Telomeres, cell senescence and human ageing

Signal Transduction

Volumn 5, Issue 3, 2005, Pages 103-114

  Von Zglinicki, Thomas ^a,b   Martin Ruiz, Carmen M ^a   Saretzki, Gabriele ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Ageing; Oxidative stress; Senescence; Telomeres

Indexed keywords

BIOLOGICAL MARKER; DNA; DNA POLYMERASE;

AGING; CARDIOVASCULAR DISEASE; CELL CYCLE; CELL TYPE; DNA DAMAGE; DNA REPLICATION; DNA STRAND; HUMAN; IMMUNOFLUORESCENCE TEST; IN VITRO STUDY; IN VIVO STUDY; MORBIDITY; OSTEOARTHRITIS; OSTEOPOROSIS; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; SENESCENCE; SIGNAL TRANSDUCTION; SKELETAL MUSCLE; STEM CELL; TELOMERE;

EID: 23844526864     PISSN: 16154053     EISSN: None     Source Type: Journal    
DOI: 10.1002/sita.200400049     Document Type: Review

References (161)

1. Griffith, J. D., Comeau, L., Rosenfield, S., Stansel, R. M., Bianchi, A., Moss, H., de Lange, T. (1999). Mammalian telomeres end in a large duplex loop. Cell 97: 503-514.
2. Smogorzewska, A., van Steensel, B., Bianchi, A., Oelmann, S., Schaefer, M. R., Schnapp, G., de Lange, T. (2000). Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20: 1659-1668.
3. Kim, S. H., Kaminker, P., Campisi, J. (1999). TIN2, a new regulator of telomere length in human cells. Nat. Genet. 23: 405-412.
4. Cook, B. D., Dynek, J. N., 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: 332-342.
5. de Lange, T. (2002). Protection of mammalian telomeres. Oncogene 21: 532-40.
6. Olovnikow, A. (1973). A theory of marginotomy. J. Theor. Biol. 41: 181-190.
7. von Zglinicki, T. (2002). Oxidative stress shortens telomeres. Trends Biochem. Sci. 27: 339-344.
8. Blackburn, E. H. (2000). Telomere states and cell fates. Nature 408: 53-56.
9. Hayflick, L., Moorehead, P. S. (1961). The serial cultivation of human diploid cell strains. Exp. Cell. Res. 25: 585-621.
10. Bayreuther, K., Rodemann, H. P., Hommel, R., Dittmann, K., Albiez, M., Francz, P. I. (1988). Human skin fibroblasts in vitro differentiate along a terminal cell lineage. Proc. Natl. Acad. Sci. U.S.A. 85: 5112-5116.
11. Friguet, B. (2002). Protein repair and degradation during aging. ScientificWorldJournal 2: 248-254.
12. Cristofalo, V. J. (1988). Cellular biomarkers of aging. Exp. Gerontol. 23: 297-307.
13. Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U.S.A. 92: 9363-9367.
14. Lundberg, A. S., Hahn, W. C., Gupta, P., Weinberg, R. A. (2000). Genes involved in senescence and immortalization. Curr. Opin. Cell Biol. 12: 705-709.
15. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J., Sedivy, J. M. (2004). Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14: 501-513.
16. Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C. P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., Wright, W. E. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352.
17. Vaziri, H., Benchimol, S. (1998). Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8: 279-282.
18. Morales, C. P., Holt, S. E., Ouellette, M., Kaur, K. J., Yan, Y., Wilson, K. S., White, M. A., Wright, W. E., Shay, J. W. (1999). Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat. Genet. 21: 115-118.
19. Jiang, X. R., Jimenez, G., Chang, E., Frolkis, M., Kusler, B., Sage, M., Beeche, M., Bodnar, A. G., Wahl, G. M., Tlsty, T. D., Chiu, C. P. (1999). Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat. Genet. 21: 111-114.
20. Noble, J. R., Zhong, Z. H., Neumann, A. A., Melki, J. R., Clark, S. J., Reddel, R. R. (2004). Alterations in the p16(INK4a) and p53 tumor suppressor genes of hTERT-immortalized human fibroblasts. Oncogene 23: 3116-3121.
