Skip to main content
SpringerLink
Log in

Telomeres, Senescence, Oxidative Stress, and Heterogeneity

  • Chapter
Telomeres and Telomerase in Ageing, Disease, and Cancer

Life span heterogeneity is a hallmark of the ageing process. It is also a characteristic feature of telomere-dependent replicative senescence. We review here evidence showing that telomere shortening is heterogeneous between telomeres and between cells, and relate this to cell-to-cell variation in mitochondrial function and production of reactive oxygen species (ROS). Telomere shortening is to a large extent governed by ROS-mediated telomeric DNA damage, and we show here that apparently stochastic variation in mitochondrial ROS production can account for vast differences in replicative potential between individual cell lineages.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  • Allen RG, Tresini M, Keogh BP, Doggett DL. Cristofalo VJ (1999) Differences in electron transport potential, antioxidant defenses, and oxidant generation in young and senescent fetal lung fibroblasts (WI-38). J Cell Physiol 180 (1): 114–22.

    Article  PubMed  CAS  Google Scholar 

  • Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dolle MET, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J (2006) Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441 (7096): 1011–14.

    Article  PubMed  CAS  Google Scholar 

  • Baird DM, Rowson J, Wynford-Thomas D. Kipling D (2003) Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat Genet 33(2): 203–07.

    Article  PubMed  CAS  Google Scholar 

  • Benanti JA, Galloway DA (2004) Normal human fibroblasts are resistant to RAS-induced senescence Mol Cell Biol 24(7): 2842–52.

    Article  PubMed  CAS  Google Scholar 

  • Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38(5): 515–17.

    Article  PubMed  CAS  Google Scholar 

  • Blackburn EH (2000) Telomere states and cell fates. Nature 408(6808): 53–56.

    Article  PubMed  CAS  Google Scholar 

  • 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): 349–52.

    Article  PubMed  CAS  Google Scholar 

  • Bond, JA, Wyllie FS. and Wynford-Thomas, D. (1994) ‘Escape from senescence in human diploid fibroblasts induced directly by mutant p53’, Oncogene, 9, (7), pp. 1885–89.

    PubMed  CAS  Google Scholar 

  • Boule, J-B. and Zakian, VA. (2006) ‘Roles of Pif1-like helicases in the maintenance of genomic stability’, Nucl. Acids Res., 34, (15), pp. 4147–4153.

    Google Scholar 

  • Cabuy, E, Newton C, Roberts, T, Newbold, R. and Slijepcevic, P. (2004) ‘Identification of subpopulations of cells with differing telomere lengths in mouse and human cell lines by flow FISH’, Cytometry Part A, 62A, (2), pp. 150–161.

    Article  CAS  Google Scholar 

  • Cao, Z, Wanagat, J, McKiernan, SH. and Aiken, JM. (2001) ‘Mitochondrial DNA deletion mutations are concomitant with ragged red regions of individual, aged muscle fibers: analysis by laser-capture microdissection’, Nucleic Acids Res, 29, (21), pp. 4502–8.

    Article  PubMed  CAS  Google Scholar 

  • de Lange, T. (2006) ‘Mammalian Telomeres’, in de lange, T., Lundbard, V. and Blackburn, E. H. (eds) Telomeres. Cold Spring Harbour Laboratory Press: New York, pp. 387–431.

    Google Scholar 

  • Dumont P, Burton M, Chen QM, Gonos ES, Frippiat C, Mazarati, JB, Eliaers, F, Remacle, J. and Toussaint, O. (2000) ‘Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast’, Free Radical Biology and Medicine, 28, (3), pp. 361–373.

    Article  PubMed  CAS  Google Scholar 

  • Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D. and Cawthon, R. M. (2004) ‘Accelerated telomere shortening in response to life stress’, PNAS, 101, (49), pp. 17312–17315.

    Google Scholar 

  • Fagagna Fd Ad, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426(6963): 194–98.

    Article  CAS  Google Scholar 

  • Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, Lowe SW (2002) Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol 22(10): 3497–3508.

    Article  PubMed  CAS  Google Scholar 

  • Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309(5738): 1253–56.

