, Volume 16, Issue 4, pp 399–410 | Cite as

iPSCs as a major opportunity to understand and cure age-related diseases

  • Camille Lemey
  • Ollivier MilhavetEmail author
  • Jean-Marc LemaitreEmail author
Review Article


Cellular senescence plays an important role in the process of aging and is often associated with age-related diseases. Senescence was originally considered as a barrier to cell reprogramming, however we developed a strategy to overcome this hurdle and derive induced pluripotent stem cells (iPSCs) from senescent cells and cells from centenarians. Furthermore we showed that the newly generated iPSCs could be re-differentiated into fully rejuvenated cells. That has increased the known beneficial properties of iPSCs to include them as a tool to model age-related diseases or even to cure them through cell therapy. In this review, we describe the hallmarks of cellular senescence before presenting how we reprogrammed aged and senescent cells into iPSCs and obtained rejuvenated re-differentiated cells. Finally, we take an interest in the way iPSCs can be used to understand and cure age-related diseases and we present their advantages for patient-specific therapy.


Cell reprogramming Induced pluripotent stem cells (iPSCs) Cellular senescence Age-related diseases Cell therapy Patient-specific therapy 


  1. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH (2012) The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol 124:339–352PubMedCrossRefGoogle Scholar
  2. Aliaga L, Lai C, Yu J, Chub N, Shim H, Sun L, Xie C, Yang WJ, Lin X, O’Donovan MJ et al (2013) Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Hum Mol Genet 22:4293–4305PubMedCentralPubMedCrossRefGoogle Scholar
  3. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031PubMedCrossRefGoogle Scholar
  4. Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, Pinho S, Silva JC, Azuara V, Walsh M et al (2009) Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23:2134–2139PubMedCentralPubMedCrossRefGoogle Scholar
  5. Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12:1133–1138PubMedCrossRefGoogle Scholar
  6. Blondel S, Jaskowiak AL, Egesipe AL, Le Corf A, Navarro C, Cordette V, Martinat C, Laabi Y, Djabali K, de Sandre-Giovannoli A et al. (2014) Induced pluripotent stem cells reveal functional differences between drugs currently investigated in patients with Hutchinson–Gilford progeria syndrome. Stem Cells Transl Med 3:510–519PubMedCentralPubMedCrossRefGoogle Scholar
  7. Cahan P, Li H, Morris SA, Lummertz da Rocha E, Daley GQ, Collins JJ (2014) Cell net: network biology applied to stem cell engineering. Cell 158:903–915PubMedCrossRefGoogle Scholar
  8. Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522PubMedCrossRefGoogle Scholar
  9. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740PubMedCrossRefGoogle Scholar
  10. Childs BG, Sluis BVD, Kirkland JL, Deursen JMV (2012) Clearance of p16Ink4a -positive senescent cells delays ageing- associated disorders. Nature 479:232–236Google Scholar
  11. Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Cook SM, Palpant NJ et al (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510:273–277PubMedCentralPubMedCrossRefGoogle Scholar
  12. Collado M, Serrano M (2010) Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 10:51–57PubMedCentralPubMedCrossRefGoogle Scholar
  13. Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233PubMedCrossRefGoogle Scholar
  14. Coppé JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868PubMedCrossRefGoogle Scholar
  15. Coppé JP, Desprez PY, Krtolica A, Campisi J (2014) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev of pathol 5:99–118CrossRefGoogle Scholar
  16. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31(6):722–733Google Scholar
  17. Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I (2012) Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 4:145ra104PubMedGoogle Scholar
  18. Feng Q, Lu SJ, Klimanskaya I, Gomes I, Kim D, Chung Y, Honig GR, Kim KS, Lanza R (2010) Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells 28:704–712PubMedCrossRefGoogle Scholar
  19. Fraga MF, Esteller M (2007) Epigenetics and aging: the targets and the marks. Trends genet 23:413–418PubMedCrossRefGoogle Scholar
  20. Freund A, Patil CK, Campisi J (2011) p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 30:1536–1548PubMedCentralPubMedCrossRefGoogle Scholar
  21. Gorgoulis VG, Halazonetis TD (2010) Oncogene-induced senescence: the bright and dark side of the response. Curr Opin Cell Biol 22:816–827PubMedCrossRefGoogle Scholar
  22. Haferkamp S, Scurr LL, Becker TM, Frausto M, Kefford RF, Rizos H (2009) Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors. J Invest Dermatol 129:1983–1991PubMedCrossRefGoogle Scholar
