RB (2007) Telomerase induction in T cells: a cure for aging and disease? Exp Gerontol 42(5):416–420CrossRefPubMedGoogle Scholar
  142. Effros RB, Allsopp R, Chiu C-p, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV (1996) Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 10(8):F17–F22Google Scholar
  143. Effros RB, Dagarag M, Valenzuela HF (2003) In vitro senescence of immune cells. Exp Gerontol 38(11–12):1243–1249Google Scholar
  144. Egan ED, Collins K (2012) Biogenesis of telomerase ribonucleoproteins. RNA 18(10):1747–1759.  https://doi.org/10.1261/rna.034629.112 CrossRefPubMedPubMedCentralGoogle Scholar
  145. Ehrlenbach S, Willeit P, Kiechl S, Willeit J, Reindl M, Schanda K, Kronenberg F, Brandstätter A (2009) 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. Int J Epidemiol 38:1725–1734.  https://doi.org/10.1093/ije/dyp273 CrossRefPubMedGoogle Scholar
  146. Eisenberg DT, Hayes MG, Kuzawa CW (2012a) Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc Natl Acad Sci USA 26:10251–10256.  https://doi.org/10.1073/pnas.1202092109 CrossRefGoogle Scholar
  147. Eisenberg DT, Hayes MG, Kuzawa CW (2012b) Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc Natl Acad Sci USA 109(26):10251–10256.  https://doi.org/10.1073/pnas.1202092109 CrossRefPubMedGoogle Scholar
  148. Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E (2012) Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med 4:313–329CrossRefPubMedPubMedCentralGoogle Scholar
  149. Entringer S, Epel ES, Lin J, Buss C, Shahbaba B, Blackburn EH, Simhan HN, Wadhwa PD (2013) Maternal psychosocial stress during pregnancy is associated with newborn leukocyte telomere length. Am J Obstet Gynecol 208(134):e131–e137.  https://doi.org/10.1016/j.ajog.2012.11.033 CrossRefGoogle Scholar
  150. Epel ES (2009) Psychological and metabolic stress: a recipe for accelerated cellular aging? Hormones (Athens) 8:7–22CrossRefGoogle Scholar
  151. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM (2004) Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA 101:17312–17315CrossRefPubMedGoogle Scholar
  152. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn E (2006) Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology 31:277–287CrossRefPubMedGoogle Scholar
  153. Epel ES, Merkin SS, Cawthon R, Blackburn EH, Adler NE, Pletcher MJ, Seeman TE (2008) The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging (Albany NY) 1(1):81–88CrossRefGoogle Scholar
  154. Epel ES, Lin J, Dhabhar FS, Wolkowitz OM, Puterman E, Karan L, Blackburn EH (2010) Dynamics of telomerase activity in response to acute psychologicalstress. Brain Behav Immun 24:531–539.  https://doi.org/10.1016/j.bbi.2009.11.018 CrossRefPubMedGoogle Scholar
  155. Espejel S, Franco S, Sgura A, Gae D, Bailey SM, Taccioli GE, Blasco MA (2002a) Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. EMBO J 21(22):6275–6287CrossRefPubMedPubMedCentralGoogle Scholar
  156. Espejel S, Franco S, Rodríguez-Perales S, Bouffler SD, Cigudosa JC, Blasco MA (2002b) Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J 21(9):2207–2219CrossRefPubMedPubMedCentralGoogle Scholar
  157. Etheridge KT, Banik SS, Armbruster BN, Zhu Y, Terns RM, Terns MP, Counter CM (2002) The nucleolar localization domain of the catalytic subunit of human telomerase. J Biol Chem 277:24764–24770CrossRefPubMedGoogle Scholar
  158. Farhana L, Dawson MI, Fontana JA (2015) Down regulation of miR-202 modulates Mxd1 and Sin3A repressor complexes to induce apoptosis of pancreatic cancer cells. Cancer Biol Ther 16(1):115–124.  https://doi.org/10.4161/15384047.2014.987070 CrossRefPubMedPubMedCentralGoogle Scholar
  159. Farooqi AA, Mansoor Q, Alaaeddine N, Xu B (2018) MicroRNA regulation of Telomerase Reverse Transcriptase (TERT): micro machines pull strings of Papier-Mâché puppets. Int J Mol Sci 19(4):pii: E1051.  https://doi.org/10.3390/ijms19041051 CrossRefGoogle Scholar
  160. Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST, Ng HL, Kitchen CM, Yang OO, Harley CB, Effros RB (2008) Telomerase-basedpharmacologic enhancement of antiviral function of human CD8+ Tlymphocytes. J Immunol 181:7400–7406CrossRefPubMedPubMedCentralGoogle Scholar
  161. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J (1995) The RNA component of human telomerase. Science 269:1236CrossRefPubMedGoogle Scholar
  162. Feuerhahn S, Iglesias N, Panza A, Porro A, Lingner J (2010) TERRA biogenesis, turnover and implications for function. FEBS Lett 584:3812–3818.  https://doi.org/10.1016/j.febslet.2010.07.032 CrossRefPubMedGoogle Scholar
  163. Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Walston J, Kimura M, Aviv A (2007) Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol 165:14–21CrossRefPubMedGoogle Scholar
  164. Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Hardikar S, Aviv A (2011) Leukocyte telomere length and mortality in the Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci 66(4):421–429.  https://doi.org/10.1093/gerona/glq224 CrossRefPubMedGoogle Scholar
  165. Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, Salmon M, Rustin MH, Akbar AN (2005) Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175(12):8218–8225CrossRefPubMedGoogle Scholar
  166. Flynn RL, Centore RC, O’Sullivan RJ, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L (2011) TERRA, hnRNP A1, and DNA-PKcs Interactions at Human TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 471(7339):532–536.  https://doi.org/10.1038/nature09772 CrossRefPubMedPubMedCentralGoogle Scholar
  167. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, DeBenedictis G (2000) Inflamm-aging—an evolutionary perspective onimmunosenescence. Ann NY Acad Sci 908:244–254CrossRefPubMedGoogle Scholar
  168. Freitas-Simoes TM, Ros E, Sala-Vila A (2015) Nutrients, foods, dietary patterns and telomere length: Update of epidemiological studies and randomized trials. Curr Opin Genet Dev 33:1–9.  https://doi.org/10.1016/j.gde.2015.06.004 CrossRefGoogle Scholar
  169. Frenck RWJ Jr, Blackburn EH, Shannon KM (1998) The rate of telomeresequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA 95:5607–5610CrossRefPubMedGoogle Scholar
  170. Friedrich U, Griese E, Schwab M, Fritz P, Thon K, Klotz U (2000) Telomere length in different tissues of elderly patients. Mech Ageing Dev 119:89–99CrossRefPubMedGoogle Scholar
  171. Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM (2009) Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci USA 106:4360–4365CrossRefPubMedGoogle Scholar
  172. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, d’Adda di Fagagna F (2012) Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14:355–365.  https://doi.org/10.1038/ncb2466 CrossRefPubMedPubMedCentralGoogle Scholar
  173. García-Calzón S, Moleres A, Martinez-Gonzalez MA, Martinez JA, Zalba G, Marti A, Member G (2015a) Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population. Clin Nutr 34:694–699.  https://doi.org/10.1016/j.clnu.2014.07.015 CrossRefPubMedGoogle Scholar
  174. García-Calzón S, Zalba G, Ruiz-Canela M, Shivappa N, Hébert JR, Martínez JA, Fitó M, Gómez-Gracia E, Martínez-González MA, Marti A (2015b) Dietary inflammatory index and telomere length in subjects with a high cardiovascular disease risk from the PREDIMED-NAVARRA study: cross-sectional and longitudinal analyses over 5 y. Am J Clin Nutr 102(4):897–904.  https://doi.org/10.3945/ajcn.115.116863 CrossRefPubMedPubMedCentralGoogle Scholar
  175. Gardner JP, Li S, Srinivasan SR, Chen W, Kimura M, Lu X, Berenson GS, Aviv A (2005) Rise in insulin resistance is associated with escalated telomere attrition. Circulation 111(17):2171–2177CrossRefPubMedGoogle Scholar
  176. Gardner MP, Martin-Ruiz C, Cooper R, Hardy R, Sayer AA, Cooper C, Deary IJ, Gallacher J, Harris SE, Shiels PG, Starr JM, Kuh D, von Zglinicki T, Ben-Shlomo Y, Halcyon Study Team (2013) Telomere length and physical performance at older ages: an individual participant meta-analysis. PLoS One 8(7):e69526.  https://doi.org/10.1371/journal.pone.0069526 CrossRefPubMedPubMedCentralGoogle Scholar
  177. Gardner M, Bann D, Wiley L, Cooper R, Hardy R, Nitsch D, Martin-Ruiz C, Shiels P, Sayer AA, Barbieri M, Bekaert S, Bischoff C, Brooks-Wilson A, Chen W, Cooper C, Christensen K, De Meyer T, Deary I, Der G, Diez Roux A, Fitzpatrick A, Hajat A, Halaschek-Wiener J, Harris S, Hunt SC, Jagger C, Jeon HS, Kaplan R, Kimura M, Lansdorp P, Li C, Maeda T, Mangino M, Nawrot TS, Nilsson P, Nordfjall K, Paolisso G, Ren F, Riabowol K, Robertson T, Roos G, Staessen JA, Spector T, Tang N, Unryn B, van derHarst P, Woo J, Xing C, Yadegarfar ME, Park JY, Young N, Kuh D, von Zglinicki T, Ben-Shlomo Y, Halcyon Study Team (2014) Gender and telomere length: systematic review and meta-analysis. Exp Gerontol 51:15–27.  https://doi.org/10.1016/j.exger.2013.12.004 CrossRefPubMedGoogle Scholar
  178. Gaullier G, Miron S, Pisano S, Buisson R, Le Bihan YV, Tellier-Lebègue C, Messaoud W, Roblin P, Guimarães BG, Thai R, Giraud-Panis MJ, Gilson E, Le Du MH (2016) A higher-order entity formed by the flexible assembly of RAP1 with TRF2. Nucleic Acids Res 44(4):1962–1976.  https://doi.org/10.1093/nar/gkv1531 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Gebreab SY, Manna ZG, Khan RJ, Riestra P, Xu R, Davis SK (2017) Less than ideal cardiovascular health is associated with shorter leukocyte telomere length: the national health and nutrition examination surveys, 1999-2002. J Am Heart Assoc 6(2):pii: e004105.  https://doi.org/10.1161/JAHA.116.004105
  180. Gewin L, Galloway DA (2001) E box-dependent activation of telomerase by human papillomavirus type 16 E6 does not require induction of c-myc. J Virol 75(15):7198–7201CrossRefPubMedPubMedCentralGoogle Scholar
  181. Ghosh AS, Tergaonkar V (2010) Telomeres and inflammation: Rap1 joins the ends? Cell Cycle 9:3834–3835CrossRefPubMedGoogle Scholar
  182. Ghosh A, Saginc G, Leow SC, Khattar E, Shin EM, Yan TD, Wong M, Zhang Z, Li G, Sung WK, Zhou J, Chng WJ, Li S, Liu E, Tergaonkar V (2012) Telomerase directly regulates NF-kappaB-dependent transcription. Nat Cell Biol 14:1270–1281.  https://doi.org/10.1038/ncb2621 CrossRefPubMedGoogle Scholar
  183. Gizard F, Heywood EB, Findeisen HM, Zhao Y, Jones KL, Cudejko C, Post GR, Staels B, Bruemmer D (2011) Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler Thromb Vasc Biol 31:245–252.  https://doi.org/10.1161/ATVBAHA.110.219808 CrossRefPubMedGoogle Scholar
  184. Gladych M, Wojtyla A, Rubis B (2011) Human telomerase expression regulation. Biochem Cell Biol 89(4):359–376.  https://doi.org/10.1139/O11-037 CrossRefPubMedGoogle Scholar
  185. Goglin SE, Farzaneh-Far R, Epel ES, Lin J, Blackburn EH, Whooley MA (2016) Change in leukocyte telomere length predicts mortality in patients with stable coronary heart disease from the heart and soul study. PLoS One 11(10):e0160748.  https://doi.org/10.1371/journal.pone.0160748. eCollection 2016
  186. Gomez DE, Amando DG, Farina HG, Menna PL, Cerrudo CS, Ghiringhelli Alonso DF (2012) Telomere structure and telomerase in health and disease. Int J Oncol 41(5):1561–1569.  https://doi.org/10.3892/ijo.2012.1611
  187. Gonzalez OG, Assfalg R, Koch S, Schelling A, Meena JK, Kraus J, Lechel A, Katz SF, Benes V, Scharffetter-Kochanek K, Kestler HA, Günes C, Iben S (2014) Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions. Nat Commun 5:4599.  https://doi.org/10.1038/ncomms5599 CrossRefPubMedGoogle Scholar
  188. González-Suárez E, Goytisolo FA, Flores JM, Blasco MA (2003) Telomere dysfunction results in enhanced organismal sensitivity to the alkylating agent N-methyl-N-nitrosourea. Cancer Res 63(21):7047–7050PubMedGoogle Scholar
