Skip to main content

Use of Induced Pluripotent Stem Cells in Aging Research

  • Chapter
Aging Mechanisms
  • 1872 Accesses

Abstract

Human populations around the world are aging, which necessitates new ways to analyze age-related functional decline and disease mechanisms in elderly patients. Further, many elderly patients are waiting for new therapies for treatment of intractable age-related diseases such as Alzheimer’s disease, Parkinson’s disease, liver cirrhosis, lung failure and renal failure. The development of induced pluripotent stem cell (iPSC) technology opens the door for new approaches to the analysis of age-related disorders and to develop personalized cell therapy for age-related diseases. Progeria syndromes present early ageing characteristics. Human iPSCs (HiPSCs) have been established from progeria syndromes, including Hutchinson Gilford Progeria Syndrome (HGPS). Directed differentiation of HGPS-iPSCs to smooth muscle cells led to the appearance of premature senescence phenotypes associated with vascular ageing. Although the efficiency of establishing murine iPSCs from aged mice is lower than that from young mice, many HiPSCs from elderly humans have been established, including centenarians. HiPSCs from patients with age-related diseases have been established and are being used to elucidate the mechanism of disease progression. HiPSCs from Parkinson’s disease (PD) patients were established soon after the discovery of HiPSCs technology. HiPSCs from PD patients have almost the same phenotype as HiPSCs from healthy people. However, long-term cultivation of dopamine neurons differentiated from Parkinson’s-HiPSCs has revealed disease-specific characteristics, including fewer neurites and a significant increase in apoptotic cells. Recently, 3D culture has permitted the construction of tissue-specific organoids from HiPSCs. These form complete tissues in immune competent mice. iPSC technology will be used more widely for analysis of age-related disorders, age-related functional declines and future personalized therapy for age-related disorders.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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

References

  • Andrade LN, Nathanson JL, Yeo GW, Menck CF, Muotri AR (2012) Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome. Hum Mol Genet 21:3825–3834

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bertola DR, Cao H, Albano LM, Oliveira DP, Kok F, Marques-Dias MJ, Kim CA, Hegele RA (2006) Cockayne syndrome type A: novel mutations in eight typical patients. J Hum Genet 51:701–705

    Article  CAS  PubMed  Google Scholar 

  • Boulting GL, Kiskinis E, Croft GF, Amoroso MW, Oakley DH, Wainger BJ, Williams DJ, Kahler DJ, Yamaki M, Davidow L, Rodolfa CT, Dimos JT, Mikkilineni S, MacDermott AB, Woolf CJ, Henderson CE, Wichterle H, Eggan K (2011) A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol 29:279–286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11:567–578

    Article  CAS  PubMed  Google Scholar 

  • Cheng Z, Ito S, Nishio N, Xiao H, Zhang R, Suzuki H, Okawa Y, Murohara T, Isobe K (2011) Establishment of induced pluripotent stem cells from aged mice using bone marrow-derived myeloid cells. J Mol Cell Biol 3:91–98

    Article  CAS  PubMed  Google Scholar 

  • Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11:791–797

    Article  CAS  PubMed  Google Scholar 

  • Cooper O, Seo H, Andrabi S, Guardia-Laguarta C, Graziotto J, Sundberg M, McLean JR, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte H, Perez-Torres E, Clark L, Moskowitz C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Scarffe LA, Dawson VL, Klein C, Feng J, Ross OA, Trojanowski JQ, Lee VM, Marder K, Surmeier DJ, Wszolek ZK, Przedborski S, Krainc D, Dawson TM, Isacson O (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci Transl Med 4:141ra90

    Article  PubMed Central  PubMed  Google Scholar 

  • Crabbe L, Verdun RE, Haggblom CI, Karlseder J (2004) Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306:1951–1953

    Article  CAS  PubMed  Google Scholar 

  • de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535

    Article  PubMed  Google Scholar 

  • De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Lévy N (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300:2055