21. Chen, Q., Fischer, A., Reagan, J. D., Yan, L. J., Ames, B. N. (1995). Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc. Natl. Acad. Sci. U.S.A. 92: 4337-4341.
22. Petersen, S., Saretzki, G., von Zglinicki, T. (1998). Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp. Cell Res. 239: 152-160.
23. Kawanishi, S., Oikawa, S. (2004). Mechanism of telomere shortening by oxidative stress. Ann. NY Acad. Sci. 1019: 278-284.
24. Sitte, N., Saretzki, G., von Zglinicki, T. (1998). Accelerated telomere shortening in fibroblasts after extended periods of confluency. Free Radic. Biol. Med. 24: 885-893.
25. Serra, V., von Zglinicki, T., Lorenz, M., Saretzki, G. (2003). Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. J. Biol. Chem. 278: 6824-6830.
26. von Zglinicki, T., Pilger, R., Sitte, N. (2000). Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic. Biol. Med. 28: 64-74.
27. Tchirkov, A., Lansdorp, P. M. (2003). Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia. Hum. Mol. Genet. 12: 227-232.
28. Saretzki, G., Murphy, M. P., von Zglinicki, T. (2003). MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress. Aging Cell 2. 141-143.
29. Forsyth, N. R., Evans, A. P., Shay, J. W., Wright, W. E. (2003). Developmental differences in the immortalization of lung fibroblasts by telomerase. Aging Cell 2: 235-243.
30. Shilo, Y. (2003). ATM and related protein kinases: safeguarding genomic integrity. Nat. Rev. Cancer 3: 155-168.
31. Rouse, J., Jackson, S. P. (2002). Interfaces between the detection, signaling, and repair of DNA damage. Science 297: 547-551.
32. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S., de Lange, T. (1999). p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283: 1321-1325.
33. Smogorzewska, A., De Lange, T. (2002). Different telomere damage signaling pathways in human and mouse cells. EMBO J. 21: 4338-4348.
34. d'Adda di Fagagna, F., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., Von Zglinicki, T., Saretzki, G., Carter, N. P., Jackson, S. P. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194-198.
35. Takai, H., Smogorzewska, A., de Lange, T. (2003). DNA damage foci at dysfunctional telomeres. Curr. Biol. 13: 1549-1556.
36. Hao, L. Y., Strong, M. A., Greider, C. W. (2004). Phosphorylation of H2AX at short telomeres in T cells and fibroblasts. J. Biol. Chem. 279: 45148-45154.
37. Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W., Wright, W. E. (2004). Does a sentinel or a subset of short telomeres determine replicative senescence? Mol. Biol. Cell 15: 3709-3718.
38. Sedelnikova, O. A., Horikawa, I., Zimonjic, D. B., Popescu, N. C., Bonner, W. M., Barrett, J. C. (2004). Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell Biol. 6: 168-170.
39. Satyanarayana, A., Greenberg, R. A., Schaetzlein, S., Buer, J., Masutomi, K., Hahn, W. C., Zimmermann, S., Martens, U. M., Manns, M. P., Rudolph, K. L. (2004). Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol. Cell. Biol. 24: 5459-5474.
40. von Zglinicki, T., Saretzki, G., Ladhoff, J., d'Adda di Fagagna, F., Jackson, S. P. (2004). Human cell senescence as a DNA damage response. Mech. Ageing Dev. 126: 111-117.
41. Bakkenist, C. J., Kastan, M. B. (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421: 499-506.
42. Stiff, T., O'Driscoll, M., Rief, N., Iwabuchi, K., Lobrich, M., Jeggo, P. A. (2004). ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 64: 2360-2366.
43. Zou, L., Liu, D., Elledge, S. J. (2003). Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc. Natl. Acad. Sci. U.S.A. 100: 13827-13832.
44. van Steensel, B., Smogorzewska, A., de Lange, T. (1998). TRF2 protects human telomeres from end-to-end fusions. Cell 92: 401-413.