    Article  PubMed  Google Scholar 

  • 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(3): 97–102.

    Article  PubMed  CAS  Google Scholar 

  • 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(4): 503–14.

    Article  PubMed  CAS  Google Scholar 

  • Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345(6274): 458–60.

    Article  PubMed  CAS  Google Scholar 

  • Harman D (1956) Aging: A theory based on free radical and radiation chemistry. J Gerontol 11: 298–300.

    PubMed  CAS  Google Scholar 

  • Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20(4): 145–47.

    PubMed  CAS  Google Scholar 

  • Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains, Exp Cell Res 25: 585–621.

    Article  Google Scholar 

  • Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM, Sakano Y, Paupard MC, Hall DH, Driscoll M (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419(6909): 808–14.

    Article  PubMed  CAS  Google Scholar 

  • Herskind C, Rodemann HP (2000) Spontaneous and radiation-induced differentiation of fibroblasts. Exp Gerontol 35(6–7): 747–55.

    Article  PubMed  CAS  Google Scholar 

  • Hutter E, Unterluggauer H, Uberall F, Schramek H, and Jansen-Durr P (2002) Replicative senescence of human fibroblasts: the role of Ras-dependent signaling and oxidative stress. Exp Gerontol 37(10–11): 1165–74.

    Article  PubMed  CAS  Google Scholar 

  • Jeyapalan J, Leake A, Ahmed S, Saretzki G, Tilby M, von Zglinicki T (2004) The role of telomeres in Etoposide induced tumor cell death. Cell Cycle 3(9): 1169–76.

    PubMed  CAS  Google Scholar 

  • Kang HJ, Choi YS, Hong S-B, Kim K-W, Woo R-S, Won SJ, Kim EJ, Jeon HK, Jo S-Y, Kim TK, Bachoo R, Reynolds I J, Gwag BJ, Lee H-W (2004) Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity. J Neurosci 24(6): 1280–87.

    Article  PubMed  CAS  Google Scholar 

  • Kang HT, Lee HI, Hwang ES (2006) Nicotinamide extends replicative life span of human cells. Aging Cell 5(5): 423–36.

    Article  PubMed  CAS  Google Scholar 

  • Kill IR, Faragher RG, Lawrence K, Shall S (1994) The expression of proliferation-dependent antigens during the life span of normal and progeroid human fibroblasts in culture. J Cell Sci 107: 571–79.

    PubMed  CAS  Google Scholar 

  • Kirkwood T, Cremer T (1982) Cytogerontology since 1881: a reappraisal of August Weissmann and a review of modern progress. Hum Genet 60: 101–21.

    Article  PubMed  CAS  Google Scholar 

  • Kirkwood TB, Finch CE (2002) Ageing: the old worm turns more slowly. Nature 419(6909): 794–95.

    Article  PubMed  CAS  Google Scholar 

  • Kirkwood TBL (2005) Understanding the odd science of aging. Cell 120(4): 437–447.

    Article  PubMed  CAS  Google Scholar 

  • Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38(5): 518–20.

    Article  PubMed  CAS  Google Scholar 

  • Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD (2004) Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 117(11): 2417–26.

    Article  PubMed  CAS  Google Scholar 

  • Laderman KA, Penny JR, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1996) Aging-dependent functional alterations of mitochondrial DNA (mtDNA) from human fibroblasts transferred into mtDNA-less cells. J Biol Chem 271(27): 15891–97.

    Article  PubMed  CAS  Google Scholar 

  • 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(5): 685–91.

    Article  PubMed  CAS  Google Scholar 

  • Lee CM, Lopez ME, Weindruch R, Aiken JM (1998) Association of age-related mitochondrial abnormalities with skeletal muscle fiber atrophy. Free Rad Biol Med 25(8): 964–72.

    Article  PubMed  CAS  Google Scholar 

  • Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12(19): 3008–19.

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Trimarchi JR, Smith PJ, Keefe DL (2002) Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell 1(1): 40–46.

    Article  PubMed  CAS  Google Scholar 

  • Ludwig A, Saretzki G, Holm PS, Tiemann F, Lorenz M, Emrich T, Harley CB, von Zglinicki T (2001) Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res 61(7): 3053–61.

