Abstract

Normal human somatic cells have strictly limited proliferative capacity and reach a state of senescence when it becomes exhausted. It is believed that senescence is a response to extensive and irreparable DNA injury, localized in telomeric and/or non-telomeric regions of the genome. Main cause of this damage is oxidative stress, increasing due to deteriorated function of mitochondria. Senescent cells accumulate in tissues during aging, which is causatively linked with the development of various pathologies in elderly individuals, including cancer. This paper, prepared exactly 50 years after Leonard Hayflick’s discovery of the relationship between cellular senescence and organismal aging is aimed at presenting the current knowledge about molecular determinants of senescence, with particular emphasis paid to the role of oxidative stress, effectors of senescence at the level of cell cycle, markers of this phenomenon, and the effect of senescent cells on the development of certain age-related diseases.

References

• 1. Acosta J.C., Banito A., Wuestefeld T., Georgilis A., Janich P., MortonJ.P., Athineos D., Kang T.W., Lasitschka F., Andrulis M., PascualG., Morris K.J., Khan S., Jin H., Dharmalingam G. i wsp.: A complexsecretory program orchestrated by the inflammasome controls paracrinesenescence. Nat. Cell Biol., 2013; 15: 978-990
  Google Scholar
• 2. Allsopp R.C., Harley C.B.: Evidence for a critical telomere lengthin senescent human fibroblasts. Exp. Cell Res., 1995; 219: 130-136
  Google Scholar
• 3. Alpan R.S., Pardee A.B.: p21WAF1/CIP1/SDI1 is elevated through a p53–independent pathway by mimosine. Cell Growth Differ., 1996; 7:893-901
  Google Scholar
• 4. Artandi S.E., Attardi L.D.: Pathways connecting telomeres andp53 in senescence, apoptosis, and cancer. Biochem. Biophys. ResCommun., 2005; 331: 881-890
  Google Scholar
• 5. Balducci L., Lyman G.H.: Cancer in the elderly. Epidemiologic andclinical implications. Clin. Geriatr. Med., 1997; 13: 1-14
  Google Scholar
• 6. Barascu A., Le Chalony C., Pennarun G., Genet D., Imam N., LopezB., Bertrand P.: Oxidative stress induces an ATM-independentsenescence pathway through p38 MAPK-mediated lamin B1 accumulation.EMBO J., 2012; 31: 1080-1094
  Google Scholar
• 7. Bavik C., Coleman I., Dean J.P., Knudsen B., Plymate S., NelsonP.S.: The gene expression program of prostate fibroblast senescencemodulates neoplastic epithelial cell proliferation through paracrinemechanisms. Cancer Res., 2006; 66: 794-802
  Google Scholar
• 8. Beausejour C.M., Krtolica A., Galimi F., Narita M., Lowe S.W.,Yaswen P., Campisi J.: Reversal of human cellular senescence: rolesof the p53 and p16 pathways. EMBO J., 2003; 22: 4212-4222
  Google Scholar
• 9. Belair C.D., Yeager T.R., Lopez P.M., Reznikoff C.A.: Telomeraseactivity: a biomarker of cell proliferation, not malignant transformation.Proc. Natl. Acad. Sci. USA, 1997; 94: 13677-13682
  Google Scholar
• 10. Brandes D., Murphy D.G., Anton E.B., Barnard S.: Ultrastructuraland cytochemical changes in cultured human lung cells. J. Ultrastruct.Res., 1972; 39: 465-483
  Google Scholar
• 11. Broccoli D.: Function, replication and structure of the mammaliantelomere. Cytotechnology, 2004; 45: 3-12
  Google Scholar
• 12. Cahill M.A., Janknecht R., Nordheim A.: Signalling pathways:jack of all cascades. Curr. Biol., 1996; 6: 16-19
  Google Scholar
• 13. Campisi J.: Cancer, aging and cellular senescence. In Vivo, 2000;14: 183-188