  189. Goytisolo FA, Blasco MA (2002) Many ways to telomere dysfunction: in vivo studies using mouse models. Oncogene 21(4):584–591CrossRefPubMedGoogle Scholar
  190. Goytisolo FA, Samper E, Martín-Caballero J, Finnon P, Herrera E, Flores JM, Bouffler SD, Blasco MA (2000) Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J Exp Med 192(11):1625–1636CrossRefPubMedPubMedCentralGoogle Scholar
  191. Goytisolo FA, Samper E, Edmonson S, Taccioli GE, Blasco MA (2001) The absence of the dna-dependent protein kinase catalytic subunit in mice results in anaphase bridges and in increased telomeric fusions with normal telomere length and G-strand overhang. Mol Cell Biol 21(11):3642–3651CrossRefPubMedPubMedCentralGoogle Scholar
  192. Graakjaer J, Bischoff C, Korsholm L, Holstebroe S, Vach W, Bohr VA, Christensen K, Kolvraa S (2003) The pattern of chromosome-specificvariations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life. Mech Ageing Dev 124:629–640CrossRefPubMedGoogle Scholar
  193. Graakjaer J, Londono-Vallejo JA, Christensen K, Kolvraa S (2006) The pattern of chromosome-specific variations in telomere length in humans shows signs of heritability and is maintained through life. Ann NY Acad Sci 1067:311–316CrossRefPubMedGoogle Scholar
  194. Graf M, Bonetti D, Lockhart A, Serhal K, Kellner V, Maicher A, Jolivet P, Teixeira MT, Luke B(2017) Telomere length determines TERRA and R-loop regulation through the cell cycle. Cell 170(1):72–85.e14.  https://doi.org/10.1016/j.cell.2017.06.006
  195. Greaves LC, Nooteboom M, Elson JL, Tuppen HA, Taylor GA, Commane DM, Arasaradnam RP, Khrapko K, Taylor RW, Kirkwood TB, Mathers JC, Turnbull DM (2014) Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. PLoS Genet 10(9):e1004620.  https://doi.org/10.1371/journal.pgen.1004620. eCollection
  196. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 33(6046):1109–1112.  https://doi.org/10.1126/science.1201940 CrossRefGoogle Scholar
  197. Greenberg RA, Allsopp RC, Chin L, Morin GB, DePinho RA (1998) Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene 16(13):1723–1730CrossRefPubMedGoogle Scholar
  198. Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337(6205):331–337CrossRefPubMedGoogle Scholar
  199. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514CrossRefPubMedGoogle Scholar
  200. Guan JZ, Guan WP, Maeda T, Makino N (2012) Different levels of hypoxia regulate telomere length and telomerase activity. Aging Clin Exp Res 24(3):213–217CrossRefPubMedGoogle Scholar
  201. Haendeler J, Hoffmann J, Brandes RP, Zeiher AM, Dimmeler S (2003) Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. Mol Cell Biol 23:4598–4610CrossRefPubMedPubMedCentralGoogle Scholar
  202. Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S (2004) Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res 94:768–775CrossRefPubMedGoogle Scholar
  203. Haendeler J, Dröse S, Büchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol 29:929–935.  https://doi.org/10.1161/ATVBAHA.109.185546 CrossRefPubMedGoogle Scholar
  204. Hahn WC, Weinberg RA (2002) Rules for making human tumor cells. N Engl J Med 347(20):1593–1603Google Scholar
  205. Hande MP, Samper E, Lansdorp P, Blasco MA (1999) Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol 144(4):589–601CrossRefPubMedPubMedCentralGoogle Scholar
  206. Hapangama DK, Kamal A, Saretzki G (2017) Implications of telomeres and telomerase in endometrial pathology. Hum Reprod Update 23(2):166–187PubMedGoogle Scholar
  207. Harley CB, Futcher AB, Greider CW (1990a) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460CrossRefGoogle Scholar
  208. Harley CB, Futcher AB, Greider CW (1990b) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460CrossRefGoogle Scholar
  209. Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM (2011) A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res 14(1):45–56.  https://doi.org/10.1089/rej.2010.1085 CrossRefPubMedPubMedCentralGoogle Scholar
  210. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC (1990) Telomere reduction in human colorectal carcinoma and with ageing. Nature 346(6287):866–868CrossRefPubMedGoogle Scholar
  211. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cellstrains. Exp Cell Res 25:585–621CrossRefGoogle Scholar
  212. Heidinger BJ, Blount JD, Boner W, Griffiths K, Metcalfe NB, Monaghan P (2012) Telomere length in early life predicts lifespan. Proc Natl Acad Sci USA 109:1743–1748CrossRefPubMedGoogle Scholar
  213. Hemann MT, Strong MA, Hao LY, Greider CW (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107(1):67–77CrossRefPubMedPubMedCentralGoogle Scholar
  214. Henderson ER, Blackburn EH (1989) An overhanging 3′ terminus is a conserved feature of telomeres. Mol Cell Biol 9(1):345–348CrossRefPubMedPubMedCentralGoogle Scholar
  215. Henson JD, Reddel RR (2010) Assaying and investigating alternative lengthening of telomeres activity in human cells and cancers. FEBS Lett 584(17):3800–3811.  https://doi.org/10.1016/j.febslet.2010.06.009 CrossRefPubMedGoogle Scholar
  216. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14:501–513CrossRefPubMedGoogle Scholar
  217. Herbig U, Ferreira M, Condel M, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311(5765):1257–1257Google Scholar
  218. Herrera E, Samper E, Martín-Caballero J, Flores JM, Lee HW, Blasco MA (1999) Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J 18(11):2950–2560CrossRefPubMedPubMedCentralGoogle Scholar
  219. Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J, Passos JF (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3:708.  https://doi.org/10.1038/ncomms1708 CrossRefPubMedPubMedCentralGoogle Scholar
  220. Hirashima K, Seimiya H (2015) Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo. Nucleic Acids Res 43(4):2022–2032.  https://doi.org/10.1093/nar/gkv063 CrossRefPubMedPubMedCentralGoogle Scholar
  221. Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M (1995) Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155(8):3711–3715PubMedGoogle Scholar
  222. Hochstrasser T, Marksteiner J, Humpel C (2012) Telomere length is age-dependent and reduced in monocytes of Alzheimer patients. Exp Gerontol 47(2):160–163.  https://doi.org/10.1016/j.exger.2011.11.012 CrossRefPubMedPubMedCentralGoogle Scholar
  223. Hodes RJ, Hathcock KS, Weng NP (2002) Telomeres in T and B cells. Nat Rev Immunol 2:699–706CrossRefPubMedGoogle Scholar
  224. Hoffmann J, Shmeleva EV, Boag SE, Fiser K, Bagnall A, Murali S, Dimmick I, Pircher H, Martin-Ruiz C, Egred M, Keavney B, von Zglinicki T, Das R, Todryk S, Spyridopoulos I (2015) Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients. Circ Res 116(1):87–98.  https://doi.org/10.1161/CIRCRESAHA.116.304393 CrossRefPubMedGoogle Scholar
  225. Honig LS, Schupf N, Lee JH, Tang MX, Mayeux R (2006) Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann Neurol 60(2):181–187CrossRefPubMedGoogle Scholar
  226. Hooijberg E, Ruizendaal JJ, Snijders PJ, Kueter EW, Walboomers JM, Spits H (2000) Immortalization of human CD8(+) T cell clones by ectopic expression of telomerase reverse transcriptase. J Immunol 165:4239–4245CrossRefPubMedGoogle Scholar
  227. Horikawa I, Cable PL, Afshari C, Barrett JC (1999) Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res 59:826–830PubMedGoogle Scholar
  228. Houben JM, Moonen HJ, van Schooten FJ, Hageman GJ (2008) Telomere length assessment: biomarker of chronic oxidative stress? Free Radic Biol Med 44:235–246CrossRefPubMedGoogle Scholar
  229. Hrdlickova R, Nehyba J, Bose HR Jr (2012) Alternatively spliced telomerase reverse transcriptase variants lacking telomerase activity stimulate cell proliferation. Mol Cell Biol 32:4283–4296CrossRefPubMedPubMedCentralGoogle Scholar
  230. Hsiao SJ, Smith S (2008) Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90(1):83–92CrossRefPubMedGoogle Scholar
  231. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ (2000) Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 14(22):2807–2812CrossRefPubMedPubMedCentralGoogle Scholar
  232. Hu C, Rai R, Huang C, Broton C, Long J, Xu Y, Xue J, Lei M, Chang S, Chen Y (2017) Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Res 27(12):1485–1502.  https://doi.org/10.1038/cr.2017.144 CrossRefPubMedPubMedCentralGoogle Scholar
  233. Hulsegge G, Herber-Gast GC, Spijkerman AM, Susan H, Picavet J, van der Schouw YT, Bakker SJ, Gansevoort RT, Dollé ME, Smit HA, Monique Verschuren WM (2016) Obesity and age-related changes in markers of oxidative stress and inflammation across four generations. Obesity (Silver Spring) 24(6):1389–1396.  https://doi.org/10.1002/oby.21515 CrossRefGoogle Scholar
  234. Huzen J, van der Harst P, de Boer RA, Lesman-Leegte I, Voors AA, van Gilst WH, Samani NJ, Jaarsma T, van Veldhuisen DJ (2010) Telomere length and psychological well-being in patients with chronic heart failure. Age Ageing 39(2):223–227.  https://doi.org/10.1093/ageing/afp256 CrossRefPubMedGoogle Scholar
  235. Iannilli F, Zalfa F, Gartner A, Bagni C, Dotti CG (2013) Cytoplasmic TERT associates to RNA granules in fully mature neurons: role in the translational control of the cell cycle inhibitor p15INK4B. PLoS One 8:e66602.  https://doi.org/10.1371/journal.pone.0066602 CrossRefPubMedPubMedCentralGoogle Scholar
  236. Ishaq A, Hanson PS, Morris CM, Saretzki G (2016) Telomerase activity is downregulated early during human brain development. Genes (Basel) 7(6):pii: E27.  https://doi.org/10.3390/genes7060027
  237. Jacobs TL, Epel ES, Lin J, Blackburn EH, Wolkowitz OM, Bridwell DA, Zanesco AP, Aichele SR, Sahdra BK, MacLean KA, King BG, Shaver PR, Rosenberg EL, Ferrer E, Wallace BA, Saron CD (2011) Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology 36(5):664–681.  https://doi.org/10.1016/j.psyneuen.2010.09.010 CrossRefPubMedGoogle Scholar
  238. Jakob S, Haendeler J (2007) Molecular mechanisms involved in endothelial cell aging: role of telomerase reverse transcriptase. Z Gerontol Geriatr 40(5):334–338CrossRefPubMedGoogle Scholar
  239. Jung HM, Phillips BL, Chan EK (2014) miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ. Mol Cancer 3:80.  https://doi.org/10.1186/1476-4598-13-80 CrossRefGoogle Scholar
  240. Jung SJ, Kim DS, Park WJ, Lee H, Choi IJ, Park JY, Lee JH (2017) Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer. Oncol Lett 14(2):1609–1614.  https://doi.org/10.3892/ol.2017.6284 CrossRefPubMedPubMedCentralGoogle Scholar
  241. Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, Gonos ES, Thrasivoulou C, Saffrey MJ, Cameron K, von Zglinicki T (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11(6):996–1004.  https://doi.org/10.1111/j.1474-9726.2012.00870.x CrossRefPubMedPubMedCentralGoogle Scholar
  242. Jurk D, Wilson C, Passos JF, Oakley F, Correia-Melo C, Greaves L, Saretzki G, Fox C, Lawless C, Anderson R, Hewitt G, Pender SL, Fullard N, Nelson G, Mann J, van de Sluis B, Mann DA, von Zglinicki T (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 2:4172.  https://doi.org/10.1038/ncomms5172
  243. Kaminski MM, Sauer SW, Klemke CD, Süss D, Okun JG, Krammer PH, Gülow K (2010) Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol 184(9):4827–4841.  https://doi.org/10.4049/jimmunol.0901662 CrossRefPubMedGoogle Scholar
  244. Kananen L, Surakka I, Pirkola S, Suvisaari J, Lönnqvist J, Peltonen L, Ripatti S, Hovatta I (2010) Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls. PLoS One 5(5):e10826.  https://doi.org/10.1371/journal.pone.0010826 CrossRefPubMedPubMedCentralGoogle Scholar
