Cellular senescence occurs when a cell enters a viable state of irreversible growth arrest. Since the first characterization of cell senescence for human cells, specifically human diploid fibroblasts, in classic experiments by Hayflick and Moorhead in the early 1960s (Hayflick and Moorhead 1961), primary cultures of human cells have been shown to undergo cell senescence in response to a number of different environmental stressors. For example, oxidative stress (von Zglinicki et al. 1995, Finkel and Holbrook 2000), exposure to irradiation (Finkel and Holbrook 2000), and inappropriate stimulation of mitogenic signaling pathways (Ridley et al 1988, Serrano et al. 1997), have all been shown to induce cell senescence in normal human cells grown in vitro. However, even when maintained in a stress-free environment under optimal growth conditions, cultures of normal diploid human cells still ultimately end up in a state of cell senescence after a finite number of population doublings. The cause of this phenomenon, specifically referred to as replicative senescence, or the Hayflick limit, after the discoverer Leonard Hayflick, eluded scientists until the mid-1990s, when researchers at Geron corporation (Bodnar et al. 1998) and the Whitehead Institute (Meyerson et al. 1998) discovered that the gradual erosion of telomeres, essential genetic elements that cap the ends of chromosomes, during proliferation of normal diploid human cells is what ultimately limits the replicative capacity of these cells and induces senescence. In this chapter, I will review the phenomenon of cell senescence, specifically, replicative senescence or telomere-induced senescence, the mechanism of telomere-induced senescence, and the role of replicative senescence in organismal aging.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Afshari CA, Vojta PJ, Annab LA, Futreal PA, Willard TB, Barrett JC. (1993) Investigation of the role of G1/S cell cycle mediators in cellular senescence. Exp Cell Res 209: 231–7.
Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA 93: 13742–7.
Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley C (1992) Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89: 10114–8.
Allsopp RC, Chang E, Kashefi-Aazam M, Rogaev EI, Piatyszek MA, Shay JW, Harley CB (1995) Telomere shortening is associated with cell division in vitro and in vivo. Exp Cell Res 220: 194–200.
Allsopp RC, Cheshier S, Weissman IL (2002) Telomerase activation and rejuvenation of telomere length in stimulated T cells derived from serially transplanted hematopoietic stem cells. J Exp Med 196: 1427–33.
Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL (2003) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102: 517–20.
Artandi SE, Chnag S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA (2000) Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406(6796): 641–454.
Bandyopadhyay D, Timchenko N, Suwa T, Hornsby PJ, Campisi J, Medrano EE (2001) The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells. Exp Gerontol 36: 1265–75.
Benn P (1976) Specific chromosome aberrations in senescent fibroblast cell lines derived from human embryos. Am J Hum Genet 28: 465–73.
Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22: 4212–22.
Bierman, J (1978) The effect of donor age on the in vitro life span of cultured human arterial smooth-muscle cells. In vitro 14: 951–5.
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: 349–52.
Bond JA, Wyllie FS, Wynford-Thomas D (1994) Escape from senescence in human diploid fibroblasts induced directly by mutant p53. Oncogene 9: 1885–9.
Bond J, Jones C, Haughton M, DeMicco C, Kipling D, Wynford-Thomas D (2004) Direct evidence from siRNA-directed “knock down” that p16(INK4a) is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation. Exp Cell Res 292: 151–6.
Broccoli D, Young JW, de Lange T (1995) Telomerase activity in normal and malignant hematopoietic cells. Proc Natl Acad Sci USA 92: 9082–6.
Brookes S, Rowe J, Ruas M, Llanos S, Clark PA, Lomax M, James MC, Vatcheva R, Bates S, Vousden KH, Parry D, Gruis N, Smit N, Bergman W, Peters G (2002) INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J 21: 2936–45.
Brown JP, Wei W, Sedivy JM (1997) Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277: 831–4.
Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR (1995) Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14: 4240–8.
Chang E, Harley, H (1995) Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci USA 92: 11190–4.
Chai W, Du Q, Shay JW, Wright WE (2006) Human telomeres have different overhang sizes at leading versus lagging strands. Mol Cell 21 427–35.
Chiu CP, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE, Harley CB, Lansdorp PM (1996) Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 14: 239–48.
Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, Lee HW, von Zglinicki T, Ganser A, Schirmacher P, Nakauchi H, Rudolph KL (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39: 99–105.
Cooke H, Smith B (1986) Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harb Symp Quant Biol 51: 213–9.