  Google Scholar
• 14. Campisi J.: Cellular senescence as a tumor-suppressor mechanism.Trends Cell Biol., 2001; 11: S27-S31
  Google Scholar
• 15. Campisi J.: Cancer and ageing: rival demons? Nat. Rev. Cancer,2003; 3: 339-349
  Google Scholar
• 16. Campisi J., Andersen J.K., Kapahi P., Melov S.: Cellular senescence:a link between cancer and age-related degenerative disease?Semin. Cancer Biol., 2011; 21: 354-359
  Google Scholar
• 17. Campisi J., d`Adda di Fagagna F.: Cellular senescence: when badthings happen to good cells. Nat. Rev. Mol. Cell Biol., 2007; 8: 729-740
  Google Scholar
• 18. Carrel A., Ebeling A.H.: Age and multiplication of fibroblasts. J.Exp. Med., 1921; 34: 599-623
  Google Scholar
• 19. Chien Y., Scuoppo C., Wang X., Fang X., Balgley B., Bolden J.E.,Premsrirut P., Luo W., Chicas A., Lee C.S., Kogan S.C., Lowe S.W.: Controlof the senescence-associated secretory phenotype by NF-κBpromotes senescence and enhances chemosensitivity. Genes Dev.,2011; 25: 2125-2136
  Google Scholar
• 20. Collins K., Mitchell J.R.: Telomerase in the human organism.Oncogene, 2002; 21: 564-579
  Google Scholar
• 21. Coppe J.P., Desprez P.Y., Krtolica A., Campisi J.: The senescence–associated secretory phenotype: the dark side of tumor suppression.Annu. Rev. Pathol., 2010; 5: 99-118
  Google Scholar
• 22. Coppe J.P., Kauser K., Campisi J., Beausejour C.M.: Secretion ofvascular endothelial growth factor by primary human fibroblastsat senescence. J. Biol. Chem., 2006; 281: 29568-29574
  Google Scholar
• 23. Coppe J.P., Patil C.K., Rodier F., Sun Y., Munoz D.P., Goldstein J.,Nelson P.S., Desprez P.Y., Campisi J.: Senescence-associated secretoryphenotypes reveal cell-nonautonomous functions of oncogenicRAS and the p53 tumor suppressor. PLoS Biol., 2008; 6: 2853-2868
  Google Scholar
• 24. Courtois-Cox S., Jones S.L., Cichowski K.: Many roads lead to oncogene-induced senescence. Oncogene, 2008; 27: 2801-2809
  Google Scholar
• 25. Datto M.B., Li Y., Panus J.F., Howe D.J., Xiong Y., Wang X.F.: Transforminggrowth factor beta induces the cyclin-dependent kinaseinhibitor p21 through a p53-independent mechanism. Proc. Natl.Acad. Sci. USA, 1995; 92: 5545-5549
  Google Scholar
• 26. Deng G., Lu Y., Zlotnikov G., Thor A.D., Smith H.S.: Loss of heterozygosityin normal tissue adjacent to breast carcinomas. Science,1996; 274: 2057-2059
  Google Scholar
• 27. DePinho R.A.: The age of cancer. Nature, 2000; 408: 248-254
  Google Scholar
• 28. 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.: A biomarker that identifies senescent human cells inculture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA, 1995;92: 9363-9367
  Google Scholar
• 29. Dolle M.E., Snyder W.K., Gossen J.A., Lohman P.H., Vijg J.: Distinctspectra of somatic mutations accumulated with age in mouseheart and small intestine. Proc. Natl. Acad. Sci. USA, 2000; 97:8403-8408
  Google Scholar
• 30. Draskovic I., Londono Vallejo A.: Telomere recombination andalternative telomere lengthening mechanisms. Front Biosci., 2013;18: 1-20
  Google Scholar
• 31. 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.: A DNAdamage checkpoint response in telomere-initiated senescence. Nature,2003; 426: 194-198
  Google Scholar
• 32. Finkel T., Serrano M., Blasco M.A.: The common biology of cancerand ageing. Nature, 2007; 448: 767-774
  Google Scholar
• 33. Forsyth N.R., Wright W.E., Shay J.W.: Telomerase and differentiationin multicellular organisms: turn it off, turn it on, and turn itoff again. Differentiation, 2002; 69: 188-197