    Article  PubMed  Google Scholar 

  • Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62:132–144

    Article  CAS  PubMed  Google Scholar 

  • Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298

    Article  CAS  PubMed  Google Scholar 

  • Filippi S, Latini P, Frontini M, Palitti F, Egly JM, Proietti-De-Santis L (2008) CSB protein is (a direct target of HIF-1 and) a critical mediator of the hypoxic response. EMBO J 27:2545–2556

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Goto M, Ishikawa Y, Sugimoto M, Furuichi Y (2013) Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends 7:13–22

    CAS  PubMed  Google Scholar 

  • Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW, Consortium IL (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7:583–590

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Isobe K, Cheng Z, Ito S, Nishio N (2012) Aging in the mouse and perspectives of rejuvenation through induced pluripotent stem cells (iPSCs). Results Probl Cell Differ 55:413–427

    Article  PubMed  Google Scholar 

  • Isobe K, Cheng Z, Nishio N, Suganya T, Tanaka Y, Ito S (2014) iPSCs, aging and age-related diseases. N Biotechnol 31:411–421

    Article  CAS  PubMed  Google Scholar 

  • Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jacobs BM (2014) Stemming the hype: what can we learn from iPSC models of Parkinson’s disease and how can we learn it? J Park Dis 4:15–27

    Google Scholar 

  • Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein WL, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 12:487–496

    Article  CAS  PubMed  Google Scholar 

  • Kudlow BA, Kennedy BK, Monnat RJ (2007) Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 8:394–404

    Article  CAS  PubMed  Google Scholar 

  • Kyng KJ, May A, Brosh RM, Cheng WH, Chen C, Becker KG, Bohr VA (2003) The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells. Oncogene 22:1135–1149

    Article  CAS  PubMed  Google Scholar 

  • Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, Lemaitre JM (2011) Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 25:2248–2253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, Blasco MA, Serrano M (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460:1136–1139

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J, Boue S, Fung HL, Sancho-Martinez I, Zhang K, Yates J, Izpisua Belmonte JC (2011) Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221–225

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U, Kim A, Ren B, Li Y, Goebl A, Kim J, Soligalla RD, Dubova I, Thompson J, Yates J, Esteban CR, Sancho-Martinez I, Izpisua Belmonte JC (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491:603–607

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mahmoudi S, Brunet A (2012) Aging and reprogramming: a two-way street. Curr Opin Cell Biol 24:744–756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B, Brooks BP, Gerber LH, Turner ML, Domingo DL, Hart TC, Graf J, Reynolds JC, Gropman A, Yanovski JA, Gerhard-Herman M, Collins FS, Nabel EG, Cannon RO, Gahl WA, Introne WJ (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 358:592–604

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, Taldone T, Fusaki N, Tomishima MJ, Krainc D, Milner TA, Rossi DJ, Studer L (2013) Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13:691–705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mori H, Tomiyama T, Maeda N, Ozawa K, Wakasa K (2003) Lack of amyloid plaque formation in the central nervous system of a patient with Werner syndrome. Neuropathology 23:51–56

    Article  PubMed  Google Scholar 

  • Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ, Young-Pearse TL (2014) The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet 23:3523–3536

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch RE, Langston W, Palmer TD, Pera RR (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8:267–280

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Okawa T, Kamiya H, Himeno T, Kato J, Seino Y, Fujiya A, Kondo M, Tsunekawa S, Naruse K, Hamada Y, Ozaki N, Cheng Z, Kito T, Suzuki H, Ito S, Oiso Y, Nakamura J, Isobe K (2013) Transplantation of neural crest-like cells derived from induced pluripotent stem cells improves diabetic polyneuropathy in mice. Cell Transplant 22:1767–1783

    Article  PubMed  Google Scholar 

  • Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16:394–406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008a) Disease-specific induced pluripotent stem cells. Cell 134:877–886

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008b) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146