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S (1992) Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11: 1921–9.
Counter CM, Hahn WC, Wei W, Caddle SD, Beijersbergen RL, Lansdorp PM, Sedivy JM, Weinberg RA (1998) Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci USA 95: 14723–8.
Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC (1998) Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc Natl Acad Sci USA 95: 10614–9.
Cristofalo VJ, Lorenzini A, Allen RG, Torres C, Tresini M (2004) Replicative senescence: a critical review. Mech Ageing Dev 125: 827–48.
d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194–8.
De Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM, Varmus HE (1990) Structure and variability of human chromosome ends. Mol Cell Biol 10: 518–27.
De Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–10.
Decary S, Mouly V, Hamida CB, Sautet A, Barbet JP, Butler-Browne GS (1997) Replicative potential and telomere length in human skeletal muscle: implications for satellite cell-mediated gene therapy. Hum Gene Ther 8: 1429–38.
Dimri GP, Hara E, Campisi J (1994) Regulation of two E2F-related genes in presenescent and senescent human fibroblasts. J Biol Chem 269: 16180–6.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira- Smith O, et al. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92: 9363–7.
Dulic V, Beney GE, Frebourg G, Drullinger LF, Stein GH (2000) Uncoupling between phenotypic senescence and cell cycle arrest in aging p21-deficient fibroblasts. Mol Cell Biol 20: 6741–54.
Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW (2000) PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14: 2015–27.
Finkel, T, Holbrook, N (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408: 239–47.
Fukami J, Anno K, Ueda K, Takahashi T, Ide T (1995) Enhanced expression of cycling D1 in senescent human fibroblasts. Mech Ageing Dev 81: 139–57.
Gire V, Roux P, Wynford-Thomas D, Brondello JM, Dulic V (2004) DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J 23: 2554–63.
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: 503–14.
Goldstein, S (1990) Replicative senescence: the human fibroblast comes of age. Science 249: 1129–1134.
Gorman, S, Cristofalo, V (1985) Reinitiation of cellular DNA synthesis in BrdU-selected nondividing senescent WI-38 cells by simian virus 40 infection. J Cell Physiol 125: 122–6.
Greider C, Blackburn, E (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43: 405–13.
Hara E, Tsurui H, Shinozaki A, Nakada S, Oda K (1991) Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. Biochem Biophys Res Commun 179: 528–34.
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–60.
Harley, C (1991) Telomere loss: mitotic clock or genetic time bomb? Mutat Res 256: 271–82.
Harley CB, Vaziri H, Counter CM, Allsopp RC (1992) The telomere hypothesis of cellular aging. Exp Gerontol 27: 375–82.
Harley C (2001) Telomerase is not an oncogene. Oncogene 21: 494–502.
Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC (1990) Telomere reduction in human colorectal carcinoma and with ageing. Nature 346: 866–8.
Hayflick, L, Moorhead, P (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585–621.
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: 67–77.
Henderson S, Allsopp R, Spector D, Wang SS, Harley C (1996) In situ analysis of changes in telomere size during replicative aging and cell transformation. J Cell Biol 134: 1–12.
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: 501–13.
Herbig U, Sedivy J. (2006) Regulation of growth arrest in senescence: telomere damage is not the end of the story. Mech Ageing Dev 127: 16–24.
Ide T, Tsuji Y, Ishibashi S, Mitsui Y. (1983). Reinitiation of host DNA synthesis in senescent human diploid cells by infection with Simian virus 40. Exp Cell Res. 143, 343–9.
Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J, Dimri GP (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 23: 389–401.
Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 66: 2011–5.
Klingelhutz AJ, Barber SA, Smith PP, Dyer K, McDougall JK (1994) Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells. Mol Cell Biol 14: 961–9.
Kortlever RM, Higgins PJ, Bernards R (2006) Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol 8: 877–84.
Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, Dirks RW, Raap AK, Tanke HJ (1996) Heterogeneity in telomere length of human chromosomes. Hum Mol Genet 5: 685–91.
Liu K, Hodes RJ, Weng NP (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: 4826–30.
Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ (1991) In vivo loss of telomeric repeats with age in humans. Mutat Res 256: 45–8.
Matsumura T, Zerrudo Z, Hayflick L (1979) Senescent human diploid cells in culture: survival, DNA synthesis and morphology. J Gerontol 34: 328–34.
McClintock B (1941) The stability of broken ends of chromosomes in Zea mays. Genetics 26: 234–282.
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA (1998) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 22: 785–95.