  245. Kang SS, Kwon T, Kwon DY, Do SI (1999) Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem 274:13085–13090CrossRefPubMedGoogle Scholar
  246. Kark JD, Goldberger N, Kimura M, Sinnreich R, Aviv A (2012) Energy intake and leukocyte telomere length in young adults. Am J Clin Nutr 95(2):479–487.  https://doi.org/10.3945/ajcn.111.024521 CrossRefPubMedPubMedCentralGoogle Scholar
  247. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T (1999) p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283:1321–1325CrossRefPubMedGoogle Scholar
  248. Karlseder J, Smogorzewska A, de Lange T (2002) Senescence induced by altered telomere state, not telomere loss. Science 295(5564):2446–2449CrossRefPubMedGoogle Scholar
  249. Kaszubowska L (2008) Telomere shortening and ageing of the immune system. J Physiol Pharmacol 59(Suppl 9):169–186PubMedGoogle Scholar
  250. Katzenellenbogen RA (2017) Activation of telomerase by HPVs. Virus Res 231:50–55.  https://doi.org/10.1016/j.virusres.11.003 CrossRefPubMedGoogle Scholar
  251. Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA, Reddel RR (2012) Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep 13:52–59CrossRefGoogle Scholar
  252. Kawauchi K, Ihjima K, Yamada O (2005) IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3’-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol 174:5261–5269CrossRefPubMedGoogle Scholar
  253. Keefe DL (2017) Telomeres, reproductive aging, and genomic instability during early development. Eur J Clin Nutr 71(2):151–158.  https://doi.org/10.1038/ejcn.2016.149 CrossRefGoogle Scholar
  254. Kelleher C, Kurth I, Lingner J (2005) Human protection of telomeres 1 (POT1) is anegative regulator of telomerase activity in vitro. Mol Cell Biol 25:808–818CrossRefPubMedPubMedCentralGoogle Scholar
  255. Kharbanda S, Kumar V, Dhar S, Pandey P, Chen C, Majumder P, Yuan ZM, Whang Y, Strauss W, Pandita TK, Weaver D, Kufe D (2000) Regulation of the hTERT telomerase catalytic subunit by the c-Abl tyrosine kinase. Curr Biol 10(10):568–575CrossRefPubMedGoogle Scholar
  256. Kiecolt-Glaser JK, Gouin JP, Weng NP, Malarkey WB, Beversdorf DQ, Glaser R (2011) Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. Psychosom Med 73:16–22CrossRefPubMedGoogle Scholar
  257. Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E (2013) Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: a randomized controlled trial. Brain Behav Immun 28:16–24.  https://doi.org/10.1016/j.bbi.2012.09.004 CrossRefPubMedGoogle Scholar
  258. Kim W, Shay JW (2018) Long-range telomere regulation of gene expression: telomere looping and telomere position effect over long distances (TPE-OLD). Differentiation 99:1–9.  https://doi.org/10.1016/j.diff.2017.11.005 CrossRefPubMedGoogle Scholar
  259. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association ofhuman telomerase activity with immortal cells and cancer. Science 266:2011–2015CrossRefGoogle Scholar
  260. Kim SH, Kaminker P, Campisi J (1999) TIN2, a new regulator of telomere length in human cells. Nat Genet 23(4):405–412CrossRefPubMedPubMedCentralGoogle Scholar
  261. Kim SH, Beausejour C, Davalos AR, Kaminker P, Heo SJ, Campisi J (2004) TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem 279:43799–43804CrossRefPubMedGoogle Scholar
  262. Kim W, Ludlow AT, Min J, Robin JD, Stadler G, Mender I, Lai TP, Zhang N, Wright WE, Shay JW (2016) Regulation of the human telomerase gene TERT by Telomere Position Effect-Over Long Distances (TPE-OLD): implications for aging and cancer. PLoS Biol 14(12):e2000016.  https://doi.org/10.1371/journal.pbio.2000016. eCollection
  263. Kimura M, Hjelmborg JV, Gardner JP, Bathum L, Brimacombe M, Lu X, Christiansen L, Vaupel JW, Aviv A, Christensen K (2008a) Telomere length and mortality: a study of leukocytes in elderly Danish twins. Am J Epidemiol 167:799–806.  https://doi.org/10.1093/aje/kwm380 CrossRefPubMedPubMedCentralGoogle Scholar
  264. Kimura M, Cherkas LF, Kato BS et al (2008b) Offspring’s leukocyte telomere length, paternal age, and telomere elongation in sperm. PLoS Genet 4:e37.  https://doi.org/10.1371/journal.pgen.0040037 CrossRefPubMedPubMedCentralGoogle Scholar
  265. Kimura M, Gazitt Y, Cao X, Zhao X, Lansdorp PM, Aviv A (2010) Synchrony of telomere length among hematopoietic cells. Exp Hematol 38:854–859.  https://doi.org/10.1016/j.exphem.2010.06.010 CrossRefPubMedPubMedCentralGoogle Scholar
  266. Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD (2017) The clinical potential of senolytic drugs. J Am Geriatr Soc 65(10):2297–2301.  https://doi.org/10.1111/jgs.14969 CrossRefPubMedPubMedCentralGoogle Scholar
  267. Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88CrossRefPubMedGoogle Scholar
  268. Klingelhutz AJ, Roman A (2012) Cellular transformation by human papillomaviruses: lessons learned by comparing high- and low-risk viruses. Virology 424(2):77–98.  https://doi.org/10.1016/j.virol.2011.12.018 CrossRefPubMedPubMedCentralGoogle Scholar
  269. Klingelhutz AJ, Foster SA, McDougall JK (1996) Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature:38079–38082Google Scholar
  270. Kordinas V, Ioannidis A, Chatzipanagiotou S (2016) The telomere/telomerase system in chronic inflammatory diseases. Cause or effect? Genes (Basel) 7(9):pii: E60.  https://doi.org/10.3390/genes7090060
  271. Kovalenko OA, Kaplunov J, Herbig U, Detoledo S, Azzam EI, Santos JH (2010) Expression of (NES-) hTERT in cancer cells delays cell cycle progression and increases sensitivity to genotoxic stress. PLoS One 5(5):e10812.  https://doi.org/10.1371/journal.pone.0010812 CrossRefPubMedPubMedCentralGoogle Scholar
  272. Krauss J, Farzaneh-Far R, Puterman E, Na B, Lin J, Epel E, Blackburn E, Whooley MA (2011) Physical fitness and telomere length in patients with coronary heart disease: findings from the Heart and Soul Study. PLoS One 6(11):e26983.  https://doi.org/10.1371/journal.pone.0026983 CrossRefPubMedPubMedCentralGoogle Scholar
  273. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479.  https://doi.org/10.1101/gad.1971610 CrossRefPubMedPubMedCentralGoogle Scholar
  274. Kurz DJ, Hong Y, Trivier E, Huang HL, Decary S, Zang GH, Lüscher TF, Erusalimsky JD (2003) Fibroblast growth factor-2, but not vascular endothelial growth factor, up-regulates telomerase activity in human endothelial cells. Arterioscler Thromb Vasc Biol 23(5):748–754CrossRefPubMedGoogle Scholar
  275. Kyo S, Takakura M, Kohama T, Inoue M (1997) Telomerase activity in human endometrium. Cancer Res 57:610–614PubMedGoogle Scholar
  276. Kyo S, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, Orimo A, Inoue M (1999) Estrogen activates telomerase. Cancer Res 59:5917–5921PubMedGoogle Scholar
  277. Lansdorp P (1995) Telomere length and proliferation potential of hematopoietic stem cells. J Cell Sci 108(Pt 1):1–6PubMedGoogle Scholar
  278. Lansdorp PM, Poon S, Chavez E, Dragowska V, Zijlmans M, Bryan T, Reddel R, Egholm M, Bacchetti S, Martens U (1997) Telomeres in the haemopoietic system. Ciba Found Symp 211:209–218 discussion 219-22PubMedGoogle Scholar
  279. Lavretsky H, Epel ES, Siddarth P, Nazarian N, Cyr NS, Khalsa DS, Lin J, Blackburn E, Irwin MR (2013) A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity. Int J Geriatr Psychiatry 28(1):57–65.  https://doi.org/10.1002/gps.3790 CrossRefPubMedGoogle Scholar
  280. Le Saux CJ, Davy P, Brampton C, Ahuja SS, Fauce S, Shivshankar P, Nguyen H, Ramaseshan M, Tressler R, Pirot Z, Harley CB, Allsopp R (2013) A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis. PLoS ONE 8:e58423CrossRefPubMedPubMedCentralGoogle Scholar
  281. Le PN, Maranon DG, Altina NH, Battaglia CL, Bailey SM (2013) TERRA, hnRNP A1, and DNA-PKcs interactions at human telomeres. Front Oncol 3:91.  https://doi.org/10.3389/fonc.2013.00091. eCollection 2013
  282. Lee JH, Cheng R, Honig LS, Feitosa M, Kammerer CM, Kang MS, Schupf N, Lin SJ, Sanders JL, Bae H, Druley T, Perls T, Christensen K, Province M, Mayeux R (2014a) Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: the Long Life Family Study. Front Genet 4:310.  https://doi.org/10.3389/fgene.2013.00310. eCollection 2013
  283. Lee JH, Lee YS, Jeong SA, Khadka P, Roth J, Chung IK (2014b) Catalytically active telomerase holoenzyme is assembled in the dense fibrillar component of the nucleolus during S phase. Histochem Cell Biol 141(2):137–152.  https://doi.org/10.1007/s00418-013-1166-x CrossRefPubMedGoogle Scholar
  284. Leger KA, Charles ST, Almeida DM (2018) Let it go: lingering negative affect in response to daily stressors is associated with physical health years later. Psychol Sci 1:956797618763097.  https://doi.org/10.1177/0956797618763097 CrossRefGoogle Scholar
  285. Lei M, Podell ER, Cech TR (2004) Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol 11:1223–1229CrossRefPubMedGoogle Scholar
  286. Lengacher CA, Reich RR, Kip KE, Barta M, Ramesar S, Paterson CL, Moscoso MS, Carranza I, Budhrani PH, Kim SJ, Park HY, Jacobsen PB, Schell MJ, Jim HS, Post-White J, Farias JR, Park JY (2014) Influence of mindfulness-based stress reduction (MBSR) on telomerase activity in women with breast cancer (BC). Biol Res Nurs 16(4):438–447.  https://doi.org/10.1177/1099800413519495 CrossRefPubMedPubMedCentralGoogle Scholar
  287. Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB (1992) Telomere end-replication problem and cell aging. J Mol Biol 225:951–960CrossRefPubMedGoogle Scholar
  288. Li JS, Miralles Fusté J, Simavorian T, Bartocci C, Tsai J, Karlseder J, Lazzerini Denchi E (2017) TZAP: a telomere-associated protein involved in telomere length control. Science 355(6325):638–641.  https://doi.org/10.1126/science.aah6752 CrossRefPubMedPubMedCentralGoogle Scholar
  289. Lin J, Jin R, Zhang B, Yang PX, Chen H, Bai YX, Xie Y, Huang C, Huang J (2007) Characterization of a novel effect of hPinX1 on hTERT nucleolar localization. Biochem Biophys Res Commun 353(4):946–952CrossRefPubMedGoogle Scholar
  290. Lin Y, Damjanovic A, Metter EJ, Nguyen H, Truong T, Najarro K, Morris C, Longo DL, Zhan M, Ferrucci L, Hodes RJ, Weng NP (2015) Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions. Clin Sci (Lond) 128(6):367–377.  https://doi.org/10.1042/CS20140481 CrossRefGoogle Scholar
  291. Lincz LF, Mudge LM, Scorgie FE, Sakoff JA, Hamilton CS, Seldon M (2008) Quantification of hTERT splice variants in melanoma by SYBR green real-time polymerase chain reaction indicates a negative regulatory role for the beta deletion variant. Neoplasia 10:1131–1137CrossRefPubMedPubMedCentralGoogle Scholar
  292. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR (1997) Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276(5312):561–567CrossRefPubMedGoogle Scholar
  293. Listerman I, Sun J, Gazzaniga FS, Lukas JL, Blackburn EH (2013) The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis. Cancer Res 73(9):2817–2828.  https://doi.org/10.1158/0008-5472.CAN-12-3082 CrossRefPubMedPubMedCentralGoogle Scholar
  294. Liu JP (1999) Studies of the molecular mechanisms in the regulation of telomerase activity. FASEB 13:2091–2104CrossRefGoogle Scholar
  295. Liu K, Schoonmaker MM, Levine BL, June HC, Hodes RJ, Weng N (1999) Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci USA 96:5147CrossRefPubMedGoogle Scholar
  296. Liu K, Hodes RJ, Weng N (2001) Cutting edge: telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation. J Immunol 166:4826–4830CrossRefPubMedGoogle Scholar
  297. Liu D, O’Connor MS, Qin J, Songyang Z (2004) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 279:51338–51342CrossRefPubMedGoogle Scholar