45. Stewart, S. A., Ben-Porath, I., Carey, V. J., O'Connor, B. F., Hahn, W. C., Weinberg, R. A. (2003). Erosion of the telomeric single-strand overhang at replicative senescence. Nat. Genet. 33: 492-496.
46. Keys, B., Serra, V., Saretzki, G., von Zglinicki, T. (2004). Telomere shortening in human fibroblasts is not dependent on the size of the telomeric overhang-. Aging Cell 3: 103-109.
47. Gardner, R., Putnam, C. W., Weinert, T. (1999). Rad53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast. EMBO J. 18: 3173-3185.
48. Maringele, L., Lydall, D. (2004). EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Delta mutants. Genes Dev. 16: 1919-1933.
49. Saretzki, G., Sitte, N., Merkel, U., Wurm, R. E., von Zglinicki, T. (1999). Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments. Oncogene 18: 5148-5158.
50. von Zglinicki, T. (2001). Telomeres and replicative senescence: Is it only length that counts? Cancer Lett. 168: 111-116.
51. Eller, M. S., Li, G. Z., Firoozabadi, R., Puri, N., Gilchrest, B. A. (2003). Induction of a p95/Nbs1-mediated S phase checkpoint by telomere 3′ overhang specific DNA. FASEB J. 17: 152-162.
52. von Zglinicki, T. (2000). Role of oxidative stress in telomere length regulation and replicative senescence. Ann. NY Acad. Sci. 908: 99-110.
53. Miller, R. A. (1991). Aging and immune function. Int. Rev. Cytol. 124: 187-215.
54. Knoflach, M., Mayrl, B., Mayerl, C., Sedivy, R., Wick, G. (2003). Atherosclerosis as a paradigmatic disease of the elderly: role of the immune system. Immunol. Allergy Clin North Am 23: 117-132.
55. Wick, G., Jansen-Durr, P., Berger, P., Blasko, I., Grubeck-Loebenstein, B. (2000). Diseases of aging. Vaccine 18: 1567-1583.
56. Butcher, S., Chahel, H., Lord, J. M. (2000). Ageing and the neutrophil: no appetite for killing? Immunology 100: 411-416.
57. Miller, R. A. (1996). The aging immune system: primer and prospectus. Science 273: 70-74.
58. Pawelec, G., Akbar, A., Caruso, C., Effros, R., Grubeck-Loebenstein, B., Wikby, A. (2004). Is immunosenescence infectious? Trends Immunol. 25: 406-410.
59. Akbar, A. N., Beverley, P. C., Salmon, M. (2004). Will telomere erosion lead to a loss of T-cell memory? Nat. Rev. Immunol. 4: 737-743.
60. Effros, R. B., Boucher, N., Porter, V., Zhu, X., Spaulding, C., Walford, R. L., Kronenberg, M., Cohen, D., Schachter, F. (1994). Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp. Gerontol. 29: 601-609.
61. Weng, N. P., Levine, B. L., June, C. H., Hodes, R. J. (1996). Regulated expression of telomerase activity in human T lymphocyte development and activation. J. Exp. Med. 183:2471-2479.
62. Spaulding, C., Guo, W., Effros, R. B. (1999). Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp. Gerontol. 34: 633-644.
63. + counterparts. J. Immunol. 156: 3587-3590.
64. Hyland, P., Barnett, C., Pawelec, G., Barnett, Y. (2001). Age-related accumulation of oxidative DNA damage and alterations in levels of p16INK4a/CDKN2a, p21WAF1/CIP1/SDI1 and p27KIP1 in human CD4+ T cell clones in vitro. Mech. Aging Dev. 122: 1151-1167.
65. Schonland, S. O., Lopez, C., Widmann, T., Zimmer, J., Bryl, E., Goronzy, J. J., Weyand, C. M. (2003). Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc. Natl. Acad. Sci. U.S.A. 100: 13471-13476.
66. Hooijberg, E., Ruizendaal, J. J., Snijders, P. J., Kueter, E. W., Walboomers, J. M., Spits, H. (2000). Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase. J. Immunol. 165: 4239-4245.
67. Rufer, N., Migliaccio, M., Antonchuk, J., Humphries, R. K., Roosnek, E., Lansdorp, P. M. (2001). Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 98: 597-603.