    PubMed  CAS  Google Scholar 

  • Martin-Ruiz C, Saretzki G, Petrie J, Ladhoff J, Jeyapalan J, Wei W, Sedivy J, von Zglinicki T (2004) Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative life span. J Biol Chem 279(17): 17826–33.

    Article  PubMed  CAS  Google Scholar 

  • Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, Hirakawa T, Inoue T, Yodoi J (2002) Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxidants Redox Signal 4(4): 693–96.

    Article  CAS  Google Scholar 

  • Muller-Hocker J (1989) Cytochrome-c-oxidase deficient cardiomyocytes in the human heart–an age-related phenomenon. A histochemical ultracytochemical study. Am J Pathol 134(5): 1167–73.

    PubMed  CAS  Google Scholar 

  • Oexle K, Zwirner A (1997) Advanced telomere shortening in respiratory chain disorders. Hum Mol Genet 6(6): 905–8.

    Article  PubMed  CAS  Google Scholar 

  • Ogryzko V, Hirai T, Russanova V, Barbie D, Howard B (1996) Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol 16(9): 5210–18.

    PubMed  CAS  Google Scholar 

  • Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry D J, Entman ML, Schneider MD (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. PNAS 100(21): 12313–18.

    Article  PubMed  CAS  Google Scholar 

  • Olovnikov AM (1971) [Principle of marginotomy in template synthesis of polynucleotides]. Dokl Akad Nauk SSSR 201(6): 1496–99.

    PubMed  CAS  Google Scholar 

  • Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birkett M, Harold G, Schaeuble K, Birch-Machin M, Kirkwood T, von Zglinicki T (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5(5): e 110.

    Google Scholar 

  • Passos JF, von Zglinicki T (2005) Mitochondria, telomeres and cell senescence. Exp Gerontol 40(6): 466–72.

    Article  PubMed  CAS  Google Scholar 

  • Passos JF, von Zglinicki T, Saretzki G (2006) Mitochondrial dysfunction and cell senescence: cause or consequence? Rejuv Res 9(1); 64–68.

    Article  CAS  Google Scholar 

  • Petersen S, Saretzki G, von Zglinicki T (1998) Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res 239(1): 152–60.

    Article  PubMed  CAS  Google Scholar 

  • Ramsey M, Sharpless N (2006) ROS as a tumour suppressor? Nat Cell Biol. 8(11): 1213–15.

    Article  PubMed  CAS  Google Scholar 

  • Rea SL, Wu D, Cypser JR, Vaupel JW, Johnson TE (2005) A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans. Nat Genet 37(8): 894–98.

    Article  PubMed  CAS  Google Scholar 

  • Robles S, Adami G (1998) Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts’. Oncogene 16(9): 1113–23.

    Article  PubMed  CAS  Google Scholar 

  • Santos JH, Hunakova L, Chen Y, Bortner C, Van Houten B (2003) Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death. J Biol Chem 278 (3): 1728–34.

    Article  PubMed  CAS  Google Scholar 

  • Santos JH, Meyer JN, Van Houten B (2006) Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis. Hum Mol Genet 15(11): 1757–68.

    Article  PubMed  CAS  Google Scholar 

  • Saretzki G, Murphy MP, von Zglinicki T (2003) MitoQ counteracts telomere shortening and elongates life span of fibroblasts under mild oxidative stress. Aging Cell 2(2): 141–43.

    Article  PubMed  CAS  Google Scholar 

  • Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E, Artandi MK, Oro AE, Artandi SE (2005) Conditional telomerase induction causes proliferation of hair follicle stem cells. 436(7053): 1048–52.

    Google Scholar 

  • Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308(5730): 1909–11.

    Article  PubMed  CAS  Google Scholar 

  • 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(9): 6824–30.

    Article  PubMed  CAS  Google Scholar 

  • 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(5): 593–602.

    Article  PubMed  CAS  Google Scholar 

  • Sitte N, Merker K, Grune T. von Zglinicki T (2001) Lipofuscin accumulation in proliferating fibroblasts in vitro: an indicator of oxidative stress. Exper Gerontol 36(3): 475–86.