  298. Liu X, Dakic A, Zhang Y, Dai Y, Chen R, Schlegel R (2009) HPV E6 protein interacts physically and functionally with the cellular telomerase complex. Proc Natl Acad Sci USA 106(44):18780–18785.  https://doi.org/10.1073/pnas.0906357106 CrossRefPubMedGoogle Scholar
  299. Liu JP, Chen SM, Cong YS, Nicholls C, Zhou SF, Tao ZZ, Li H (2010) Regulation of telomerase activity by apparently opposing elements. Ageing Res Rev 9:245–256CrossRefPubMedGoogle Scholar
  300. Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR, Frye RL, Weyand CM (2000) Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101(25):2883–1888CrossRefPubMedGoogle Scholar
  301. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217.  https://doi.org/10.1016/j.cell.2013.05.039 CrossRefPubMedPubMedCentralGoogle Scholar
  302. Loprinzi PD, Loenneke JP (2018) Leukocyte telomere length and mortality among U.S. adults: effect modification by physical activity behaviour. J Sports Sci 36(2):213–219.  https://doi.org/10.1080/02640414.2017.1293280 CrossRefPubMedGoogle Scholar
  303. Lorenz M, Saretzki G, Sitte N, Metzkow S, von Zglinicki T (2001) BJ fibroblasts display high antioxidant capacity and slow telomere shortening independent of hTERT transfection. Free Radic Biol Med 31:824–831CrossRefPubMedGoogle Scholar
  304. Ludlow AT, Zimmerman JOB, Witkowski S, Hearn JW, Hatfield BD, Roth SM (2008) Relationship between physical activity level, telomere length, and telomerase activity. Med Sci Sports Exerc 40(10):1764–1771.  https://doi.org/10.1249/MSS.0b013e31817c92aa
  305. Ludlow AT, Witkowski S, Marshall MR, Wang J, Lima LC, Guth LM, Spangenburg EE, Roth SM (2012) Chronic exercise modifies age-related telomere dynamics in a tissue-specific fashion. J Gerontol 67(9):911–926.  https://doi.org/10.1093/gerona/gls002 CrossRefGoogle Scholar
  306. Luke B, Panza A, Redon S, Iglesias N, Li Z, Lingner J (2008) The Rat1p 5′ to 3′ exonuclease degrades telomeric repeat-containing RNA and promotes telomere elongation in Saccharomyces cerevisiae. Mol Cell 32:465–477.  https://doi.org/10.1016/j.molcel.2008.10.019 CrossRefPubMedGoogle Scholar
  307. Ma D, Zhu W, Hu S, Yu X, Yang Y (2013) Association between oxidative stress and telomere length in Type 1 and Type 2 diabetic patients. J Endocrinol Invest 36(11):1032–1037.  https://doi.org/10.3275/9036 CrossRefPubMedGoogle Scholar
  308. Maicher A, Kastner L, Dees M, Luke B (2012) Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence. Nucleic Acids Res 40(14):6649–6659.  https://doi.org/10.1093/nar/gks358 CrossRefPubMedPubMedCentralGoogle Scholar
  309. Makarov VL, Hirose Y, Langmore JP (1997) Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 88(5):657–666CrossRefPubMedGoogle Scholar
  310. Mangerich A, Burkle A (2012) Pleiotropic cellular functions of PARP1 in longevityand aging: genome maintenance meets inflammation. Oxid Med Cell Longev 2012:321653.  https://doi.org/10.1155/2012/321653 CrossRefPubMedPubMedCentralGoogle Scholar
  311. Mangino M, Hwang SJ, Spector TD, Hunt SC, Kimura M, Fitzpatrick AL, Christiansen L, Petersen I, Elbers CC, Harris T, Chen W, Srinivasan SR, Kark JD, Benetos A, El Shamieh S, Visvikis-Siest S, Christensen K, Berenson GS, Valdes AM, Viñuela A, Garcia M, Arnett DK, Broeckel U, Province MA, Pankow JS, Kammerer C, Liu Y, Nalls M, Tishkoff S, Thomas F, Ziv E, Psaty BM, Bis JC, Rotter JI, Taylor KD, Smith E, Schork NJ, Levy D, Aviv A (2012) Genome-wide metaanalysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. Hum Mol Genet 21:5385–5394.  https://doi.org/10.1093/hmg/dds382 CrossRefPubMedPubMedCentralGoogle Scholar
  312. Martínez P, Blasco MA (2011) Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer 11(3):161–176.  https://doi.org/10.1038/nrc3025 CrossRefPubMedGoogle Scholar
  313. Martínez P, Blasco MA (2017) Telomere-driven diseases and telomere-targeting therapies. J Cell Biol 216(4):875–887.  https://doi.org/10.1083/jcb.201610111 CrossRefPubMedPubMedCentralGoogle Scholar
  314. Martinez P, Thanasoula M, Carlos AR, Gomez-Lopez G, Tejera AM, Schoeftner S, Dominguez O, Pisano DG, Tarsounas M, Blasco MA (2010) Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat Cell Biol 12:768–780.  https://doi.org/10.1038/ncb2081 CrossRefPubMedPubMedCentralGoogle Scholar
  315. 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):287–290CrossRefPubMedPubMedCentralGoogle Scholar
  316. 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):174–180CrossRefPubMedGoogle Scholar
  317. Martín-Rivera L, Herrera E, Albar JP, Blasco MA (1998 Sep 1) Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc Natl Acad Sci U S A 95(18):10471–10476Google Scholar
  318. Matsumoto C, Jiang Y, Emathinger J, Quijada P, Nguyen N, De La Torre A, Moshref M, Nguyen J, Levinson AB, Shin M, Sussman MA, Hariharan N (2018) Short telomeres induce p53 and autophagy and modulate age-associated changes in cardiac progenitor cell fate. Stem Cells.  https://doi.org/10.1002/stem.2793
  319. Mazidi M, Kengne AP, Sahebkar A, Banach M (2018) Telomere length is associated with cardiometabolic factors in US adults. Angiology 69(2):164–169.  https://doi.org/10.1177/0003319717712860 CrossRefPubMedGoogle Scholar
  320. Melk A, Tegtbur U, Hilfiker-Kleiner D, Eberhard J, Saretzki G, Eulert C, Kerling A, Nelius AK, Hömme M, Strunk D, Berliner D, Röntgen P, Kück M, Bauersachs J, Hilfiker A, Haverich A, Bara C, Stiesch M (2014) Improvement of biological age by physical activity. Int J Cardiol S0167-5273(14):01446–01446.  https://doi.org/10.1016/j.ijcard.2014.07.236 CrossRefGoogle Scholar
  321. Min KB, Min JY (2017) Association between leukocyte telomere length and serum carotenoid in US adults. Eur J Nutr 56(3):1045–1052.  https://doi.org/10.1007/s00394-016-1152-x CrossRefPubMedGoogle Scholar
  322. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105(13):1541–1544CrossRefPubMedGoogle Scholar
  323. Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW, Piaggio G, Sacchi A, Pontecorvi A, Bacchetti S, Farsetti A (2000) Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol Cell Biol 20:3764–3771CrossRefPubMedPubMedCentralGoogle Scholar
  324. Mons U, Müezzinler A, Schöttker B, Dieffenbach AK, Butterbach K, Schick M, Peasey A, De Vivo I, Trichopoulou A, Boffetta P, Brenner H (2017) Leukocyte telomere length and all-cause, cardiovascular disease, and cancer mortality: results from individual-participant-data meta-analysis of 2 large prospective cohort studies. Am J Epidemiol 185(12):1317–1326.  https://doi.org/10.1093/aje/kww210 CrossRefPubMedPubMedCentralGoogle Scholar
  325. Montero JJ, Lopez de Silanes I, Grana O, Blasco MA (2016) Telomeric RNAs are essential tomaintain telomeres. Nat Commun 7:12534.  https://doi.org/10.1038/ncomms12534 CrossRefPubMedPubMedCentralGoogle Scholar
  326. Moosig F, Csernok E, Wang G, Gross WL (1998) Costimulatory molecules in Wegener’s granulomatosis (WG): lack of expression of CD28 and preferential up-regulation of its ligands B7-1 (CD80) and B7-2 (CD86) on T cells. Clin Exp Immunol 114(1):113–118CrossRefPubMedPubMedCentralGoogle Scholar
  327. Moro-García MA, Mayo JC, Sainz RM, Alonso-Arias R (2018) Influence of inflammation in the process of T lymphocyte differentiation: proliferative, metabolic, and oxidative changes. Front Immunol 9:339.  https://doi.org/10.3389/fimmu.2018.00339. eCollection 2018
  328. Morris GE (2008) The Cajal body. Biochim Biophys Acta 1783(11):2108–2115.  https://doi.org/10.1016/j.bbamcr.2008.07.016 CrossRefPubMedGoogle Scholar
  329. Morrison SJ, Prowse KR, Ho P, Weissman IL (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5(3):207–216CrossRefPubMedPubMedCentralGoogle Scholar
  330. Muezzinler A, Mons U, Dieffenbach AK, Butterbach K, Saum KU, Schick M, Stammer H, Boukamp P, Holleczek B, Stegmaier C, Brenner H (2016) Body mass index and leukocyte telomere length dynamics among older adults: results from the ESTHER cohort. Exp Gerontol 74:1–8.  https://doi.org/10.1016/j.exger.2015.11.019 CrossRefPubMedGoogle Scholar
  331. Mullins MR, Rajavel M, Hernandez-Sanchez W, de la Fuente M, Biendarra SM, Harris ME, Taylor DJ (2016) POT1-TPP1 binding and unfolding of telomere DNA discriminates against structural polymorphism. J Mol Biol 428(13):2695–2708.  https://doi.org/10.1016/j.jmb.2016.04.031 CrossRefPubMedPubMedCentralGoogle Scholar
  332. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959CrossRefGoogle Scholar
  333. Nakamura AJ, Chiang YJ, Hathcock KS, Horikawa I, Sedelnikova OA, Hodes RJ, Bonner WM (2008) Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence. Epigenetics Chromatin 1(1):6.  https://doi.org/10.1186/1756-8935-1-6 CrossRefPubMedPubMedCentralGoogle Scholar
  334. Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR (2012) The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492:285–289.  https://doi.org/10.1038/nature11648 CrossRefPubMedPubMedCentralGoogle Scholar
  335. Nandakumar J, Cech TR (2013) Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol 14(2):69–82.  https://doi.org/10.1038/nrm/3505
  336. Nawrot TS, Staessen JA, Gardner JP, Aviv A (2004) Telomere length and possible link to X chromosome. Lancet 363:507–510CrossRefPubMedGoogle Scholar
  337. Nawrot TS, Staessen JA, Holvoet P, Struijker-Boudier HA, Schiffers P, Van Bortel LM, Fagard RH, Gardner JP, Kimura M, Aviv A (2010) Telomere length and its associations with oxidized-LDL, carotid artery distensibility and smoking. Front Biosci (Elite Ed) 2:1164–1168Google Scholar
  338. Needham BL, Fernandez JR, Lin J, Epel ES, Blackburn EH (2012) Socioeconomic status and cell aging in children. Soc Sci Med 74(12):1948–1951.  https://doi.org/10.1016/j.socscimed.2012.02.019 CrossRefPubMedGoogle Scholar
  339. Nergadze SG, Farnung BO, Wischnewski H, Khoriauli L, Vitelli V, Chawla R, Giulotto E, Azzalin CM (2009) CpG-island promoters drive transcription of human telomeres. RNA 15:2186–2194.  https://doi.org/10.1261/rna.1748309 CrossRefPubMedPubMedCentralGoogle Scholar
  340. Njajou OT, Cawthon RM, Damcott CM, Wu SH, Ott S, Garant MJ, Blackburn EH, Mitchell BD, Shuldiner AR, Hsueh WC (2007) Telomere length is paternally inherited and is associated with parental lifespan. Proc Natl Acad Sci USA 104:12135–12139CrossRefPubMedGoogle Scholar
  341. Nordfjäll K, Svenson U, Norrback KF, Adolfsson R, Lenner P, Roos G (2009) The individual blood cell telomere attrition rate is telomere length dependent. PLoS Genet 5(2):e1000375.  https://doi.org/10.1371/journal.pgen.1000375 CrossRefPubMedPubMedCentralGoogle Scholar
  342. Nordfjäll K, Svenson U, Norrback K-F, Adolfsson R, Roos G (2010) Large-scale parentchild comparison confirms a strong paternal influence on telomere length. Eur J Hum Genet 18:385–389.  https://doi.org/10.1038/ejhg.2009.178 CrossRefPubMedGoogle Scholar
  343. Norrback KF, Hultdin M, Dahlenborg K, Osterman P, Carlsson R, Roos G (2001) Telomerase regulation and telomere dynamics in germinal centers. Eur J Haematol 67:309–317CrossRefPubMedGoogle Scholar
  344. Nordfjäll K, Larefalk A, Lindgren P, Holmberg D, Roos G (2005 Nov 8) Telomere length and heredity: indications of paternal inheritance. Proc Natl Acad Sci U S A 102(45):16374–16378Google Scholar
  345. Nzietchueng R, Elfarra M, Nloga J, Labat C, Carteaux JP, Maureira P, Lacolley P, Villemot JP, Benetos A (2011) Telomere length in vascular tissues from patients with atherosclerotic disease. J Nutr Health Aging 15(2):153–156CrossRefPubMedGoogle Scholar