68. Roth, A., Yssel, H., Pene, J., Chavez, E. A., Schertzer, M., Lansdorp, P. M., Spits, H., Luiten, R. M. (2003). Telomerase levels control the lifespan of human T lymphocytes. Blood 102: 849-857.
69. Weng, N.-p. (2001). Interplay between telomere length and telomerase in human leukocyte differentiation and aging. J. Leukoc. Biol. 70: 861-867.
70. Son, N. H., Murray, S., Yanovski, J., Hodes, R. J., Weng, N.-p. (2000). Lineage-Specific Telomere Shortening and Unaltered Capacity for Telomerase Expression in Human T and B Lymphocytes with Age. J. Immunol. 165: 1191-1196.
71. Mariani, E., Meneghetti, A., Formentini, I., Neri, S., Cattini, L., Ravaglia, G., Forti, P., Facchini, A. (2003). Different rates of telomere shortening and telomerase activity reduction in CD8 T and CD16 NK lymphocytes with ageing. Exp. Gerontol. 38: 653-659.
72. Rufer, N., Brummendorf, T. H., Kolvraa, S., Bischoff, C., Christensen, K., Wadsworth, L., Schulzer, M., Lansdorp, P. M. (1999). Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoetic stem cells and memory T cells in early childhood. J. Exp. Med. 190: 157-167.
73. Robertson, J. D., Gale, R. E., Wynn, R. F., Dougal, M., Linch, D. C., Testa, N. G., Chopra, R. (2000). Dynamics of telomere shortening in neutrophils and T lymphocytes during ageing and the relationship to skewed X chromosome inactivation patterns. Br. J. Haematol. 109: 272-279.
74. Sedgwick, R. P., Boder, E. (1991). Handbook of Clinical Neurology. In (J. M. J. V. de Jong, Ed.), Elsevier Science, Amsterdam.
75. Dokal, I. (2000). Dyskeratosis congenita in all its forms. Br. J. Haematol. 110: 768-779.
76. Metcalfe, J. A., Parkhill, J., Campbell, L., Stacey, M., Biggs, P., Byrd, P. J., Taylor, A. M. (1996). Accelerated telomere shortening in ataxia telangiectasia. Nat. Genet. 13: 350-353.
77. Kruk, P. A., Bohr, V. A. (1999). Telomeric length in individuals and cell lines with altered p53 status. Radiat. Oncol. Investig. 7: 13-21.
78. Hande, M. P., Balajee, A. S., Tchirkov, A., Wynshaw-Boris, A., Lansdorp, P. M. (2001). Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxiatelangiectasia. Hum. Mol. Genet. 10: 519-528.
79. Mason, P. J., Bessler, M. (2004). Heterozygous telomerase deficiency in mouse and man: when less is definitely not more. Cell Cycle 3: 1127-1129.
80. Chang, E., Harley, C. B. (1995). Telomere length and replicative aging in human vascular tissues. Proc. Natl. Acad. Sci. U.S.A. 92: 11190-11194.
81. Okuda, K., Khan, M. Y., Skurnick, J., Kimura, M., Aviv, H., Aviv, A. (2000). Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis. Atherosclerosis 152: 391-398.
82. 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: 546-550.
83. 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: 1541-1544.
84. Fenton, M., Barker, S., Kurz, D. J., Erusalimsky, J. D. (2001). Cellular Senescence After Single and Repeated Balloon Catheter Denudations of Rabbit Carotid Arteries. Arterioscler. Thromb. Vasc. Biol. 21: 220-226.
85. Leri, A., Franco, S., Zacheo, A., Barlucchi, L., Chimenti, S., Limana, F., Nadal-Ginard, B., Kajstura, J., Anversa, P., Blasco, M. A. (2003). Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22: 131-139.
86. Oh, H., Taffet, G. E., Youker, K. A., Entman, M. L., Overbeek, P. A., Michael, L. H., Schneider, M. D. (2001). Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc. Natl. Acad. Sci. U.S.A. 98: 10308-10313.