  23. Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636PubMedCrossRefGoogle Scholar
  24. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefGoogle Scholar
  25. Ho JC, Zhou T, Lai WH, Huang Y, Chan YC, Li X, Wong NL, Li Y, Au KW, Guo D et al (2011) Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging (Albany NY) 3:380–390Google Scholar
  26. Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009) Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460:1132–1135PubMedCentralPubMedCrossRefGoogle Scholar
  27. Isotani A, Hatayama H, Kaseda K, Ikawa M, Okabe M (2011) Formation of a thymus from rat ES cells in xenogeneic nude mouse/rat ES chimeras. Genes Cells 16:397–405PubMedCrossRefGoogle Scholar
  28. Jaskelioff M, Muller FL, Paik J-H, Thomas E, Jiang S, Sahin E, Kost-alimova M, Protopopov A, Cadiñanos J, Horner JW et al (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice. Nature 469:102–106PubMedCentralPubMedCrossRefGoogle Scholar
  29. Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech Ageing Dev 129:467–474PubMedCentralPubMedCrossRefGoogle Scholar
  30. Kamao H, Mandai M, Okamoto S, Sakai N, Suga A, Sugita S, Kiryu J, Takahashi M (2014) Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Rep 2:205–218CrossRefGoogle Scholar
  31. Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Izpisua Belmonte JC (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460:1140–1144PubMedCentralPubMedCrossRefGoogle Scholar
  32. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12:487–496PubMedCrossRefGoogle Scholar
  33. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479PubMedCentralPubMedCrossRefGoogle Scholar
  34. Kurz DJ, Decary S, Hong Y, Erusalimsky JD (2000) Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113(Pt 20):3613–3622PubMedGoogle Scholar
  35. Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez J-M, De Vos J, Lehmann S, Lemaitre JM (2011) Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 25:2248–2253PubMedCentralPubMedCrossRefGoogle Scholar
  36. Lehmann J, Schubert S, Emmert S (2014) Xeroderma pigmentosum: diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches. J Dtsch Dermatol Ges 12:867–872PubMedGoogle Scholar
  37. Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, Blasco MA, Serrano M (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460:1136–1139PubMedCentralPubMedCrossRefGoogle Scholar
  38. Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C et al (2011) Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature 472:221–225PubMedCentralPubMedCrossRefGoogle Scholar
  39. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217PubMedCentralPubMedCrossRefGoogle Scholar
  40. Lu T, Finkel T (2009) Free radicals and senescence. Exp Cell Res 314:1918–1922CrossRefGoogle Scholar
  41. Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, Zhang N, Liang S, Donehower LA, Issa J-PJ (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20:332–340PubMedCentralPubMedCrossRefGoogle Scholar
  42. Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460:1149–1153PubMedCentralPubMedCrossRefGoogle Scholar
  43. Maumus M, Guerit D, Toupet K, Jorgensen C, Noel D (2011) Mesenchymal stem cell-based therapies in regenerative medicine: applications in rheumatology. Stem Cell Res Ther 2:14PubMedCentralPubMedCrossRefGoogle Scholar
  44. Moiseeva O, Bourdeau V, Roux A, Deschenes-Simard X, Ferbeyre G (2009) Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol Cell Biol 29:4495–4507PubMedCentralPubMedCrossRefGoogle Scholar
  45. Munoz-Espin D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, Rodriguez-Baeza A, Varela-Nieto I, Ruberte J, Collado M et al (2013) Programmed cell senescence during mammalian embryonic development. Cell 155:1104–1118PubMedCrossRefGoogle Scholar
  46. Nemudryi AA, Valetdinova KR, Medvedev SP, Zakian SM (2014) TALEN and CRISPR/Cas genome editing systems: tools of discovery. Acta Naturae 6:19–40PubMedCentralPubMedGoogle Scholar
  47. Noth U, Steinert AF, Tuan RS (2008) Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol 4:371–380PubMedGoogle Scholar
  48. Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747PubMedCrossRefGoogle Scholar
  49. Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A et al (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347PubMedCentralPubMedCrossRefGoogle Scholar
  50. Pegoraro G, Nard K, Ute W, Heike G, Katrin H, Misteli T (2010) Aging-related chromatin defects via loss of the NURD complex. Nat Cell Biol 11:1261–1267CrossRefGoogle Scholar