  346. Ogami M, Ikura Y, Ohsawa M, Matsuo T, Kayo S, Yoshimi N, Hai E, Shirai N, Ehara S, Komatsu R, Naruko T, Ueda M (2004) Telomere shortening in human coronary artery diseases. Arterioscler Thromb Vasc Biol 24(3):546–550Google Scholar
  347. Ogawa EF, Leveille SG, Wright JA, Shi L, Camhi SM, You T (2017) Physical activity domains/recommendations and leukocyte telomere length in U.S. adults. Med Sci Sports Exerc 49(7):1375–1382.  https://doi.org/10.1249/MSS.0000000000001253 CrossRefPubMedGoogle Scholar
  348. Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, Day CP, Burt A, Palmer A, Anstee QM, Grellscheid SN, Hoeijmakers JHJ, Barnhoorn S, Mann DA, Bird TG, Vermeij WP, Kirkland JL, Passos JF, von Zglinicki T, Jurk D (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691.  https://doi.org/10.1038/ncomms15691 CrossRefPubMedPubMedCentralGoogle Scholar
  349. Oh S, Song YH, Yim J, Kim TK (2000) Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene 19(11):1485–1490CrossRefPubMedGoogle Scholar
  350. Olovnikov AM (1971) Principle of marginotomy in template synthesis ofpolynucleotides. Dokl Akad Nauk USSR 201:1496–1499Google Scholar
  351. Ornish D, Lin J, Daubenmier J, Weidner G, Epel E, Kemp C, Magbanua MJ, Marlin R, Yglecias L, Carroll PR, Blackburn EH (2008) Increased telomeraseactivity and comprehensive lifestyle changes: a pilot study. Lancet Oncol 9:1048–1057.  https://doi.org/10.1016/S1470-2045(08)70234-1 CrossRefPubMedGoogle Scholar
  352. Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJ, Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR, Blackburn EH (2013) Effect of comprehensive lifestyle changes ontelomerase activity and telomere length in men with biopsy-proven low-riskprostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol 14:1112–1120.  https://doi.org/10.1016/S1470-2045(13)70366-8 CrossRefPubMedGoogle Scholar
  353. Osler M, Bendix L, Rask L, Rod NH (2016) Stressful life events and leucocyte telomere length: do lifestyle factors, somatic and mental health, or low grade inflammation mediate this relationship? Results from a cohort of Danish men born in 1953. Brain Behav Immun 58:248–253.  https://doi.org/10.1016/j.bbi.2016.07.154 CrossRefPubMedGoogle Scholar
  354. Ouellette MM, Liao M, Herbert BS, Johnson M, Holt SE, Liss HS, Shay JW, Wright WE (2000) Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J Biol Chem 275(14):10072–10076CrossRefPubMedGoogle Scholar
  355. Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu RevGenet 42:301–334.  https://doi.org/10.1146/annurev.genet.41.110306.130350 CrossRefGoogle Scholar
  356. Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TBL, von Zglinicki T (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347.  https://doi.org/10.1038/msb.2010.5 CrossRefPubMedPubMedCentralGoogle Scholar
  357. Pavanello S, Hoxha M, Dioni L, Bertazzi PA, Snenghi R, Nalesso A, Ferrara SD, Montisci M, Baccarelli A (2011) Shortened telomeres in individuals with abuse in alcohol consumption. Int J Cancer 129:983–992.  https://doi.org/10.1002/ijc.25999 CrossRefPubMedPubMedCentralGoogle Scholar
  358. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7:161–167CrossRefPubMedGoogle Scholar
  359. Petersen S, Saretzki G, von Zglinicki T (1998) Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res 239:152–160CrossRefPubMedGoogle Scholar
  360. Pfeiffer V, Lingner J (2012) TERRA promotes telomere shortening through exonuclease 1-mediated resection of chromosome ends. PLoS Genet 8(6):e1002747.  https://doi.org/10.1371/journal.pgen.1002747 CrossRefPubMedPubMedCentralGoogle Scholar
  361. Pickett HA, Cesare AJ, Johnston RL, Neumann AA, Reddel RR (2009) Control of telomere length by a trimming mechanism that involves generation of t-circles. EMBO J 28:799–809.  https://doi.org/10.1038/emboj.2009.42 CrossRefPubMedPubMedCentralGoogle Scholar
  362. Pickett HA, Henson JD, Au AY, Neumann AA, Reddel RR (2011) Normal mammalian cells negatively regulate telomere length by telomere trimming. Hum Mol Genet 20:4684–4692.  https://doi.org/10.1093/hmg/ddr402 CrossRefPubMedGoogle Scholar
  363. Plunkett FJ, Franzese O, Belaramani LL, Fletcher JM, Gilmour KC, Sharifi R, Khan N, Hislop AD, Cara A, Salmon M, Gaspar HB, Rustin MH, Webster D, Akbar AN (2005) The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome. Mech Ageing Dev 126(8):855–865.  https://doi.org/10.1016/j.mad.2005.03.006 CrossRefPubMedGoogle Scholar
  364. Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belara-mani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN (2007) The loss of telomerase activity in highly differentiated CD8+CD28−CD27−T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 178:7710–7719CrossRefPubMedGoogle Scholar
  365. Poole JC, Andrews LG, Tollefsbol TO (2001) Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT). Gene 269(1–2):1–12Google Scholar
  366. Porro A, Feuerhahn S, Reichenbach P, Lingner J (2010) Molecular dissection of telomeric repeat-containing RNA biogenesis unveils the presence of distinct and multiple regulatory pathways. Mol Cell Biol 30:4808–4817.  https://doi.org/10.1128/MCB.00460-10 CrossRefPubMedPubMedCentralGoogle Scholar
  367. Porro A, Feuerhahn S, Delafontaine J, Riethman H, Rougemont J, Lingner J (2014) Functional characterization of the TERRA transcriptome at damagedtelomeres. Nat Commun 5:5379.  https://doi.org/10.1038/ncomms6379 CrossRefPubMedPubMedCentralGoogle Scholar
  368. Prescott J, Du M, Wong JY, Han J, De Vivo I (2012) Paternal age at birth is associated with offspring leukocyte telomere length in the nurses’ health study. Hum Reprod 27:3622–3631.  https://doi.org/10.1093/humrep/des314 CrossRefPubMedPubMedCentralGoogle Scholar
  369. Price CM, Boltz KA, Chaiken MF, Stewart JA, Beilstein MA, Shippen DE (2010) Evolution of CST function in telomere maintenance. Cell Cycle 9:3157–3165.  https://doi.org/10.4161/cc.9.16.12547 CrossRefPubMedPubMedCentralGoogle Scholar
  370. Puterman E, Lin J, Blackburn E, O’Donovan A, Adler N, Epel E (2010) The power of exercise: Buffering the effect of chronic stress on telomere length. PLoS One 5(5):e10837.  https://doi.org/10.1371/journal.pone.0010837 CrossRefPubMedPubMedCentralGoogle Scholar
  371. Qing H, Aono J, Findeisen HM, Jones KL, Heywood EB, Bruemmer D (2016) Differential regulation of telomerase reverse transcriptase promoter activation and protein degradation by histone deacetylase inhibition. J Cell Physiol 231(6):1276–1282.  https://doi.org/10.1002/jcp.25226 CrossRefPubMedGoogle Scholar
  372. Radan L, Hughes CS, Teichroeb JH, Vieira Zamora FM, Jewer M, Postovit LM, Betts D (2014) Microenvironmental regulation of telomerase isoforms in human embryonic stem cells. Stem Cells Dev 23:2046–2066.  https://doi.org/10.1089/scd.2013.0373 CrossRefPubMedPubMedCentralGoogle Scholar
  373. Rafie N, Golpour Hamedani S, Barak F, Safavi SM, Miraghajani M (2016) Dietary patterns, food groups and telomere length: a systematic review of current studies. Genes (Basel) 7(7):pii: E30.  https://doi.org/10.3390/genes7070030
  374. Ramírez R, Carracedo J, Jiménez R, Canela A, Herrera E, Aljama P, Blasco MA (2003) Massive telomere loss is an early event of DNA damage-induced apoptosis. J Biol Chem 278(2):836–842CrossRefPubMedGoogle Scholar
  375. Ramlee MK, Wang J, Toh WX, Li S (2016) Transcription regulation of the Human Telomerase Reverse Transcriptase (hTERT) gene. Genes (Basel) 7(8):pii: E50. doi:  https://doi.org/10.3390/genes7080050.
  376. Rao KS, Chakraharti SK, Dongare VS, Chetana K, Ramirez CM, Koka PS, Deb KD (2015) Antiaging effects of an intensive mind and body therapeutic program through enhancement of telomerase activity and adult stem cell counts. J Stem Cells 10(2):107–125PubMedGoogle Scholar
  377. Reddel RR (2003) Alternative lengthening of telomeres, telomerase, and cancer. Cancer Lett 194(2):155–162CrossRefPubMedGoogle Scholar
  378. Redon S, Reichenbach P, Lingner J (2010) The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res 38(17):5797–5806.  https://doi.org/10.1093/nar/gkq296 CrossRefPubMedPubMedCentralGoogle Scholar
  379. Redon S, Zemp I, Lingner J (2013) A three-state model for the regulation of telomerase by TERRA and hnRNPA1. Nucleic Acids Res 41(19):9117–9128.  https://doi.org/10.1093/nar/gkt695 CrossRefPubMedPubMedCentralGoogle Scholar
  380. Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M, Beverley PC, Rustin MH, Akbar AN (2004) Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo. J Exp Med 199(10):1433–1443CrossRefPubMedPubMedCentralGoogle Scholar
  381. Reig-Viader R, Vila-Cejudo M, Vitelli V, Buscà R, Sabaté M, Giulotto E, Caldés MG, Ruiz-Herrera A (2014) Telomeric repeat-containing RNA (TERRA) and telomerase are components of telomeres during mammalian gametogenesis. Biol Reprod 90(5):103.  https://doi.org/10.1095/biolreprod.113.116954
  382. Rentoukas E, Tsarouha K, Kaplanis I, Korou E, Nikolaou M, Marathonitis G, Kokkinou S, Haliassos A, Mamalaki A, Kouretas D, Tsitsimpikou C (2012) Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome. PLoS One 7(4):e35739.  https://doi.org/10.1371/journal.pone.0035739 CrossRefPubMedPubMedCentralGoogle Scholar
  383. Richardson G, Sage A, Bennaceur K, Al Zhrany N, Coelho-Lima J, Dookun E, Draganova L, Saretzki G, Breault DT, Mallat Z, Spyridopoulos I (2018) Telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory t-cells. Arterioscler Thromb Vasc Biol pii: ATVBAHA.117.309940.  https://doi.org/10.1161/ATVBAHA.117.309940
  384. Richter T, von Zglinicki T (2007) A continuous correlation between oxidative stress and telomere shortening in fibroblasts. Exp Gerontol 42(11):1039–1042CrossRefPubMedGoogle Scholar
  385. Richter T, Saretzki G, Nelson G, Melcher M, Olijslagers S, von Zglinicki T (2007) TRF2 overexpression diminishes repair of telomeric single-strand breaks and accelerates telomere shortening in human fibroblasts. Mech Ageing Dev 128(4):340–345CrossRefPubMedGoogle Scholar
  386. Rippe K, Luke B (2015) TERRA and the state of the telomere. Nat Struct Mol Biol 22(11):853–858.  https://doi.org/10.1038/nsmb.3078 CrossRefPubMedGoogle Scholar
  387. Robin JD, Ludlow AT, Batten K, Magdinier F, Stadler G, Wagner KR, Shay JW, Wright WE (2014) Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev 28:2464–2476.  https://doi.org/10.1101/gad.251041.114 CrossRefPubMedPubMedCentralGoogle Scholar
  388. Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 19:547–556.  https://doi.org/10.1083/jcb.201009094 CrossRefGoogle Scholar
  389. Rohde V, Sattler HP, Bund T, Bonkhoff H, Fixemer T, Bachmann C, Lensch R, Unteregger G, Stoeckle M, Wullich B (2000) Expression of the human telomerase reverse transcriptase is not related to telomerase activity in normal and malignant renal tissue. Clin Cancer Res 6(12):4803–4809PubMedGoogle Scholar
  390. Roth A, Yssel H, Pene J, Chavez EA, Schertzer M, Lansdorp PM, Spits H, Luiten RM (2003) Telomerase levels control the lifespan of human T lymphocytes. Blood 102(3):849–857CrossRefPubMedGoogle Scholar
  391. Rouse J, Jackson SP (2002) Interfaces between the detection, ignalling, and repair of DNA damage. Science 297(5581):547–551CrossRefGoogle Scholar
  392. Rufer N, Dragowska W, Thornbury G, Roosnek E, Lansdorp PM (1998) Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol 16(8):743–747CrossRefPubMedGoogle Scholar
  393. Rufer N, Brummendorf TH, Dragowska V, Shultzer M, Wadsworth LD, Lansdorp PM (1999a) Turnover of stem cells, naive and memory Tl ymphocytes, estimated from telomere fluorescence measurements. Cytotherapy 1:342CrossRefPubMedGoogle Scholar
  394. Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L, Schulzer M, Lansdorp PM (1999b) Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 190:157–168CrossRefPubMedPubMedCentralGoogle Scholar