87. Urbanek, K., Quaini, F., Tasca, G., Torella, D., Castaldo, C., Nadal-Ginard, B., Leri, A., Kajstura, J., Quaini, E., Anversa, P. (2003). Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc. Natl. Acad. Sci. U.S.A. 100: 10440-10445.
88. Oh, H., Wang, S. C., Prahash, A., Sano, M., Moravec, C. S., Taffet, G. E., Michael, L. H., Youker, K. A., Entman, M. L., Schneider, M. D. (2003). Telomere attrition and Chk2 activation in human heart failure. Proc. Natl. Acad. Sci. U.S.A. 100: 5378-5383.
89. Chimenti, C., Kajstura, J., Torella, D., Urbanek, K., Heleniak, H., Colussi, C., Di Meglio, F., Nadal-Ginard, B., Frustaci, A., Leri, A., Maseri, A., Anversa, P. (2003). Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart Failure. Circ. Res. 93: 604-613.
90. Larsson, L. (1998). The age-related motor disability: Underlying mechanisms in skeletal muscle at the motor unit, cellular and molecular level. Acta Physiol. Scand. 163: S27-S29.
91. Bross, R., Storer, T., Bhasin, S. (1999). Aging and Muscle Loss. Trends Endocrinol. Metab. 10: 194-198.
92. Lexell, J. (1995). Human aging, muscle mass, and fiber type composition. J. Gerontol. A Biol. Sci. Med. Sci. 50: 11-16.
93. Renault, V., Thornell, L. E., Eriksson, P. O., Butler-Browne, G., Mouly, V., Thorne, L. E. (2002). Regenerative potential of human skeletal muscle during aging. Aging Cell 1: 132-139.
94. Monemi, M., Thornell, L., Eriksson, P. (1999). Diverse changes in fibre type composition of the human lateral pterygoid and digastric muscles during aging. J. Neurol. Sci. 171: 38-48.
95. Monemi, M., Eriksson, P. O., Kadi, F., Butler-Browne, G. S., Thornell, L. E. (1999). Opposite changes in myosin heavy chain composition of human masseter and biceps brachii muscles during aging. J. Muscle Res. Cell Motil. 20: 351-361.
96. Decary, S., Mouly, V., Hamida, C. B., Sautet, A., Barbet, J. P., Butler-Browne, G. S. (1997). Replicative potential and telomere length in human skeletal muscle: implications for satellite cell-mediated gene therapy. Hum. Gene Ther. 8: 1429-1438.
97. Wootton, M., Steeghs, K., Watt, D., Munro, J., Gordon, K., Ireland, H., Morrison, V., Behan, W., Parkinson, E. K. (2003). Telomerase alone extends the replicative life span of human skeletal muscle cells without compromising genomic stability. Hum. Gene Ther. 14: 1473-1487.
98. Di Donna, S., Mamchaoui, K., Cooper, R. N., Seigneurin-Venin, S., Tremblay, J., Butler-Browne, G. S., Mouly, V. (2003). Telomerase can extend the proliferative capacity of human myoblasts, but does not lead to their immortalization. Mol. Cancer Res. 1: 643-653.
99. Collins, M., Renault, V., Grobler, L. A., St Clair Gibson, A., Lambert, M. I., Wayne Derman, E., Butler-Browne, G. S., Noakes, T. D., Mouly, V. (2003). Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres. Med. Sci. Sports Exerc. 35: 1524-1528.
100. Decary, S., Hamida, C. B., Mouly, V., Barbet, J. P., Hentati, F., Butler-Browne, G. S. (2000). Shorter telomeres in dystrophic muscle consistent with extensive regeneration in young children. Neuromuscul. Disord. 10: 113-120.
101. Renault, V., Thornell, L. E., Butler-Browne, G., Mouly, V. (2002). Human skeletal muscle satellite cells: aging, oxidative stress and the mitotic clock. Exp. Gerontol. 37: 1229-1236.
102. Lips, P., Courpron, P., Meunier, P. J. (1978). Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcified Tissue Res. 26: 13-17.
