Skip to main content
SpringerLink
Log in

Aging of Mammalian Intestinal Stem Cells

  • Chapter
Book cover Stem Cell Aging: Mechanisms, Consequences, Rejuvenation

  • 1170 Accesses

Abstract

The intestinal epithelium forms the internal barrier towards all components of nutriment and a multitude of bacteria. It is the most rapidly renewing tissue in mammals and keeps up basic homeostatic function over most of the organism’s lifespan. Its stress capacitance is lowered with progressive age, though. This remarkably high capacity of regeneration requires the maintenance of functional stem cells. DNA damage accumulation has been implicated in limiting organ maintenance; thus, checkpoint and repair mechanisms have been devoted to keep up genomic integrity of stem and progenitor cells. Checkpoints engaged include p53, as well as upstream regulators (Exo1, ATM, ATR, Chk1) and downstream targets (p21, PUMA). Repair or clearance of damaged cells blocks cancer development but may dampen organ maintenance thus speeding up aging. Depending on the context, modulation of checkpoint responses allows accelerating or slowing down aging and age-related malignancies. The result depends on the cells affected, the level and kind of DNA damage accumulation and the clearance of damaged cells.

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 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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

  • Artandi SE, Chang 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):641–645

    CAS  PubMed  Google Scholar 

  • Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007

    CAS  PubMed  Google Scholar 

  • Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457(7229):608–611

    CAS  PubMed  Google Scholar 

  • Begus-Nahrmann Y, Lechel A, Obenauf AC, Nalapareddy K, Peit E, Hoffmann E, Schlaudraff F, Liss B, Schirmacher P, Kestler H, Danenberg E, Barker N, Clevers H, Speicher MR, Rudolph KL (2009) p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nat Genet 41(10):1138–1143

    CAS  PubMed  Google Scholar 

  • Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9(5):356–368. doi:10.1038/nrmicro2546

    CAS  PubMed  Google Scholar 

  • Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255(5505):197–200

    CAS  PubMed  Google Scholar 

  • Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev 8(9):729–740

    CAS  Google Scholar 

  • Chambon-Savanovitch C, Felgines C, Farges MC, Pernet P, Cezard J, Raul F, Cynober L, Vasson MP (1999) Severe dietary restriction initiated in aged rats: evidence for poor adaptation in terms of protein metabolism and intestinal functions. Eur J Clin Invest 29(6):504–511

    CAS  PubMed  Google Scholar 

  • 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(1):99–105

    CAS  PubMed  Google Scholar 

  • Ciccocioppo R, Di Sabatino A, Luinetti O, Rossi M, Cifone MG, Corazza GR (2002) Small bowel enterocyte apoptosis and proliferation are increased in the elderly. Gerontology 48(4):204–208

    CAS  PubMed  Google Scholar 

  • Cimprich KA (2007) Probing ATR activation with model DNA templates. Cell Cycle (Georgetown Tex) 6(19):2348–2354

    CAS  Google Scholar 

  • Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627. doi:10.1038/nrm2450

    CAS  PubMed Central  PubMed  Google Scholar 

  • Corazza GR, Ginaldi L, Quaglione G, Ponzielli F, Vecchio L, Biagi F, Quaglino D (1998) Proliferating cell nuclear antigen expression is increased in small bowel epithelium in the elderly. Mech Ageing Dev 104(1):1–9

    CAS  PubMed  Google Scholar 

  • Corn BW, Lanciano RM, Greven KM, Noumoff J, Schultz D, Hanks GE, Fowble BL (1994) Impact of improved irradiation technique, age, and lymph node sampling on the severe complication rate of surgically staged endometrial cancer patients: a multivariate analysis. J Clin Oncol 12(3):510–515

    CAS  PubMed  Google Scholar 

  • de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H, Weeda G, van der Horst GT, van Leeuwen W, Themmen AP, Meradji M, Hoeijmakers JH (2002) Premature aging in mice deficient in DNA repair and transcription. Science (New York, NY) 296(5571):1276–1279

    Google Scholar 

  • Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284. doi:10.1038/nrc1590

    CAS  PubMed  Google Scholar 

  • Dekaney CM, Rodriguez JM, Graul MC, Henning SJ (2005) Isolation and characterization of a putative intestinal stem cell fraction from mouse jejunum. Gastroenterology 129(5):1567–1580. doi:10.1053/j.gastro.2005.08.011

    CAS  PubMed  Google Scholar 

  • 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 U S A 92(20):9363–9367

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dolle ME, Snyder WK, Gossen JA, Lohman PH, Vijg J (2000) Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc Natl Acad Sci U S A 97(15):8403–8408

    CAS  PubMed Central  PubMed  Google Scholar 

  • El-Assal ON, Besner GE (2004) Heparin-binding epidermal growth factor-like growth factor and intestinal ischemia-reperfusion injury. Semin Pediatr Surg 13(1):2–10