    Article  CAS  PubMed  Google Scholar 

  • Prigione A, Hossini AM, Lichtner B, Serin A, Fauler B, Megges M, Lurz R, Lehrach H, Makrantonaki E, Zouboulis CC, Adjaye J (2011) Mitochondrial-associated cell death mechanisms are reset to an embryonic-like state in aged donor-derived iPS cells harboring chromosomal aberrations. PLoS One 6:e27352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reinhardt P, Schmid B, Burbulla LF, Schöndorf DC, Wagner L, Glatza M, Höing S, Hargus G, Heck SA, Dhingra A, Wu G, Müller S, Brockmann K, Kluba T, Maisel M, Krüger R, Berg D, Tsytsyura Y, Thiel CS, Psathaki OE, Klingauf J, Kuhlmann T, Klewin M, Müller H, Gasser T, Schöler HR, Sterneckert J (2013) Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12:354–367

    Article  CAS  PubMed  Google Scholar 

  • Rohani L, Johnson AA, Arnold A, Stolzing A (2014) The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell 13(1):2–7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sánchez-Danés A, Richaud-Patin Y, Carballo-Carbajal I, Jiménez-Delgado S, Caig C, Mora S, Di Guglielmo C, Ezquerra M, Patel B, Giralt A, Canals JM, Memo M, Alberch J, López-Barneo J, Vila M, Cuervo AM, Tolosa E, Consiglio A, Raya A (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol Med 4:380–395

    Article  PubMed Central  PubMed  Google Scholar 

  • Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312:1059–1063

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schulz VP, Zakian VA, Ogburn CE, McKay J, Jarzebowicz AA, Edland SD, Martin GM (1996) Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells. Hum Genet 97:750–754

    Article  CAS  PubMed  Google Scholar 

  • Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R (2009) Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964–977

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  CAS  PubMed  Google Scholar 

  • 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 131:861–872

    Article  CAS  PubMed  Google Scholar 

  • Wang B, Miyagoe-Suzuki Y, Yada E, Ito N, Nishiyama T, Nakamura M, Ono Y, Motohashi N, Segawa M, Masuda S, Takeda S (2011) Reprogramming efficiency and quality of induced Pluripotent Stem Cells (iPSCs) generated from muscle-derived fibroblasts of mdx mice at different ages. PLoS Curr 3:RRN1274

    Article  PubMed Central  PubMed  Google Scholar 

  • Watson CL, Mahe MM, Múnera J, Howell JC, Sundaram N, Poling HM, Schweitzer JI, Vallance JE, Mayhew CN, Sun Y, Grabowski G, Finkbeiner SR, Spence JR, Shroyer NF, Wells JM, Helmrath MA (2014) An in vivo model of human small intestine using pluripotent stem cells. Nat Med 20:1310

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Weidenheim KM, Dickson DW, Rapin I (2009) Neuropathology of Cockayne syndrome: evidence for impaired development, premature aging, and neurodegeneration. Mech Ageing Dev 130:619–636

    Article  CAS  PubMed  Google Scholar 

  • World Alzheimer’s Disease Report 2013 (2013) Available from: http://www.alz.co.uk/research/world-report-2013

  • Worman HJ, Ostlund C, Wang Y (2010) Diseases of the nuclear envelope. Cold Spring Harb Perspect Biol 2:a000760

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 20:4530–4539

    Article  CAS  PubMed  Google Scholar 

  • Yagi T, Kosakai A, Ito D, Okada Y, Akamatsu W, Nihei Y, Nabetani A, Ishikawa F, Arai Y, Hirose N, Okano H, Suzuki N (2012) Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research. PLoS One 7:e41572

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  CAS  PubMed  Google Scholar 

  • Yuan X, Feng W, Imhof A, Grummt I, Zhou Y (2007) Activation of RNA polymerase I transcription by cockayne syndrome group B protein and histone methyltransferase G9a. Mol Cell 27:585–595

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ken-ichi Isobe .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Japan

About this chapter

Cite this chapter

Isobe, Ki. (2015). Use of Induced Pluripotent Stem Cells in Aging Research. In: Mori, N., Mook-Jung, I. (eds) Aging Mechanisms. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55763-0_4

Download citation

Publish with us

Policies and ethics