  395. Rufer N, Migliaccio M, Antonchuk J, Humphries RK, Roosnek E, Lansdorp PM (2001) Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 98:597–603CrossRefPubMedGoogle Scholar
  396. Saebøe-Larssen S, Fossberg E, Gaudernack G (2006) Characterization of novel alternative splicing sites in human telomerase reverse transcriptase (hTERT): analysis of expression and mutual correlation in mRNA isoforms from normal and tumour tissues. BMC Mol Biol 7:26CrossRefPubMedPubMedCentralGoogle Scholar
  397. Salminen A, Kaarniranta K, Kauppinen A (2012) Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging-(Albany, NY) 4:166–175CrossRefGoogle Scholar
  398. Salvador L, Singaravelu G, Harley CB, Flom P, Suram A, Raffaele JM (2016) A natural product telomerase activator lengthens telomeres in humans: a randomized, double blind, and placebo controlled study. Rejuvenation Res 19(6):478–484CrossRefPubMedPubMedCentralGoogle Scholar
  399. Samper E, Goytisolo FA, Slijepcevic P, van Buul PP, Blasco MA (2000) Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep 1(3):244–252CrossRefPubMedPubMedCentralGoogle Scholar
  400. Samper E, Flores JM, Blasco MA (2001) Restoration of telomerase activityrescues chromosomal instability and premature aging in Terc-/- mice withshort telomeres. EMBO Rep 2:800–807CrossRefPubMedPubMedCentralGoogle Scholar
  401. Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA (2006) Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care 29(2):283–289CrossRefPubMedGoogle Scholar
  402. Sanders JL, Newman AB (2013) Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev 35:112–131.  https://doi.org/10.1093/epirev/mxs008 CrossRefPubMedPubMedCentralGoogle Scholar
  403. Sandhir R, Halder A, Sunkaria A (2017) Mitochondria as a centrally positioned hub in the innate immune response. Biochim Biophys Acta 1863(5):1090–1097.  https://doi.org/10.1016/j.bbadis.2016.10.020 CrossRefGoogle Scholar
  404. Santambrogio F, Gandellini P, Cimino-Reale G, Zaffaroni N, Folini M (2014) MicroRNA-dependent regulation of telomere maintenance mechanisms: a field as much unexplored as potentially promising. Curr Pharm Des 20(41):6404–6421CrossRefPubMedGoogle Scholar
  405. Santiso R, Tamayo M, Gosalvez J, Meseguer M, Garrido N, Fernandez JL (2010) Swim-up procedure selects spermatozoa with longer telomere length. Mutat Res 688:88–90.  https://doi.org/10.1016/j.mrfmmm.2010.03.003 CrossRefPubMedGoogle Scholar
  406. Santos JH, Meyer JN, Skorvaga M, Annab LA, Van Houten B (2004) Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell 3:399–411CrossRefPubMedGoogle Scholar
  407. Saretzki G (2014) Extra-telomeric functions of human telomerase: cancer, mitochondria and oxidative stress. Curr Pharm Des 20(41):6386–6403CrossRefPubMedGoogle Scholar
  408. Saretzki G, Walter T, Atkinson S, Passos JF, Bareth B, Keith WN, Stewart R, Hoare S, Stojkovic M, Armstrong L, von Zglinicki T, Lako M (2008) Down-regulation of multiple stress defence mechanisms during differentiation of human embryonic stem cells. Stem Cells 26(2):455–465CrossRefPubMedGoogle Scholar
  409. Sarkar D, Fisher PB (2006) Molecular mechanisms of aging-associated inflammation. Cancer Lett 236:13–23CrossRefPubMedGoogle Scholar
  410. Saßenroth D, Meyer A, Salewsky B, Kroh M, Norman K, Steinhagen-Thiessen E, Demuth I (2015) Sports and exercise at different ages and leukocyte telomere length in later life–data from the Berlin Aging Study II (BASE-II). PLoS One 10(12):e0142131.  https://doi.org/10.1371/journal.pone.0142131 CrossRefPubMedPubMedCentralGoogle Scholar
  411. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK (2017) Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8:14532.  https://doi.org/10.1038/ncomms14532 CrossRefPubMedPubMedCentralGoogle Scholar
  412. Schoeftner S, Blasco MA (2008) Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 10:228–236CrossRefPubMedGoogle Scholar
  413. Schoenmaker M, de Craen AJ, de Meijer PH, Beekman M, Blauw GJ, Slagboom PE, Westendorp RG (2006) Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet 14(1):79–84CrossRefPubMedGoogle Scholar
  414. Schreck R, Albermann K, Baeuerle PA (1992) Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 17(4):221–237CrossRefPubMedGoogle Scholar
  415. Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6:168–170CrossRefPubMedGoogle Scholar
  416. Seimiya H, Sawada H, Muramatsu Y, Shimizu M, Ohko K, Yamane K, Tsuruo T (2000) Involvement of 14-3-3 proteins in nuclear localization of telomerase. EMBO J 2(19):2652–2661CrossRefGoogle Scholar
  417. Sen A, Marsche G, Freudenberger P, Schallert M, Toeglhofer AM, Nagl C, Schmidt R, Launer LJ, Schmidt H (2014) Association between higher plasma lutein, zeaxanthin, and vitamin C concentrations and longer telomere length: results of the Austrian Stroke Prevention Study. J Am Geriatr Soc 62(2):222–229.  https://doi.org/10.1111/jgs.12644 CrossRefPubMedGoogle Scholar
  418. Sexton AN, Regalado SG, Lai CS, Cost GJ, O’Neil CM, Urnov FD, Gregory PD, Jaenisch R, Collins K, Hockemeyer D (2014) Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes De 28:1885–1899.  https://doi.org/10.1101/gad.246819.114 CrossRefGoogle Scholar
  419. Sfeir A, de Lange T (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336(6081):593–597.  https://doi.org/10.1126/science.1218498 CrossRefPubMedPubMedCentralGoogle Scholar
  420. Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae S, Karlseder J, Schildkraut C, de Lange T (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138:90–103.  https://doi.org/10.1016/j.cell.2009.06.021 CrossRefPubMedPubMedCentralGoogle Scholar
  421. Shadyab AH, LaMonte MJ, Kooperberg C, Reiner AP, Carty CL, Manini TM, Hou L, Di C, LaCroix AZ (2017) Association of accelerometer-measured physical activity with leukocyte telomere length among older women. J Gerontol A Biol Sci Med Sci 72(11):1532–1537.  https://doi.org/10.1093/gerona/glx037 CrossRefPubMedPubMedCentralGoogle Scholar
  422. Shalev I, Entringer S, Wadhwa PD, Wolkowitz OM, Puterman E, Lin J, Epel ES (2013a) Stress and telomere biology: a lifespan perspective. Psychoneuroendocrinology 38(9):1835–1842.  https://doi.org/10.1016/j.psyneuen.2013.03.010 CrossRefPubMedPubMedCentralGoogle Scholar
  423. Shalev I, Moffitt TE, Sugden K, Williams B, Houts RM, Danese A, Mill J, Arseneault L, Caspi A (2013b) Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. Mol Psychiatry 18(5):576–581.  https://doi.org/10.1038/mp.2012.32 CrossRefPubMedGoogle Scholar
  424. Sharma NK, Reyes A, Green P, Caron MJ, Bonini MG, Gordon DM, Holt IJ, Santos JH (2012) Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria. Nucleic Acids Res 40:712–725.  https://doi.org/10.1093/nar/gkr758 CrossRefPubMedGoogle Scholar
  425. Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33(5):787–791CrossRefPubMedGoogle Scholar
  426. Shiels PG, McGlynn LM, MacIntyre A, Johnson PC, Batty GD, Burns H, Cavanagh J, Deans KA, Ford I, McConnachie A, McGinty A, McLean JS, Millar K, Sattar N, Tannahill C, Velupillai YN, Packard CJ (2011) Accelerated telomere attrition is associated with relative household income, diet and inflammation in the pSoBid cohort. PLoS One 6(7):e22521.  https://doi.org/10.1371/journal.pone.0022521 CrossRefPubMedPubMedCentralGoogle Scholar
  427. Shimoi T, Yoshida M, Kitamura Y, Yoshino T, Kawachi A, Shimomura A, Noguchi E, Yunokawa M, Yonemori K, Shimizu C, Kinoshita T, Ichimura K, Fukuda T, Fujiwara Y, Tamura K (2017) TERT promoter hotspot mutations in breast cancer. Breast Cancer epub ahead of print.  https://doi.org/10.1007/s12282-017-0825-5
  428. Sillanpää E, Törmäkangas T, Rantanen T, Kaprio J, Sipilä S (2016) Does telomere length predict decline in physical functioning in older twin sisters during an 11-year follow-up? Age (Dordr) 38(2):34.  https://doi.org/10.1007/s11357-016-9898-x CrossRefGoogle Scholar
  429. Simons MJ (2015) Questioning causal involvement of telomeres in aging. Ageing Res Rev 24:191–196.  https://doi.org/10.1016/j.arr.2015.08.002 CrossRefPubMedGoogle Scholar
  430. Simpson RJ, Cosgrove C, Chee MM, McFarlin BK, Bartlett DB, Spielmann G, O’Connor DP, Pircher H, Shiels PG (2010) Senescent phenotypes and telomere lengths of peripheral blood T-cells mobilized by acute exercise in humans. Exerc Immunol Rev 16:40–55PubMedGoogle Scholar
  431. Singhapol C, Pal D, Czapiewski R, Porika M, Nelson G, Saretzki G (2013) Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PloS One 8(1):e52989.  https://doi.org/10.1371/journal.pone.0052989 CrossRefPubMedPubMedCentralGoogle Scholar
  432. Sitte N, Saretzki G, von Zglinicki T (1998) Accelerated telomere shortening in fibroblasts after extended periods of confluency. Free Radic Biol Med 24(6):885–893CrossRefPubMedGoogle Scholar
  433. Slagboom PE, Droog S, Boomsma DI (1994) Genetic determination of telomeresize in humans: a twin study of three age groups. Am J Hum Genet 55:876–882PubMedPubMedCentralGoogle Scholar
  434. Slagboom PE, Beekman M, Passtoors WM, Deelen J, Vaarhorst AA, Boer JM, van den Akker EB, van Heemst D, de Craen AJ, Maier AB, Rozing M, Mooijaart SP, Heijmans BT, Westendorp RG (2011) Genomics of human longevity. Philos Trans R Soc Lond B Biol Sci 366(1561):35–42.  https://doi.org/10.1098/rstb.2010.0284 CrossRefPubMedPubMedCentralGoogle Scholar
  435. Slattery ML, Herrick JS, Pellatt AJ, Wolff RK, Mullany LE (2016) Telomere Length, TERT, and miRNA Expression. PLoS One 11(9):e0162077.  https://doi.org/10.1371/journal.pone.0162077. eCollection 2016
  436. Smith S, Giriat I, Schmitt A, de Lange T (1998) Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282(5393):1484–1487CrossRefPubMedGoogle Scholar
  437. Smogorzewska A, de Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem 73:177–208CrossRefPubMedGoogle Scholar
  438. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T (2000) Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 20(5):1659–1668CrossRefPubMedPubMedCentralGoogle Scholar
  439. Soares-Miranda L, Imamura F, Siscovick D, Jenny NS, Fitzpatrick AL, Mozaffarian D (2015) Physical activity, physical fitness, and leukocyte telomere length: the cardiovascular health study. Med Sci Sports Exerc 47(12):2525–2534.  https://doi.org/10.1249/MSS.0000000000000720 CrossRefPubMedPubMedCentralGoogle Scholar
  440. Soder AI, Hoare SF, Muir S, Going JJ, Parkinson EK, Keith WN (1997) Amplification, increased dosage and in situ expression of the telomerase RNA gene in human cancer. Oncogene 14(9):1013–1021CrossRefPubMedGoogle Scholar
  441. Songyang Z, Liu D (2006) Inside the mammalian telomere interactome: regulation and regulatory activities of telomeres. Crit Rev Eukaryot Gene Exp 16(2):103–118CrossRefGoogle Scholar
  442. Spaulding C, Guo W, Effros RB (1999) Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen- specific proliferation. Exp Gerontol 34(5):633–644.  https://doi.org/10.1016/S0531-5565(99)00033-9 CrossRefPubMedGoogle Scholar
  443. Spilsbury A, Miwa S, Attems J, Saretzki G (2015) The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J of Neuroscience 35(4):1659–1674.  https://doi.org/10.1523/JNEUROSCI.2925-14.2015 CrossRefGoogle Scholar
  444. Spyridopoulos I, Martin-Ruiz C, Hilkens C, Yadegarfar ME, Isaacs J, Jagger C, Kirkwood T, von Zglinicki T (2016) CMV-seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians – results from the Newcastle 85+ study. Aging Cell 15(2):392.  https://doi.org/10.1111/acel.12430 CrossRefGoogle Scholar