  51. Pendas AM, Zhou Z, Cadinanos J, Freije JM, Wang J, Hultenby K, Astudillo A, Wernerson A, Rodriguez F, Tryggvason K et al (2002) Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat Genet 31:94–99PubMedGoogle Scholar
  52. Piaceri I, Nacmias B, Sorbi S (2013) Genetics of familial and sporadic Alzheimer’s disease. Front Biosci (Elite Ed) 5:167–177Google Scholar
  53. Pii E, Olovnikov AM, Physics B, Academy R (1996) Historical perspective telomeres, telomerase, and aging : origin of the theory. Exp Gerontol 31:443–448CrossRefGoogle Scholar
  54. Rashid T, Kobayashi T, Nakauchi H (2014) Revisiting the flight of Icarus: making human organs from PSCs with large animal chimeras. Cell Stem Cell 15:406–409PubMedCrossRefGoogle Scholar
  55. Rattan SIS (2000) ‘Just a fellow who did his job…′, an interview with Leonard Hayflick. Interview by Suresh I.S. Rattan. Biogerontology 1:79–87CrossRefGoogle Scholar
  56. Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192:547–556PubMedCentralPubMedCrossRefGoogle Scholar
  57. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979PubMedCentralPubMedCrossRefGoogle Scholar
  58. Serrano M, Lin AW, Mccurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16 INK4a. Cell 88:593–602PubMedCrossRefGoogle Scholar
  59. Sharpless NE, DePinho RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8:703–713PubMedCrossRefGoogle Scholar
  60. Sherr CJ, DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102:407–410PubMedCrossRefGoogle Scholar
  61. Shimamoto A, Kagawa H, Zensho K, Sera Y, Kazuki Y, Osaki M, Oshimura M, Ishigaki Y, Hamasaki K, Kodama Y et al (2014) Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture. PLoS One 9:e112900PubMedCentralPubMedCrossRefGoogle Scholar
  62. Shuo H, Brunet A (2013) Histone methylation makes its mark on longevity. Trends cell biol 22:42–49Google Scholar
  63. Sinha JK, Ghosh S, Raghunath M (2014) Progeria: a rare genetic premature ageing disorder. Indian J Med Res 139:667–674PubMedCentralPubMedGoogle Scholar
  64. Stadtfeld M, Hochedlinger K (2010) Induced pluripotency: history, mechanisms, and applications. Genes Dev 24:2239–2263PubMedCentralPubMedCrossRefGoogle Scholar
  65. Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–1130PubMedCrossRefGoogle Scholar
  66. Suhr ST, Chang EA, Rodriguez RM, Wang K, Ross PJ, Beyhan Z, Murthy S, Cibelli JB (2009) Telomere dynamics in human cells reprogrammed to pluripotency. PLoS One 4:e8124PubMedCentralPubMedCrossRefGoogle Scholar
  67. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  68. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedCrossRefGoogle Scholar
  69. Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM (2012) Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 11:147–152PubMedCrossRefGoogle Scholar
  70. Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H et al (2013) Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12:310–322PubMedCrossRefGoogle Scholar
  71. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K (2009) Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460:1145–1148PubMedCentralPubMedCrossRefGoogle Scholar
  72. Vaziri H, Chapman KB, Guigova A, Teichroeb J, Lacher MD, Sternberg H, Singec I, Briggs L, Wheeler J, Sampathkumar J et al (2010) Spontaneous reversal of the developmental aging of normal human cells following transcriptional reprogramming. Regen Med 5:345–363PubMedCrossRefGoogle Scholar
  73. Wang T, Warren ST, Jin P (2013) Toward pluripotency by reprogramming: mechanisms and application. Protein Cell 4:820–832PubMedCrossRefGoogle Scholar
  74. Xue Y, Cai X, Wang L, Liao B, Zhang H, Shan Y, Chen Q, Zhou T, Li X, Hou J et al (2013) Generating a non-integrating human induced pluripotent stem cell bank from urine-derived cells. PLoS One 8:e70573PubMedCentralPubMedCrossRefGoogle Scholar
  75. Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011) Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet 20:4530–4539PubMedCrossRefGoogle Scholar
  76. Yamanaka S (2009) A fresh look at iPS cells. Cell 137:13–17PubMedCrossRefGoogle Scholar
  77. Yang NC, Hu ML (2005) The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol 40:813–819PubMedCrossRefGoogle Scholar
  78. Yu J, Vodyanik Ma, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir Ga, Ruotti V, Stewart R, et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Institute of Regenerative Medicine and Biotherapies (IRMB), INSERM U1183, University of Montpellier, Laboratory of Genome and Stem Cell Plasticity in Development and Aging , Saint Eloi HospitalMontpellier Cedex 05France
  2. 2.Stem Cell Core Facility SAFE-iPSC, INGESTEM, IRMB, CHRU Montpellier, Saint Eloi HospitalMontpellier Cedex 05France

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