  Google Scholar
• 34. Freund A., Patil C.K., Campisi J.: p38MAPK is a novel DNA damageresponse-independent regulator of the senescence-associatedsecretory phenotype. EMBO J., 2011; 30: 1536-1548
  Google Scholar
• 35. Gartel A.L., Tyner A.L.: Transcriptional regulation of the p21(WAF1/CIP1) gene. Exp. Cell Res., 1999; 246: 280-289
  Google Scholar
• 36. Greider C.W.: Telomere length regulation. Annu. Rev. Biochem.,1996; 65: 337-365
  Google Scholar
• 37. Greider C.W.: Telomeres and senescence: the history, the experiment,the future. Curr. Biol, 1998; 8: R178-R181
  Google Scholar
• 38. Greider C.W., Blackburn E.H.: Identification of a specific telomereterminal transferase activity in Tetrahymena extracts. Cell,1985; 43: 405-413
  Google Scholar
• 39. Guney I., Wu S., Sedivy J.M.: Reduced c-Myc signaling triggerstelomere-independent senescence by regulating Bmi-1 and p16INK4a.Proc. Natl. Acad. Sci. USA, 2006; 103: 3645-3650
  Google Scholar
• 40. Hampel B., Wagner M., Teis D., Zwerschke W., Huber L.A., Jansen-Durr P.: Apoptosis resistance of senescent human fibroblasts iscorrelated with the absence of nuclear IGFBP-3. Aging Cell, 2005;4: 325-330
  Google Scholar
• 41. Harley C.B., Futcher A.B., Greider C.W.: Telomeres shorten duringageing of human fibroblasts. Nature, 1990; 345: 458-460
  Google Scholar
• 42. Hayflick L.: The limited in vitro lifetime of human diploid cellstrains. Exp. Cell Res, 1965; 37: 614-636
  Google Scholar
• 43. Hayflick L., Moorhead P.S.: The serial cultivation of human diploidcell strains. Exp. Cell Res, 1961; 25: 585-621
  Google Scholar
• 44. Herbig U., Jobling W.A., Chen B.P., Chen D.J., Sedivy J.M.: Telomereshortening triggers senescence of human cells through a pathwayinvolving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell,2004; 14: 501-513
  Google Scholar
• 45. Herbig U., Sedivy J.M.: Regulation of growth arrest in senescence:telomere damage is not the end of the story. Mech. AgeingDev., 2006; 127: 16-24
  Google Scholar
• 46. Hoshi H., McKeehan W.L.: Isolation, growth requirements, cloning,prostacyclin production and life-span of human adult endothelialcells in low serum culture medium. In Vitro Cell Dev. Biol.,1986; 22: 51-56
  Google Scholar
• 47. Itahana K., Dimri G., Campisi J.: Regulation of cellular senescenceby p53. Eur. J. Biochem., 2001; 268: 2784-2791
  Google Scholar
• 48. Jacobs J.J., de Lange T.: Significant role for p16INK4a in p53-independenttelomere-directed senescence. Curr. Biol., 2004; 14: 2302-2308
  Google Scholar
• 49. Jacobs J.J., Kieboom K., Marino S., DePinho R.A., van LohuizenM.: The oncogene and Polycomb-group gene bmi-1 regulates cellproliferation and senescence through the ink4a locus. Nature, 1999;397: 164-168
  Google Scholar
• 50. Jemal A., Siegel R., Xu J., Ward E.: Cancer statistics, 2010. CACancer J. Clin., 2010; 60: 277-300
  Google Scholar
• 51. Johnson J.E.Jr.: Fine structure of IMR-90 cells in culture as examinedby scanning and transmission electron microscopy. Mech.Ageing Dev., 1979; 10: 405-443
  Google Scholar
• 52. Jonason A.S., Kunala S., Price G.J., Restifo R.J., Spinelli H.M.,Persing J.A., Leffell D.J., Tarone R.E., Brash D.E.: Frequent clones ofp53-mutated keratinocytes in normal human skin. Proc. Natl. Acad.Sci. USA, 1996; 93: 14025-14029
  Google Scholar