103. Cohen-Solal, M. E., Shin, M. S., Lundy, M. W., Parfitt, A. M. (1991). A new method for measuring cancellous bone erosion depth: application to the cellular mechanisms of bone loss in postmenopausal osteoporosis. J. Bone Miner. Res. 6: 1331-1338.
104. Kassem, M., Ankersen, L., Eriksen, E. F., Clark, B. F., Rattan, S. I. (1997). Demonstration of cellular aging and senescence in serially passaged long-term cultures of human trabecular osteoblasts. Osteoporos Int. 7: 514-524.
105. Kveiborg, M., Kassem, M., Langdahl, B., Eriksen, E. F., Clark, B. F. C., Rattan, S. I. S. (1999). Telomere shortening during aging of human osteoblasts in vitro and leukocytes in vivo: lack of excessive telomere loss in osteoporotic patients. Mech Aging Dev. 106: 261-271.
106. Christiansen, M., Stevnsner, T., Bohr, V. A., Clark, B. F., Rattan, S. I. (2000). Gene-specific DNA repair of pyrimidine dimers does not decline during cellular aging in vitro. Exp. Cell Res. 256: 308-314.
107. Yudoh, K., Matsuno, H., Nakazawa, F., Katayama, R., Kimura, T. (2001). Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts. J. Bone Miner. Res. 16: 1453-1464.
108. Yudoh, K., Nishioka, K. (2004). Telomerized presenescent osteoblasts prevent bone mass loss in vivo. Gene Ther. 11:909-915.
109. Banfi, A., Bianchi, G., Notaro, R., Luzzatto, L., Cancedda, R., Quarto, R. (2002). Replicative Aging and Gene Expression in Long-Term Cultures of Human Bone Marrow Stromal Cells. Tissue Eng. 8: 901-910.
110. Stenderup, K., Justesen, J., Clausen, C., Kassem, M. (2003). Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33: 919-926.
111. Price, J. S., Waters, J. G., Darrah, C., Pennington, C., Edwards, D. R., Donell, S. T., Clark, I. M. (2002). The role of chondrocyte senescence in osteoarthritis. Aging Cell 1: 57-65.
112. Martin, J. A., Buckwalter, J. A. (2003). The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J. Bone Joint Surg. Am. 85-A Suppl 2: 106-110.
113. Martin, J. A., Klingelhutz, A. J., Moussavi-Harami, F., Buckwalter, J. A. (2004). Effects of oxidative damage and telomerase activity on human articular cartilage chondrocyte senescence. J. Gerontol. A Biol. Sci. Med. Sci. 59: 324-337.
114. Yudoh, K., Matsuno, H., Osada, R., Nakazawa, F., Katayama, R., Kimura, T. (2000). Decreased cellular activity and replicative capacity of osteoblastic cells isolated from the periarticular bone of rheumatoid arthritis patients compared with osteoarthritis patients. Arthritis Rheum. 43: 2178-2188.
115. Harley, C. B., Futcher, A. B., Greider, C. W. (1990). Telomeres shorten during ageing of human fibroblasts. Nature 345: 458-460.
116. Bandyopadhyay, D., Timchenko, N., Suwa, T., Hornsby, P. J., Campisi, J., Medrano, E. E. (2001). The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells. Exp. Gerontol. 36: 1265-1275.
117. Harle-Bachor, C., Boukamp, P. (1996). Telomerase activity in the regenerative basal layer of the epidermis inhuman skin and in immortal and carcinoma-derived skin keratinocytes. Proc. Natl. Acad. Sci. U.S.A. 93: 6476-6481.
118. Kang, M. K., Guo, W., Park, N. H. (1998). Replicative senescence of normal human oral keratinocytes is associated with the loss of telomerase activity without shortening of telomeres. Cell Growth Differ. 9: 85-95.
119. Matsui, M., Miyasaka, J., Hamada, K., Ogawa, Y., Hiramoto, M., Fujimori, R., Aioi, A. (2000). Influence of aging and cell senescence on telomerase activity in keratinocytes. J. Dermatol. Sci. 22: 80-87.
120. Kang, M. K., Swee, J., Kim, R. H., Baluda, M. A., Park, N. H. (2002). The telomeric length and heterogeneity decrease with age in normal human oral keratinocytes. Mech. Ageing Dev. 123: 585-592.