  445. Strååt K, Liu C, Rahbar A, Zhu Q, Liu L, Wolmer-Solberg N, Lou F, Liu Z, Shen J, Jia J, Kyo S, Bjorkholm M, Sjoberg J, Soderberg-Naucler C, Xu D (2009) Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst 101(7):488–497.  https://doi.org/10.1093/jnci/djp031
  446. Steinert S, Shay JW, Wright WE (2000) Transient expression of human telomerase extends the life span of normal human fibroblasts. Biochem Biophys Res Commun 273(3):1095–1098CrossRefPubMedGoogle Scholar
  447. Steptoe A, Hamer M, Butcher L, Lin J, Brydon L, Kivimäki M, Marmot M, Blackburn E, Erusalimsky JD (2011) Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women. Brain Behav Immun 25(7):1292–1298.  https://doi.org/10.1016/j.bbi.2011.04.010 CrossRefPubMedGoogle Scholar
  448. Stewart S (2002) Multiple levels of telomerase regulation. Mol Interv 2(8):481–483CrossRefPubMedGoogle Scholar
  449. Stewart SA, Weinberg RA (2006) Telomeres: cancer to human aging. Annu Rev Cell Dev Biol 22:531–557CrossRefPubMedGoogle Scholar
  450. Strioga M, Pasukoniene V, Characiejus D (2011) CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology 134:17–32CrossRefPubMedPubMedCentralGoogle Scholar
  451. Sullivan LB, Santos JH, Chandel NS (2012) Mitochondria and telomeres: the promiscuous roles of TIN2. Mol Cell 47:823–824CrossRefPubMedGoogle Scholar
  452. Surtees PG, Wainwright NW, Pooley KA, Luben RN, Khaw KT, Easton DF, Dunning AM (2012) Educational attainment and mean leukocyte telomere length in women in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study. Brain Behav Immun 26(3):414–418.  https://doi.org/10.1016/j.bbi.2011.11.009 CrossRefPubMedGoogle Scholar
  453. Svenson U, Nordfjäll K, Baird D, Roger L, Osterman P, Hellenius ML, Roos G (2011) Blood cell telomere length is a dynamic feature. PLoS One 6(6):e21485.  https://doi.org/10.1371/journal.pone.0021485 CrossRefPubMedPubMedCentralGoogle Scholar
  454. Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Curr Biol 13:1549–1556CrossRefPubMedGoogle Scholar
  455. Takai KK, Hooper S, Blackwood S, Gandhi R, de Lange T (2010) In vivo stoichiometry of shelterin components. J Biol Chem 285:1457–1467.  https://doi.org/10.1074/jbc.M109.038026 CrossRefPubMedGoogle Scholar
  456. Takai KK, Kibe T, Donigian JR, Frescas D, de Lange T (2011) Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol Cell 44(4):647–659.  https://doi.org/10.1016/j.molce.2011.08.043 CrossRefPubMedPubMedCentralGoogle Scholar
  457. Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, Inoue M (1999) Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res 59:551–557PubMedGoogle Scholar
  458. Takata Y, Kikukawa M, Hanyu H, Koyama S, Shimizu S, Umahara T, Sakurai H, Iwamoto T, Ohyashiki K, Ohyashiki JH (2012) Association between ApoE phenotypes and telomere erosion in Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 67(4):33033–33035.  https://doi.org/10.1093/gerona/glr185 CrossRefGoogle Scholar
  459. Takubo K, Izumiyama-Shimomura N, Honma N, Sawabe M, Arai T, Kato M, Oshimura M, Nakamura K (2002) Telomere lengths are characteristic in each human individual. Exp Gerontol 37(4):523–431CrossRefPubMedGoogle Scholar
  460. Tanaka M, Kyo S, Takakura M, Kanaya T, Sagawa T, Yamashita K, Okada Y, Hiyama E, Inoue M (1998) Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation. Am J Pathol 153:1985–1991CrossRefPubMedPubMedCentralGoogle Scholar
  461. Tanaka H, Mendonca MS, Bradshaw PS, Hoelz DJ, Malkas LH, Meyn MS, Gilley D (2005) DNA damage-induced phosphorylation of the human telomereassociated protein TRF2. Proc Natl Acad Sci U S A 102(43):5539–5544Google Scholar
  462. Tarhan F, Vural F, Kosova B, Aksu K, Cogulu O, Keser G, Gündüz C, Tombuloglu M, Oder G, Karaca E, Doganavsargil E (2008) Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis. Rheumatol Int 28(6):579–583CrossRefPubMedGoogle Scholar
  463. Teixeira MT, Arneric M, Sperisen P, Lingner J (2004) Telomere length homeostasis is achieved via a switch between telomerase-extendible and –nonextendible states. Cell 117:323–335CrossRefPubMedGoogle Scholar
  464. Teo H, Ghosh S, Luesch H, Ghosh A, Wong ET, Malik N, Orth A, de Jesus P, Perry AS, Oliver JD, Tran NL, Speiser LJ, Wong M, Saez E, Schultz P, Chanda SK, Verma IM, Tergaonkar V (2010) Telomere-independent Rap1 isan IKK adaptor and regulates NF-kappaB-dependent gene expression. Nat Cell Biol 12:758–767.  https://doi.org/10.1038/ncb2080 CrossRefPubMedGoogle Scholar
  465. Tomlinson RL, Ziegler TD, Supakorndej T, Terns RM, Terns MP (2006) Cell cycle-regulated trafficking of human telomerase to telomeres. Mol Biol Cell 17(2):955–965CrossRefPubMedPubMedCentralGoogle Scholar
  466. Townsley DM, Dumitriu B, Young NS (2014) Bone marrow failure and the telomeropathies. Blood 124(18):2775–2783.  https://doi.org/10.1182/blood-2014-05-526285 CrossRefPubMedPubMedCentralGoogle Scholar
  467. Tricola GM, Simons MJP, Atema E, Boughton RK, Brown JL, Dearborn DC, Divoky G, Eimes JA, Huntington CE, Kitaysky AS, Juola FA, Lank DB, Litwa HP, Mulder EGA, Nisbet ICT, Okanoya K, Safran RJ, Schoech SJ, Schreiber EA, Thompson PM, Verhulst S, Wheelwright NT, Winkler DW, Young R, Vleck CM, Haussmann MF (2018) The rate of telomere loss is related to maximum lifespan in birds. Phil Trans R Soc B 373(1741):pii: 20160445.  https://doi.org/10.1098/rstb.2016.0445
  468. Tu W, Zhang DK, Cheung PT, Tsao SW, Lau YL (1999) Effect of insulin-like growth factor 1 on PHA-stimulated cord blood mononuclear cell telomerase activity. Br J Haematol 104(4):785–794CrossRefPubMedGoogle Scholar
  469. Tutton S, Azzam GA, Stong N, Vladimirova O, Wiedmer A, Monteith JA, Beishline K, Wang Z, Deng Z, Riethman H, McMahon SB, Murphy M, Lieberman PM (2016) Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres. EMBO J 35:193–207.  https://doi.org/10.15252/embj.201490880 CrossRefPubMedGoogle Scholar
  470. Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA, Carpenter LL (2010) Childhood maltreatment and telomere shortening: preliminary support for an effect of early stress on cellular aging. Biol Psychiatry 67(6):531–534.  https://doi.org/10.1016/j.biopsych.2009.08.014 CrossRefPubMedGoogle Scholar
  471. Ulaner GA, Giudice LC (1997) Developmental regulation of telomerase activity in human fetal tissues during gestation. Mol Hum Reprod 3(9):769–773CrossRefPubMedGoogle Scholar
  472. Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR (1998) Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res 58:4168–4172PubMedGoogle Scholar
  473. Ulaner GA, Hu JF, Vu TH, Oruganti H, Giudice LC, Hoffman AR (2000) Regulation of telomerase by alternate splicing of human telomerase reverse transcriptase (hTERT) in normal and neoplastic ovary, endometrium and myometrium. Int J Cancer 85:330–335CrossRefPubMedGoogle Scholar
  474. Unryn BM, Cook LS, Riabowol KT (2005) Paternal age is positively linked to telomere length of children. Aging Cell 4(2):97–101CrossRefPubMedGoogle Scholar
  475. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD (2005) Obesity, cigarette smoking, and telomere length in women. Lancet 366(9486):662–664CrossRefPubMedPubMedCentralGoogle Scholar
  476. Valentijn AJ, Saretzki G, Tempest N, Critchley HOD, Hapangama DK (2015) Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis. Hum Reprod 30(12):2816–2828.  https://doi.org/10.1093/humrep/dev267 CrossRefPubMedGoogle Scholar
  477. Valenzuela HF, Effros RB (2002) Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clinical Immunology 105:117–125CrossRefPubMedGoogle Scholar
  478. van Ockenburg SL, Bos EH, de Jonge P, van der Harst P, Gans RO, Rosmalen JG (2012) Stressful life events and leukocyte telomere attrition in adulthood: a prospective population-based cohort study. Psychol Med 45(14):2975–2984.  https://doi.org/10.1017/S0033291715000914 CrossRefGoogle Scholar
  479. van Steensel B, de Lange T (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385(6618):740–743CrossRefPubMedGoogle Scholar
  480. van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92(3):401–413CrossRefPubMedGoogle Scholar
  481. Vannier JB, Pavicic-Kaltenbrunner V, Petalcorin MI, Ding H, Boulton SJ (2012) RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149(4):795–806.  https://doi.org/10.1016/j.cell.2012.03.030 CrossRefPubMedGoogle Scholar
  482. Veldman T, Horikawa I, Barrett JC, Schlegel R (2001) Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol 75:4467–4472CrossRefPubMedPubMedCentralGoogle Scholar
  483. Vera E, Bernardes de Jesus B, Foronda M, Flores JM, Blasco MA (2012) The rate of increase of short telomeres predicts longevity in mammals. Cell Rep 2:732–737.  https://doi.org/10.1016/j.celrep.2012.08.023 CrossRefPubMedGoogle Scholar
  484. von Känel R, Bruwer EJ, Hamer M, de Ridder JH, Malan L (2017) Association between objectively measured physical activity, chronic stress and leukocyte telomere length. J Sports Med Phys Fitness 57(10):1349–1358.  https://doi.org/10.23736/S0022-4707.16 CrossRefGoogle Scholar
  485. von Zglinicki T (2000) Role of oxidative stress in telomere length regulation andreplicative senescence. Ann NY Acad Sci 908:99–110CrossRefGoogle Scholar
  486. von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344CrossRefGoogle Scholar
  487. von Zglinicki T, Saretzki G, Döcke W, Lotze C (1995) Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp Cell Res 220(1):186–193CrossRefGoogle Scholar
  488. von Zglinicki T, Serra V, Lorenz M, Saretzki G, Lenzen-Grossimlighaus R, Gessner R, Risch A, Steinhagen-Thiessen E (2000) Short telomeres in patients with vascular dementia: an indicator of low antioxidative capacity and a possible risk factor? Lab Invest 80(11):1739–1747CrossRefGoogle Scholar
  489. von Zglinicki T, Pilger R, Sitte N (2000b) Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 28(1):64–74CrossRefGoogle Scholar
  490. von Zglinicki T, Saretzki G, Ladhoff J, Fagagna F, Jackson SP (2005) Human cell senescence as a DNA damage response. Mech Ageing Dev 126(1):111–117CrossRefGoogle Scholar
  491. Wallace DL, Berard M, Soares MV, Oldham J, Cook JE, Akbar AN, Tough D, Beverley PC (2006) Prolonged exposure of naive CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation nor loss of telomere length. Immunology 119:243–253CrossRefPubMedPubMedCentralGoogle Scholar
  492. Wallace DC, Fan W, Procaccio V (2010) Mitochondrial energetics andtherapeutics. Annu Rev Pathol 5:297–348CrossRefPubMedPubMedCentralGoogle Scholar
  493. Wang C, Maddick M, Miwa S, Jurk D, Czapiewski R, Saretzki G, Langie SAS, Godschalk RWL, Cameron K, von Zglinicki T (2010) Adult-onset, short-term dietary restriction reduces cell senescence in mice. Aging 2(9):555–566Google Scholar
  494. Wang C, Meier UT (2004) Architecture and assembly of mammalian H/ACA small nucleolar and telomerase ribonucleoproteins. EMBO J 23(8):1857–1867CrossRefPubMedPubMedCentralGoogle Scholar
  495. Wang C, Zhao L, Lu S (2015) Role of TERRA in the regulation of telomere length. Int J Biol Sci 11(3):316–323.  https://doi.org/10.7150/ijbs.10528. eCollection 2015
  496. Wang F, Lei M (2011) Human telomere POT1-TPP1 complex and its role in telomerase activity regulation. Methods Mol Biol 735:173–187.  https://doi.org/10.1007/978-1-61779-092-8_17 CrossRefPubMedGoogle Scholar
  497. Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, Cech TR, Lei M (2007) The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445(7127):506–410CrossRefPubMedGoogle Scholar
  498. Wang F, Stewart JA, Kasbek C, Zhao Y, Wright WE, Price CM (2012) Human CST has independent functions during telomere duplex replication and C-strand fill-in. Cell Rep 2(5):1096–1103.  https://doi.org/10.1016/j.celrep.2012.10.007 CrossRefPubMedPubMedCentralGoogle Scholar