• 53. Kang M.K., Guo W., Park N.H.: Replicative senescence of normalhuman oral keratinocytes is associated with the loss of telomeraseactivity without shortening of telomeres. Cell Growth Differ.,1998; 9: 85-95
  Google Scholar
• 54. Kiyono T., Foster S.A., Koop J.I., McDougall J.K., Galloway D.A.,Klingelhutz A.J.: Both Rb/p16INK4a inactivation and telomerase activityare required to immortalize human epithelial cells. Nature,1998; 396: 84-88
  Google Scholar
• 55. Kleinerman D.I., Dinney C.P., Zhang W.W., Lin S.H., Van N.T.,Hsieh J.T.: Suppression of human bladder cancer growth by increasedexpression of C-CAM1 gene in an orthotopic model. CancerRes., 1996; 56: 3431-3435
  Google Scholar
• 56. Krtolica A., Campisi J.: Cancer and aging: a model for the cancerpromoting effects of the aging stroma. Int. J. Biochem. Cell Biol.,2002; 34: 1401-1414
  Google Scholar
• 57. Krtolica A., Parrinello S., Lockett S., Desprez P.Y., Campisi J.:Senescent fibroblasts promote epithelial cell growth and tumorigenesis:a link between cancer and aging. Proc. Natl. Acad. Sci. USA,2001; 98: 12072-12077
  Google Scholar
• 58. Książek K., Passos J.F., Olijslagers S., Saretzki G., Martin-Ruiz C.,von Zglinicki T.: Premature senescence of mesothelial cells is associatedwith non-telomeric DNA damage. Biochem. Biophys. ResCommun., 2007; 362: 707-711
  Google Scholar
• 59. Książek K., Winckiewicz M., Staniszewski R., Breborowicz A., Witowski J.: Correlation between the donor age and the proliferativelifespan of human peritoneal mesothelial cells in vitro: is TGF-β1a link? Exp Gerontol., 2007; 42: 840-843
  Google Scholar
• 60. Lamkanfi M., Dixit V.M.: Inflammasomes: guardians of cytosolicsanctity. Immunol. Rev., 2009; 227: 95-105
  Google Scholar
• 61. Le Maitre C.L., Freemont A.J., Hoyland J.A.: Accelerated cellularsenescence in degenerate intervertebral discs: a possible rolein the pathogenesis of intervertebral disc degeneration. ArthritisRes. Ther., 2007; 9: R45
  Google Scholar
• 62. Lee A.C., Fenster B.E., Ito H., Takeda K., Bae N.S., Hirai T., Yu Z.X.,Ferrans V.J., Howard B.H., Finkel T.: Ras proteins induce senescenceby altering the intracellular levels of reactive oxygen species. J. Biol.Chem., 1999; 274: 7936-7940
  Google Scholar
• 63. Li G.Z., Eller M.S., Firoozabadi R., Gilchrest B.A.: Evidence thatexposure of the telomere 3’ overhang sequence induces senescence.Proc. Natl. Acad. Sci. USA, 2003; 100: 527-531
  Google Scholar
• 64. Lin A.W., Barradas M., Stone J.C., van Aelst L., Serrano M., LoweS.W.: Premature senescence involving p53 and p16 is activated inresponse to constitutive MEK/MAPK mitogenic signaling. GenesDev., 1998; 12: 3008-3019
  Google Scholar
• 65. Liu D., Hornsby P.J.: Senescent human fibroblasts increase theearly growth of xenograft tumors via matrix metalloproteinase secretion.Cancer Res, 2007; 67: 3117-3126
  Google Scholar
• 66. Liu F., Wu S., Ren H., Gu J.: Klotho suppresses RIG-I-mediatedsenescence-associated inflammation. Nat. Cell Biol., 2011; 13:254-262
  Google Scholar
• 67. Lopez-Otin C., Blasco M.A., Partridge L., Serrano M., KroemerG.: The hallmarks of aging. Cell, 2013; 153: 1194-1217
  Google Scholar
• 68. Lowe S.W., Sherr C.J.: Tumor suppression by Ink4a-Arf: progressand puzzles. Curr. Opin. Genet. Dev., 2003; 13: 77-83
  Google Scholar
• 69. Macleod K.F., Sherry N., Hannon G., Beach D., Tokino T., KinzlerK., Vogelstein B., Jacks T.: p53-dependent and independent expressionof p21 during cell growth, differentiation, and DNA damage.Genes Dev., 1995; 9: 935-944