Minamino T, Mitsialis SA, Kourembanas S (2001) Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol 21: 3336–42.
Morin G (1989) The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59: 521–9.
Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR (1988) A highly conserved repetitive DNA sequence, (TTAGGG) n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85: 6622–6.
Mueller SN, Rosen EM, Levine EM (1980) Cellular senescence in a cloned strain of bovine fetal aortic endothelial cells. Science 207: 889–91.
Muntoni A, Reddel R (2005) The first molecular details of ALT in human tumor cells. Hum Mol Genet 14: R191–6.
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: 955–9.
Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211: 90–8.
Norwood TH, Pendergrass WR, Sprague CA, Martin GM (1974) Dominance of the senescent phenotype in heterokaryons between replicative and post-replicative human fibroblast-like cells. Proc Natl Acad Sci SA 71: 2231–5.
Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409: 1067–70.
Olovnikov A (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 14: 181–90.
Parrinello S, Coppe JP, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118: 485–96.
Pereira-Smith O, Smith J (1982) Phenotype of low proliferative potential is dominant in hybrids of normal human fibroblasts. Somatic Cell Genet 8:731–42.
Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW, Wright WE (2001) Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev 15: 398–403.
Rheinwald, J, Green, H (1975) Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6: 331–43.
Ridley AJ, Paterson HF, Noble M, Land H (1988) Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J 7: 1635–45.
Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD (2001) Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409: 633–7.
Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in aging telomerase- deficient mice. Cell 96: 701–12.
Samper E, Fernandez P, Eguia R, Martin-Rivera L, Bernad A, Blasco MA, Aracil M (2002) Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood 99: 2767–75.
Schneider E, Mitsui Y (1976) The relationship between in vitro cellular aging and in vivo human age. Proc Natl Acad Sci USA 73: 3584–8.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.
Shay J, Wright W (1989) Quantitation of the frequency of immortalization of normal human diploid fibroblasts by SV40 large T-antigen. Exp Cell Res 184: 109–18.
Shay JW, Pereira-Smith OM, Wright WE (1991) A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 196: 33–9.
Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999) Microarray analysis of replicative senescence. I 9: 939–45.
Sherwood SW, Rush D, Ellsworth JL, Schimke RT (1988) Defining cellular senescence in IMR-90 cells: a flow cytometric analysis. Proc Natl Acad Sci USA 85: 9086–90.
Stampfer MR, Bodnar A, Garbe J, Wong M, Pan A, Villeponteau B, Yaswen P (1997) Gradual phenotypic conversion associated with immortalization of cultured human mammary epithelial cells. Mol Biol Cell 8: 2391–405.
Stein GH, Beeson M, Gordon L (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249: 666–9.
Takada T, Hayashi T, Arakawa M, Kominami R (1992) Telomere elongation frequently observed during tumor metastasis. Jpn J Cancer Res 83: 1124–7.
Tassin J, Malaise E, Courtois Y (1979) Human lens cells have an in vitro proliferative capacity inversely proportional to the donor age. Exp Cell Res 123: 388–92.
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145–7.
Tice RR, Schneider EL, Kram D, Thorne P (1979) Cytokinetic analysis of the impaired proliferative response of peripheral lymphocytes from aged humans to phytohemagglutinin. J Exp Med 149: 1029–41.
Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA. 91: 9857–60.
Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I (2001) The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413: 432–5.
Wang JC, Warner JK, Erdmann N, Lansdorp PM, Harrington L, Dick JE (2005) Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc Natl Acad Sci USA 102: 14398–403.
Watson, J (1972) Origin of concatemeric T7 DNA. Nat New Biol. 239: 197–20.
Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, Hupp T, Wynford-Thomas D (2000) Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 20: 2803–8.
Weng NP, Levine 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: 11091–4.
Wistrom C, Villeponteau B (1992) Cloning and expression of SAG: a novel marker of cellular senescence. Exp Cell Res 199: 355–62.
Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW (1995) Telomerase activity in human germline and embryonic tissues and cells. Dev Genet 18: 173–9.
von Zglinicki T, Saretzki G, Docke W, Lotze C (1995). Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp Cell Res 220: 186–93.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Allsopp, R. (2008). Telomere-Induced Senescence of Primary Cells. In: Rudolph, K.L. (eds) Telomeres and Telomerase in Ageing, Disease, and Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73709-4_2
Download citation
DOI: https://doi.org/10.1007/978-3-540-73709-4_2
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-73708-7
Online ISBN: 978-3-540-73709-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)