  499. Wang Z, Deng Z, Tutton S, Liebermann PM (2017) The telomeric response to viral infection. Viruses 9(8):218.  https://doi.org/10.3390/v9080218
  500. Wang Z, Kyo S, Takakura M, Tanaka M, Yatabe N, Maida Y, Fujiwara M, Hayakawa J, Ohmichi M, Koike K, Inoue M (2000) Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase ignalling pathway. Cancer Res 60(19):5376–5381PubMedGoogle Scholar
  501. Wang Z, Lieberman PM (2016) The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes. RNA Biol 13(8):690–695.  https://doi.org/10.1080/15476286.2016.1203503 CrossRefPubMedPubMedCentralGoogle Scholar
  502. Watson JD (1972) Origin of concatemeric T7 DNA. Nat New Biol 239:197–201CrossRefPubMedGoogle Scholar
  503. Weekes MP, Wills MR, Mynard K, Hicks R, Sissons JG, Carmichael AJ (1999) Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28-CD8+ T-cell population. Immunology 98:443–449CrossRefPubMedPubMedCentralGoogle Scholar
  504. Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar AG, Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright WE, Shay JW, Harley CB, Morin GB (1997) Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet 17(4):498–502CrossRefPubMedGoogle Scholar
  505. Weng NP (2002) Regulation of telomerase expression in human lymphocytes. Springer Semin Immunopathol 24(1):23–33CrossRefPubMedGoogle Scholar
  506. Weng NP, Levin BL, June CH, Hodes RJ (1995) Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci USA 92:11091–11094CrossRefPubMedGoogle Scholar
  507. Weng NP, Levin BL, June CH, Hodes RJ (1996) Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183:2471–2479CrossRefPubMedGoogle Scholar
  508. Weng NP, Palmer LD, Levine BL, Lane HC, June CH, Hodes RJ (1997a) Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation and aging. Immunol Rev 160:43–54CrossRefPubMedGoogle Scholar
  509. Weng NP, Granger L, Hodes RJ (1997b) Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci USA 94:10827CrossRefPubMedGoogle Scholar
  510. Weng NP, Hathcock KS, Hodes RJ (1998) Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. Immunity 9:151–157CrossRefPubMedGoogle Scholar
  511. Werner C, Hanhoun M, Widmann T, Kazakov A, Semenov A, Pöss J, Bauersachs J, Thum T, Pfreundschuh M, Müller P, Haendeler J, Böhm M, Laufs U (2008) Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis. J Am Coll Cardiol 52:470–482.  https://doi.org/10.1016/j.jacc.2008.04.034 CrossRefPubMedGoogle Scholar
  512. Werner C, Furster T, Widmann T, Pöss J, Roggia C, Hanhoun M, Scharhag J, Büchner N, Meyer T, Kindermann W, Haendeler J, Böhm M, Laufs U (2009) Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation 120(24):2438–2447.  https://doi.org/10.1161/CIRCULATIONAHA.109.861005 CrossRefPubMedGoogle Scholar
  513. Westendorp RG, van Heemst D, Rozing MP, Frölich M, Mooijaart SP, Blauw GJ, Beekman M, Heijmans BT, de Craen AJ, Slagboom PE (2009) Leiden Longevity Study Group Nonagenarian siblings and their offspring display lower risk of mortality and morbidity than sporadic nonagenarians: The Leiden Longevity Study. J Am Geriatr Soc 57(9):1634-1637. doi:  https://doi.org/10.1111/j.1532-5415.2009.02381.x
  514. Wilbourn RV, Moatt JP, Froy H, Walling CA, Nussey DH, Boonekamp JJ (2018) The relationship between telomere length and mortality risk in non-model vertebrate systems: a meta-analysis. Phil Trans R Soc B 373:20160447.  https://doi.org/10.1098/rstb.2016.0447 CrossRefPubMedGoogle Scholar
  515. Willeit P, Willeit J, Kloss-Brandstatter A, Kronenberg F, Kiechl S (2011) Fifteen-year follow-up of association between telomere length and incident cancer and cancer mortality. JAMA 306:42–44.  https://doi.org/10.1001/jama.2011.901 CrossRefPubMedGoogle Scholar
  516. Wilson CB, McLaughlin LD, Nair A, Ebenezer PJ, Dange R, Francis J (2013) Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model. PLoS One 8(10):e76146.  https://doi.org/10.1371/journal.pone.0076146. eCollection 2013
  517. Woo J, Suen EW, Leung JC, Tang NL, Ebrahim S (2009) Older men with higher self-rated socioeconomic status have shorter telomeres. Age Ageing 38(5):553–558.  https://doi.org/10.1093/ageing/afp098 CrossRefPubMedPubMedCentralGoogle Scholar
  518. Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW (1996) Telomerase activity in human germline and embryonic tissues and cells. Dev Genet 18(2):173–179CrossRefPubMedGoogle Scholar
  519. Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R (1999) Direct activation of TERT transcription by c-Myc. Nat Genet 21:220–224CrossRefPubMedGoogle Scholar
  520. Wu P, Takai H, de Lange T (2012) Telomeric 3_overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150:39–52.  https://doi.org/10.1016/j.cell.2012.05.026 CrossRefPubMedPubMedCentralGoogle Scholar
  521. Wulaningsih W, Watkins J, Matsuguchi T, Hardy R (2016) Investigating the associations between adiposity, life course overweight trajectories, and telomere length. Aging 8:2689–26701.  https://doi.org/10.18632/aging.101036 CrossRefPubMedPubMedCentralGoogle Scholar
  522. Xi P, Zhou L, Wang M, Liu JP, Cong YS (2013) Serine/threonine-protein phosphatase 2A physically interacts with human telomerase reverse transcriptase hTERT and regulates its subcellular distribution. J Cell Biochem 114(2):409–417.  https://doi.org/10.1002/jcb.24378 CrossRefPubMedGoogle Scholar
  523. Xiong S, Patrushev N, Forouzandeh F, Hilenski L, Alexander RW (2015) PGC-1α modulates telomere function and DNA damage in protecting against aging-related chronic diseases. Cell Rep 12(9):1391–1399.  https://doi.org/10.1016/j.celrep.2015.07.047 CrossRefPubMedPubMedCentralGoogle Scholar
  524. Yabuta S, Masaki M, Shidoji Y (2016) Associations of buccal cell telomere length with daily intake of β-carotene or α-tocopherol are dependent on carotenoid metabolism-related gene polymorphisms in healthy Japanese adults. J Nutr Health Aging 20(3):267–274.  https://doi.org/10.1007/s12603-015-0577-x CrossRefPubMedGoogle Scholar
  525. Yamada O, Motoji T, Mizoguchi H (1996) Upregulation of telomerase activity in human lymphocytes. Biochim Biophys Acta 1314:260–266CrossRefPubMedGoogle Scholar
  526. Yang Z, Huang X, Jiang H, Zhang Y, Liu H, Qin C, Eisner GM, Jose PA, Rudolph L, Ju Z (2009) Short telomeres and prognosis of hypertension in a chinese population. Hypertension 53(4):639–645.  https://doi.org/10.1161/HYPERTENSIONAHA.108.123752 CrossRefPubMedPubMedCentralGoogle Scholar
  527. Ye JZ, Donigian JR, van Overbeek M, Loayza D, Lu Y, Krutchinsky AN, Chait BT, de Lange T (2004) TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem 279:47264–47271CrossRefPubMedGoogle Scholar
  528. Yehezkel S, Segev Y, Viegas-Pequignot E, Skorecki K, Selig S (2008) Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions. Hum Mol Genet 17:2776–2789.  https://doi.org/10.1093/hmg/ddn177 CrossRefPubMedGoogle Scholar
  529. Yi X, White DM, Aisner DL, Baur JA, Wright WE, Shay JW (2000) An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. Neoplasia 2(5):433–440Google Scholar
  530. Yoshimura SH, Maruyama H, Ishikawa F, Ohki R, Takeyasu K (2004) Molecular mechanisms of DNA end-loop formation by TRF2. Genes Cells 9(3):205–218CrossRefPubMedGoogle Scholar
  531. Young AR, Narita M (2009) SASP reflects senescence. EMBO Rep 10:228–230.  https://doi.org/10.1038/embor.2009.22 CrossRefPubMedPubMedCentralGoogle Scholar
  532. Young AT, Lakey JR, Murray AG, Mullen JC, Moore RB (2003) In vitro senescence occurring in normal human endothelial cells can be rescued by ectopic telomerase activity. Transplant Proc 35(7):2483–2485CrossRefPubMedGoogle Scholar
  533. Yu TY, Kao YW, Lin JJ (2014) Telomeric transcripts stimulate telomere recombination to suppress senescencein cells lacking telomerase. Proc Natl Acad Sci USA 111(9):3377–3782.  https://doi.org/10.1073/pnas.1307415111 CrossRefPubMedGoogle Scholar
  534. Zakian VA (1996) Structure, function, and replication of Saccharomyces cerevisiae telomeres. Annu Rev Genet 30:141–172CrossRefPubMedGoogle Scholar
  535. Zalenskaya IA, Zalensky AO (2002) Telomeres in mammalian male germline cells. Int Rev Cytol 218:37–67CrossRefPubMedGoogle Scholar
  536. Zalli A, Carvalho LA, Lin J, Hamer M, Erusalimsky JD, Blackburn EH, Steptoe A (2014) Shorter telomeres with high telomerase activity are associated withraised allostatic load and impoverished psychosocial resources. Proc Natl Acad Sci USA 111:4519–4524.  https://doi.org/10.1073/pnas.1322145111 CrossRefPubMedGoogle Scholar
  537. Zhang QS, Manche L, Xu RM, Krainer AR (2006) hnRNP A1 associates with telomere ends and stimulates telomerase activity. RNA 12(6):1116–1128CrossRefPubMedPubMedCentralGoogle Scholar
  538. Zhang Q, Kim NK, Feigon J (2011) Architecture of human telomerase RNA. Proc Natl Acad Sci USA 108(51):20325–20332.  https://doi.org/10.1073/pnas.1100279108 CrossRefPubMedGoogle Scholar
  539. Zhang F, Cheng D, Wang S, Zhu J (2016a) Human specific regulation of the telomerase reverse transcriptase gene. Genes (Basel) 7(7):pii: E30.  https://doi.org/10.3390/genes7070030
  540. Zhang F, Cheng D, Wang S, Zhu J (2016b) Human specific regulation of the telomerase reverse transcriptase gene. Metabolism 65(4):406–415.  https://doi.org/10.1016/j.metabol.2015.11.004 CrossRefGoogle Scholar
  541. Zhang J, Rane G, Dai X, Shanmugam MK, Arfuso F, Samy RP, Lai MK, Kappei D, Kumar AP, Sethi G (2016c) Ageing and the telomere connection: an intimate relationship with inflammation. Ageing Res Rev 25:55–69.  https://doi.org/10.1016/j.arr.2015.11.006 CrossRefPubMedGoogle Scholar
  542. Zhang Y, Dakic A, Chen R, Dai Y, Schlegel R, Liu X (2017) Direct HPV E6/Myc interactions induce histone modifications, Pol II phosphorylation, and hTERT promoter activation. Oncotarget 8(56):96323–96339.  https://doi.org/10.18632/oncotarget.22036. eCollection 2017
  543. Zhao F, Pang W, Zhang Z, Zhao J, Wang X, Liu Y, Wang X, Feng Z, Zhang Y, Sun W, Liu J (2016) Pomegranate extract and exercise provide additive benefits on improvement of immune function by inhibiting inflammation and oxidative stress in high-fat-diet-induced obesity in rats. J Nutr Biochem 32:20–28.  https://doi.org/10.1016/j.jnutbio.2016.02.003 CrossRefPubMedGoogle Scholar
  544. Zheng YL, Zhang F, Sun B, Du J, Sun C, Yuan J, Wang Y, Tao L, Kota K, Liu X, Schlegel R, Yang Q (2014) Telomerase enzymatic component hTERT shortens long telomeres in human cells. Cell Cycle 13(11):1765–1776.  https://doi.org/10.4161/cc.28705 CrossRefPubMedPubMedCentralGoogle Scholar
  545. Zhong FL, Batista LF, Freund A, Pech MF, Venteicher AS, Artandi SE (2012) TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150:481–494.  https://doi.org/10.1016/j.cell.2012.07.012 CrossRefPubMedPubMedCentralGoogle Scholar
  546. Zhu H, Guo D, Li K, Pedersen-White J, Stallmann-Jorgensen IS, Huang Y, Parikh S, Liu K, Dong Y (2012) Increased telomerase activity and vitamin D supplementation in overweight African Americans. Int J Obes (Lond) 36:805–809.  https://doi.org/10.1038/ijo.2011.197 CrossRefGoogle Scholar
  547. Zhu HY, Li C, Bai WD, Su LL, Liu JQ, Li Y, Shi JH, Cai WX, Bai XZ, Jia YH, Zhao B, Wu X, Li J, Hu DH (2014) MicroRNA-21 regulates hTERT via PTEN in hypertrophic scar fibroblasts. PLoS One 9(5):e97114.  https://doi.org/10.1371/journal.pone.0097114. eCollection 2014

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.The Ageing Biology Centre, Newcastle University Institute of Ageing and Institute for Cell and Molecular Biosciences, Newcastle UniversityNewcastle Upon TyneUK

Personalised recommendations