  Google Scholar
• 70. Martinez P., Ferrara-Romeo I., Flores J.M., Blasco M.A.: Essentialrole for the TRF2 telomere protein in adult skin homeostasis. AgingCell, 2014; 13: 656-668
  Google Scholar
• 71. Matthews C., Gorenne I., Scott S., Figg N., Kirkpatrick P., RitchieA., Goddard M., Bennett M.: Vascular smooth muscle cells undergotelomere-based senescence in human atherosclerosis: effects of telomeraseand oxidative stress. Circ. Res, 2006; 99: 156-164
  Google Scholar
• 72. McCullough K.D., Coleman W.B., Smith G.J., Grishan J.W.: Age–dependent regulation of the tumorigenic potential of neoplasticallytransformed rat liver epithelial cells by the liver microenvironment.Cancer Res., 1994; 54: 3668-3671
  Google Scholar
• 73. Moll U.M., Petrenko O.: The MDM2-p53 interaction. Mol. CancerRes., 2003; 1: 1001-1008
  Google Scholar
• 74. Moyzis R.K., Buckingham J.M., Cram L.S., Dani M., Deaven L.L.,Jones M.D., Meyne J., Ratliff R.L., Wu J.R.: A highly conserved repetitiveDNA sequence, (TTAGGG)n, present at the telomeres of humanchromosomes. Proc. Natl. Acad. Sci. USA, 1988; 85: 6622-6626
  Google Scholar
• 75. Nabetani A., Ishikawa F.: Alternative lengthening of telomerespathway: recombination-mediated telomere maintenance mechanismin human cells. J. Biochem., 2011; 149: 5-14
  Google Scholar
• 76. Narita M., Nunez S., Heard E., Narita M., Lin A.W., Hearn S.A.,Spector D.L., Hannon G.J., Lowe S.W.: Rb-mediated heterochromatinformation and silencing of E2F target genes during cellular senescence.Cell, 2003; 113: 703-716
  Google Scholar
• 77. Naylor R.M., Baker D.J., van Deursen J.M.: Senescent cells: a noveltherapeutic target for aging and age-related diseases. Clin. Pharmacol.Ther., 2013; 93: 105-116
  Google Scholar
• 78. Nishida N., Yano H., Nishida T., Kamura T., Kojiro M.: Angiogenesisin cancer. Vasc. Health Risk Manag., 2006; 2: 213-219
  Google Scholar
• 79. Noureddine H., Gary-Bobo G., Alifano M., Marcos E., Saker M.,Vienney N., Amsellem V., Maitre B., Chaouat A., Chouaid C., Dubois-Rande J.L., Damotte D., Adnot S.: Pulmonary artery smoothmuscle cell senescence is a pathogenic mechanism for pulmonaryhypertension in chronic lung disease. Circ. Res., 2011; 109: 543-553
  Google Scholar
• 80. Nuss J.E., Choksi K.B., DeFord J.H., Papaconstantinou J.: Decreasedenzyme activities of chaperones PDI and BiP in aged mouselivers. Biochem. Biophys. Res. Commun., 2008; 365: 355-361
  Google Scholar
• 81. Ogryzko V.V., Hirai T.H., Russanova V.R., Barbie D.A., HowardB.H.: Human fibroblast commitment to a senescence-like state inresponse to histone deacetylase inhibitors is cell cycle dependent.Mol. Cell Biol., 1996; 16: 5210-5218
  Google Scholar
• 82. Ohtani N., Zebedee Z., Huot T.J., Stinson J.A., Sugimoto M., OhashiY., Sharrocks A.D., Peters G., Hara E.: Opposing effects of Ets and Idproteins on p16INK4a expression during cellular senescence. Nature,2001; 409: 1067-1070
  Google Scholar
• 83. Olovnikov A.M.: Principle of marginotomy in template synthesisof polynucleotides. Dokl. Akad. Nauk SSSR, 1971; 201: 1496-1499
  Google Scholar
• 84. Olovnikov AM.: Telomeres, telomerase, and aging: origin of thetheory. Exp. Gerontol., 1996; 31: 443-448
  Google Scholar
• 85. Park C.C., Bissell M.J., Barcellos-Hoff M.H.: The influence of themicroenvironment on the malignant phenotype. Mol. Med. Today,2000; 6: 324-329
  Google Scholar