121. West, M. D. (1994). The cellular and molecular biology of skin aging. Arch. Dermatol. 130: 87-95.
122. Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., Pereira-Smith, O., Peacocke, M., Campisi, J. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U.S.A. 92: 9363-9367.
123. Funk, W. D., Wang, C. K., Shelton, D. N., Harley, C. B., Pagon, G. D., Hoeffler, W. K. (2000). Telomerase expression restores dermal integrity to in vitro-aged fibroblasts in a reconstituted skin model. Exp. Cell Res. 258: 270-278.
124. Severino, J., Allen, R. G., Balin, S., Balin, A., Cristofalo, V. J. (2000). Is beta-galactosidase staining a marker of senescence in vitro and in vivo? Exp. Cell Res. 257: 162-171.
125. Cristofalo, V. J., Allen, R. G., Pignolo, R. J., Martin, B. G., Beck, J. C. (1998). Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc. Natl. Acad. Sci. U.S.A. 95: 10614-10619.
126. Dokal, I., Vulliamy, T. (2003). Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev. 17: 217-225.
127. Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., Dokal, I. (2001). The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413: 432-435.
128. Vulliamy, T., Marrone, A., Szydlo, R., Walne, A., Mason, P. J., Dokal, I. (2004). Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat. Genet 36: 447-449.
129. Slagboom, P. E., Droog, S., Boomsma, D. I. (1994). Genetic determination of telomere size in humans: a twin study of three age groups. Am. J. Hum. Genet. 55: 876-882.
130. Nawrot, T. S., Staessen, J. A., Gardner, J. P., Aviv, A. (2004). Telomere length and possible link to X chromosome. Lancet 363: 507-510.
131. Graakjaer, J., Pascoe, L., Der-Sarkissian, H., Thomas, G., Kolvraa, S., Christensen, K., Londono-Vallejo, J. A. (2004). The relative lengths of individual telomeres are defined in the zygote and strictly maintained during life. Aging Cell 3: 97-102.
132. Allsopp, R. C., Vaziri, H., Patterson, C., Goldstein, S., Younglai, E. V., Futcher, A. B., Greider, C. W., Harley, C. B. (1992). Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 89: 10114-10118.
133. Vaziri, H., Dragowska, W., Allsopp, R. C., Thomas, T. E., Harley, C. B., Lansdorp, P. M. (1994). Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc. Natl. Acad. Sci. U.S.A. 91: 9857-9860.
134. 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: 1739-1747.
135. Benetos, A., Okuda, K., Lajemi, M., Kimura, M., Thomas, F., Skurnick, J., Labat, C., Bean, K., Aviv, A. (2001). Telomere length as an indicator of biological aging: The gender effect and relation with pulse pressure and pulse wave velocity. Hypertension 37: 381-385.
136. Jeanclos, E., Schork, N. J., Kyvik, K. O., Kimura, M., Skurnick, J. H., Aviv, A. (2000). Telomere length inversely correlates with pulse pressure and is highly familial. Hypertension 36: 195-200.
137. Brouilette, S., Singh, R. K., Thompson, J. R., Goodall, A. H., Samani, N. J. (2003). White cell telomere length and risk of premature myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 23: 842-846.
138. Samani, N. J., Boultby, R., Butler, R., Thompson, J. R., Goodall, A. H. (2001). Telomere shortening in atherosclerosis. Lancet 358: 472-473.
139. Nakashima, H., Ozono, R., Suyama, C., Sueda, T., Kambe, M., Oshima, T. (2004). Telomere attrition in white blood cell correlating with cardiovascular damage. Hypertens. Res. 27: 319-325.
140. Obana, N., Takagi, S., Kinouchi, Y., Tokita, Y., Sekikawa, A., Takahashi, S., Hiwatashi, N., Oikawa, S., Shimosegawa, T. (2003). Telomere shortening of peripheral blood mononuclear cells in coronary disease patients with metabolic disorders. Intern. Med. 42: 150-153.