    Article  CAS  Google Scholar 

  • Sitte N, Merker K, von Zglinicki T, Grune T (2000) Protein oxidation and degradation during proliferative senescence of human MRC-5 fibroblasts. Free Rad Biol Med 28(5): 701–08.

    Article  PubMed  CAS  Google Scholar 

  • Sitte N, Saretzki G, von Zglinicki T (1998) Accelerated telomere shortening in fibroblasts after extended periods of confluency. Free Rad Biol Med 24(6): 885–93.

    Article  PubMed  CAS  Google Scholar 

  • Smith JR, Hayflick L (1974) Variation in the life-span of clones derived from human diploid cell strains. J Cell Biol 62(1): 48–53.

    Article  PubMed  CAS  Google Scholar 

  • Smith JR, Whitney RG (1980) Intraclonal variation in proliferative potential of human diploid fibroblasts: stochastic mechanism for cellular aging. Science 207(4426): 82–84.

    Article  PubMed  CAS  Google Scholar 

  • Sozou PD, Kirkwood T (2001) A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA. J Theor Biol 213: 573–86.

    Article  PubMed  CAS  Google Scholar 

  • Stampfer MR, Yaswen P (2003) Human epithelial cell immortalization as a step in carcinogenesis. Cancer Lett 194(2): 199–208.

    Article  PubMed  CAS  Google Scholar 

  • Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, Taylor GA, Plusa SM, Needham SJ, Greaves LC, Kirkwood T, Turnbull DM (2003) Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Inv 112(9): 1351–60.

    CAS  Google Scholar 

  • Thomas E, Al-Baker E, Dropcova S, Denyer S, Ostad N, Lloyd A, Kill IR, Faragher RGA (1997) Different kinetics of senescence in human fibroblasts and peritoneal mesothelial cells. Exper Cell Res 236(1): 355–58.

    Article  CAS  Google Scholar 

  • Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ., Huang TT, Nelson J, Strong R, Richardson A (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genom 16: 29–37.

    Article  CAS  Google Scholar 

  • von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27(7): 339–44.

    Article  Google Scholar 

  • von Zglinicki T, Petrie J, Kirkwood TB (2003) Telomere-driven replicative senescence is a stress response. Nat Biotechnol 21(3): 229–30.

    Article  CAS  Google Scholar 

  • Wanagat J, Cao Z, Pathare P, Aiken JM (2001) Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. Faseb J 15 (2): 322–32.

    Article  PubMed  CAS  Google Scholar 

  • Watson JD (1972) Origin of concatemeric T7 DNA. Nat New Biol 239(94): 197–201.

    PubMed  CAS  Google Scholar 

  • Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 94(2): 514–49.

    Article  PubMed  CAS  Google Scholar 

  • Zhang P, Chan SL, Fu W, Mendoza M, Mattson MP (2003) TERT suppresses apoptosis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14–3-3 protein binding ability. FASEB J pp. 02–0603.

    Google Scholar 

  • Zou Y, Sfeir A, Gryaznov SM, Shay JW, Wright WE (2004) Does a sentinel or a subset of short telomeres determine replicative senescence? Mol Biol Cell 15(8): 3709–18.

    Article  PubMed  CAS  Google Scholar 

  • Zwerschke W, Mazurek S, Stockl P, Hutter E, Eigenbrodt E, Jansen-Durr P (2003) Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence. Biochem J 376 (Pt 2): 403–11.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Integrated Systems Biology of Ageing and Nutrition, University of Newcastle upon Tyne, NE4 6BE, UK

    João F. Passos, Glyn Nelson & Thomas von Zglinicki

Authors
  1. João F. Passos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glyn Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas von Zglinicki
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Ulm, Albert-Einstein-Allee 11, 89091, Ulm, Germany

    K. Lenhard Rudolph

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Passos, J.F., Nelson, G., von Zglinicki, T. (2008). Telomeres, Senescence, Oxidative Stress, and Heterogeneity. 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_3

Download citation

Publish with us

Policies and ethics

Search

Navigation