• 86. Parrinello S., Coppe J.P., Krtolica A., Campisi J.: Stromal-epithelialinteractions in aging and cancer: senescent fibroblasts alter epithelialcell differentiation. J. Cell Sci., 2005; 118: 485-496
  Google Scholar
• 87. Pascal T., Debacq-Chainiaux F., Chretien A., Bastin C., DabeeA.F., Bertholet V., Remacle J., Toussaint O.: Comparison of replicativesenescence and stress-induced premature senescence combiningdifferential display and low-density DNA arrays. FEBS Lett.,2005; 579: 3651-3659
  Google Scholar
• 88. Pazolli E., Alspach E., Milczarek A., Prior J., Piwnica-Worms D.,Stewart S.A.: Chromatin remodeling underlies the senescence-associatedsecretory phenotype of tumor stromal fibroblasts that supportscancer progression. Cancer Res., 2012; 72: 2251-2261
  Google Scholar
• 89. Ramirez R.D., Morales C.P., Herbert B.S., Rohde J.M., Passons C.,Shay J.W., Wright W.E.: Putative telomere-independent mechanismsof replicative aging reflect inadequate growth conditions. GenesDev, 2001; 15: 398-403
  Google Scholar
• 90. Ressler S., Bartkova J., Niederegger H., Bartek J., Scharffetter–Kochanek K., Jansen-Durr P., Wlaschek M.: p16INK4A is a robust invivo biomarker of cellular aging in human skin. Aging Cell, 2006;5: 379-389
  Google Scholar
• 91. Rheinwald J.G., Green H.: Serial cultivation of strains of humanepidermal keratinocytes: the formation of keratinizing colonies fromsingle cells. Cell, 1975; 6: 331-343
  Google Scholar
• 92. Robles S.J., Adami G.R.: Agents that cause DNA double strandbreaks lead to p16INK4a enrichment and the premature senescenceof normal fibroblasts. Oncogene, 1998; 16: 1113-1123
  Google Scholar
• 93. Rodier F., Campisi J.: Four faces of cellular senescence. J. CellBiol., 2011; 192: 547-556
  Google Scholar
• 94. Rodier F., Coppe J.P., Patil C.K., Hoeijmakers W.A., Munoz D.P.,Raza S.R., Freund A., Campeau E., Davalos A.R., Campisi J.: PersistentDNA damage signalling triggers senescence-associated inflammatorycytokine secretion. Nat. Cell Biol., 2009; 11: 973-979
  Google Scholar
• 95. Rodier F., Munoz D.P., Teachenor R., Chu V., Le O., Bhaumik D.,Coppe J.P., Campeau E., Beausejour C.M., Kim S.H., Davalos A.R.,Campisi J.: DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokinesecretion. J. Cell Sci., 2011; 124: 68-81
  Google Scholar
• 96. Roninson IB.: Oncogenic functions of tumour suppressor p21Waf1/Cip1/Sdi1: association with cell senescence and tumour-promoting activitiesof stromal fibroblasts. Cancer Lett., 2002; 179: 1-14
  Google Scholar
• 97. Saretzki G., Sitte N., Merkel U., Wurm R.E., von Zglinicki T.: Telomereshortening triggers a p53-dependent cell cycle arrest viaaccumulation of G-rich single stranded DNA fragments. Oncogene,1999; 18: 5148-5158
  Google Scholar
• 98. Serrano M., Lin A.W., McCurrach M.E., Beach D., Lowe S.W.: Oncogenicras provokes premature cell senescence associated withaccumulation of p53 and p16INK4a. Cell, 1997; 88: 593-602
  Google Scholar
• 99. Severino J., Allen R.G., Balin S., Balin A., Cristofalo V.J.: Is beta–galactosidase staining a marker of senescence in vitro and in vivo?Exp. Cell Res., 2000; 257: 162-171
  Google Scholar
• 100. Shay J.W., Bacchetti S.: A survey of telomerase activity in humancancer. Eur. J. Cancer, 1997; 33: 787-791
  Google Scholar
• 101. Sherr C.J., DePinho R.A.: Cellular senescence: mitotic clock orculture shock? Cell, 2000; 102: 407-410
  Google Scholar
• 102. Shirangi T.R., Zaika A., Moll U.M.: Nuclear degradation of p53occurs during down-regulation of the p53 response after DNA damage.FASEB J., 2002; 16: 420-422