141. Benetos, A., Gardner, J. P., Zureik, M., Labat, C., Xiaobin, L., Adamopolous, C., Temmar, M., Bean, K. E., Thomas, F., Aviv, A. (2004). Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects. Hypertension 43: 182-185.
142. Panossian, L. A., Porter, V. R., Valenzuela, H. F., Zhu, X., Reback, E., Masterman, D., Cummings, J. L., Effros, R. B. (2003). Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol. Aging 24: 77-84.
143. Brummendorf, T. H., Maciejewski, J. P., Mak, J., Young, N. S., Lansdorp, P. M. (2001). Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 97: 895-900.
144. Wu, K. D., Orme, L. M., Shaughnessy, J., Jr., Jacobson, J., Barlogie, B., Moore, M. A. (2003). Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, overall survival. Blood 101: 4982-4989.
145. Cottliar, A., Pedrazzini, E., Corrado, C., Engelberger, M. I., Narbaitz, M., Slavutsky, I. (2003). Telomere shortening in patients with plasma cell disorders. Eur. J. Haematol. 71: 334-340.
146. Damle, R. N., Batliwalla, F. M., Ghiotto, F., Valetto, A., Albesiano, E., Sison, C., Allen, S. L., Kolitz, J., Vinciguerra, V. P., Kudalkar, P., Wasil, T., Rai, K. R., Rerrarini, M., Gregersen, P. K., Chiorazzi, N. (2004). Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations. Blood 103: 375-382.
147. Rigolin, G. M., Porta, M. D., Bugli, A. M., Castagnari, B., Mauro, E., Bragotti, L. Z., Ciccone, M., Cuneo, A., Castoldi, G. (2004). Flow cytometric detection of accelerated telomere shortening in myelodysplastic syndromes: correlations with aetiological and clinical-biological findings. Eur. J. Haematol. 73: 351-358.
148. Kubuki, Y., Suzuki, M., Sasaki, H., Toyama, T., Yamashita, K., Maeda, K., Ido, A., Matsuoka, H., Okayama, A., Nakanishi, T., Tsubouchi, H. (2005). Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia. Leuk. Lymphoma 46: 393-399.
149. Artandi, S. E., DePinho, R. A. (2000). A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr. Opin. Genet. Dev. 10: 39-46.
150. Rufer, N., Dragowska, W., Thornbury, G., Roosnek, E., Lansdorp, P. M. (1998). Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat. Biotechnol. 16: 743-747.
151. Cawthon, R. M., Smith, K. R., O'Brien, E., Sivatchenko, A., Kerber, R. A. (2003). Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361: 393-395.
152. Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., de Benedictis, G. (2000). Inflammaging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908: 244-254.
153. Jonasson, L., Tompa, A., Wikby, A. (2003). Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection. J. Intern. Med. 254: 472-478.
154. Shay, K. (2002). Infectious complications of dental and periodontal diseases in the elderly population. Clin. Infect. Dis. 34: 1215-1223.
155. Danesh, J., Collins, R., Peto, R. (1997). Chronic infections and coronary heart disease: is there a link? Lancet 350: 430-436.
156. Lin, W.-R., Wozniak, M. A., Wilcock, G. K., Itzhaki, R. F. (2002). Cytomegalovirus Is Present in a Very High Proportion of Brains from Vascular Dementia Patients. Neurobiol. Dis. 9: 82-87.
157. Dobson, C. B., Itzhaki, R. F. (1999). Herpes simplex virus type 1 and Alzheimer's disease. Neurobiol. Aging 20: 457-465.
158. Balin, B. J., Gerard, H. C., Arking, E. J., Appelt, D. M., Branigan, P. J., Abrams, J. T., Whittum-Hudson, J. A., Hudson, A. P. (1998). Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Med. Microbiol. Immunol. (Berl) 187: 23-42.
159. von Zglinicki, T. (2003). "Aging at the Molecular Level," Kluwer Academic Pub, Dordrecht, The Netherlands.
160. 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: 89-99.
161. Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D., Cawthon, R. M. (2004). Accelerated telomere shortening in response to life stress. Proc. Natl. Acad. Sci. U.S.A. 101: 17312-17315.