  Google Scholar
• 103. Sitte N., Merker K., Grune T., von Zglinicki T.: Lipofuscin accumulationin proliferating fibroblasts in vitro: an indicator of oxidativestress. Exp. Gerontol., 2001; 36: 475-486
  Google Scholar
• 104. Smogorzewska A., de Lange T.: Different telomere damagesignaling pathways in human and mouse cells. EMBO J., 2002; 21:4338-4348
  Google Scholar
• 105. Stein G.H., Drullinger L.F., Soulard A., Dulic V.: Differential rolesfor cyclin-dependent kinase inhibitors p21 and p16 in the mechanismsof senescence and differentiation in human fibroblasts. Mol.Cell. Biol., 1999; 19: 2109-2117
  Google Scholar
• 106. Terman A., Gustafsson B., Brunk U.T.: Autophagy, organellesand ageing. J. Pathol., 2007; 211: 134-143
  Google Scholar
• 107. Venable M.E., Lee J.Y., Smyth M.J., Bielawska A., Obeid L.M.:Role of ceramide in cellular senescence. J. Biol. Chem., 1995; 270:30701-30708
  Google Scholar
• 108. von Zglinicki T.: Oxidative stress shortens telomeres. TrendsBiochem. Sci., 2002; 27: 339-344
  Google Scholar
• 109. von Zglinicki T., Pilger R., Sitte N.: Accumulation of single-strand breaks is the major cause of telomere shortening in humanfibroblasts. Free Radic. Biol. Med., 2000; 28: 64-74
  Google Scholar
• 110. von Zglinicki T., Saretzki G., Docke W., Lotze C.: Mild hyperoxiashortens telomeres and inhibits proliferation of fibroblasts: a modelfor senescence? Exp. Cell Res., 1995; 220: 186-193
  Google Scholar
• 111. von Zglinicki T., Saretzki G., Ladhoff J., d`Adda di Fagagna F.,Jackson S.P.: Human cell senescence as a DNA damage response.Mech. Ageing Dev., 2005; 126: 111-117
  Google Scholar
• 112. Wang J.C., Bennett M.: Aging and atherosclerosis: mechanisms,functional consequences, and potential therapeutics for cellular senescence.Circ. Res., 2012; 111: 245-259
  Google Scholar
• 113. Watson J.D.: Origin of concatemeric T7 DNA. Nat. New Biol.,1972; 239: 197-201
  Google Scholar
• 114. Witkowski J.A.: Dr. Carrel’s immortal cells. Med. Hist., 1980;24: 129-142
  Google Scholar
• 115. Wolf F.I., Torsello A., Covacci V., Fasanella S., Montanari M.,Boninsegna A., Cittadini A.: Oxidative DNA damage as a marker ofaging in WI-38 human fibroblasts. Exp. Gerontol., 2002; 37: 647-656
  Google Scholar
• 116. Wu C., Miloslavskaya I., Demontis S., Maestro R., GalaktionovK.: Regulation of cellular response to oncogenic and oxidative stressby Seladin-1. Nature, 2004; 432: 640-645
  Google Scholar
• 117. Xiao X., Wang Y., Gong H., Chen P., Xie L.: Molecular evidenceof senescence in corneal endothelial cells of senescence-acceleratedmice. Mol. Vis., 2009; 15: 747-761
  Google Scholar
• 118. Yoon I.K., Kim H.K., Kim Y.K., Song I.H., Kim W., Kim S., BaekS.H., Kim J.H., Kim J.R.: Exploration of replicative senescence-associatedgenes in human dermal fibroblasts by cDNA microarraytechnology. Exp. Gerontol., 2004; 39: 1369-1378
  Google Scholar
• 119. Zhang R., Poustovoitov M.V., Ye X., Santos H.A., Chen W., DaganzoS.M., Erzberger J.P., Serebriiskii I.G., Canutescu A.A., DunbrackR.L., Pehrson J.R., Berger J.M., Kaufman P.D., Adams P.D.: Formation ofMacroH2A-containing senescence-associated heterochromatin fociand senescence driven by ASF1a and HIRA. Dev. Cell, 2005; 8: 19-30
  Google Scholar
• 120. Zimmerman J.A., Trombetta L.D., Carter T.H., Weisbroth S.H.:Pancreatic carcinoma induced by N-methyl-N’-nitrosourea in agedmice. Gerontology, 1982; 28: 114-120
  Google Scholar

Full text