    PubMed  Google Scholar 

  • Escobar M, Nicolas P, Sangar F, Laurent-Chabalier S, Clair P, Joubert D, Jay P, Legraverend C (2011) Intestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation. Nat Commun 2:258. doi:10.1038/ncomms1260

    PubMed Central  PubMed  Google Scholar 

  • Espejel S, Klatt P, Menissier-de Murcia J, Martin-Caballero J, Flores JM, Taccioli G, de Murcia G, Blasco MA (2004) Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs. J Cell Biol 167(4):627–638. doi:10.1083/jcb.200407178

    CAS  PubMed Central  PubMed  Google Scholar 

  • Feng Z, Hu W, Teresky AK, Hernando E, Cordon-Cardo C, Levine AJ (2007) Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci U S A 104(42):16633–16638. doi:10.1073/pnas.0708043104

    CAS  PubMed Central  PubMed  Google Scholar 

  • Finkel T, Serrano M, Blasco MA (2007) The common biology of cancer and ageing. Nature 448(7155):767–774. doi:10.1038/nature05985

    CAS  PubMed  Google Scholar 

  • Franzin G, Grigioni WF, Dina R, Scarpa A, Zamboni G (1983) Mucin secretion and morphological changes of the mucosa in non-neoplastic diseases of the colon. Histopathology 7(5):707–718

    CAS  PubMed  Google Scholar 

  • Garrett WS, Gordon JI, Glimcher LH (2010) Homeostasis and inflammation in the intestine. Cell 140(6):859–870. doi:10.1016/j.cell.2010.01.023

    CAS  PubMed Central  PubMed  Google Scholar 

  • George RJ, Sturmoski MA, May R, Sureban SM, Dieckgraefe BK, Anant S, Houchen CW (2009) Loss of p21Waf1/Cip1/Sdi1 enhances intestinal stem cell survival following radiation injury. Am J Physiol Gastrointest Liver Physiol 296(2):G245–G254. doi:10.1152/ajpgi.00021.2008

    CAS  PubMed Central  PubMed  Google Scholar 

  • Greenow KR, Clarke AR, Jones RH (2009) Chk1 deficiency in the mouse small intestine results in p53-independent crypt death and subsequent intestinal compensation. Oncogene 28(11):1443–1453. doi:10.1038/onc.2008.482

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hamilton E, Franks LM (1980) Cell proliferation and ageing in mouse colon. II. Late effects of repeated x-irradiation in young and old mice. Eur J Cancer 16(5):663–669

    CAS  PubMed  Google Scholar 

  • Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J (2003) Aging and genome maintenance: lessons from the mouse? Science (New York, NY) 299(5611):1355–1359

    CAS  Google Scholar 

  • Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311(5765):1257. doi:10.1126/science.1122446

    CAS  PubMed  Google Scholar 

  • Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J, Passos JF (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3:708. doi:10.1038/ncomms1708

    PubMed Central  PubMed  Google Scholar 

  • Higgins PD, Davis KJ, Laine L (2004) Systematic review: the epidemiology of ischaemic colitis. Aliment Pharmacol Ther 19(7):729–738

    CAS  PubMed  Google Scholar 

  • Holt PR, Yeh KY, Kotler DP (1988) Altered controls of proliferation in proximal small intestine of the senescent rat. Proc Natl Acad Sci U S A 85(8):2771–2775

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hua G, Thin TH, Feldman R, Haimovitz-Friedman A, Clevers H, Fuks Z, Kolesnick R (2012) Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 143(5):1266–1276. doi:10.1053/j.gastro.2012.07.106

    CAS  PubMed Central  PubMed  Google Scholar 

  • Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4(12):988–993. doi:10.1038/nrc1507

    CAS  PubMed  Google Scholar 

  • Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7(4):536–540. doi:10.1038/ng0894-536

    CAS  PubMed  Google Scholar 

  • Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N, Ikeda Y, Mak TW, Suda T (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431(7011):997–1002. doi:10.1038/nature02989

    CAS  PubMed  Google Scholar 

  • Itoh H, Yagi M, Fushida S, Tani T, Hashimoto T, Shimizu K, Miwa K (2000) Activation of immediate early gene, c-fos, and c-jun in the rat small intestine after ischemia/reperfusion. Transplantation 69(4):598–604

    CAS  PubMed  Google Scholar 

  • Itzkovitz S, Lyubimova A, Blat IC, Maynard M, van Es J, Lees J, Jacks T, Clevers H, van Oudenaarden A (2012) Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat Cell Biol 14(1):106–114. doi:10.1038/ncb2384

    CAS  Google Scholar 

  • Jiang H, Ju Z, Rudolph KL (2007) Telomere shortening and ageing. Z Gerontol Geriatr 40(5):314–324

    CAS  PubMed  Google Scholar 

  • Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432(7015):316–323. doi:10.1038/nature03097

    CAS  PubMed  Google Scholar 

  • Liu D, Ou L, Clemenson GD Jr, Chao C, Lutske ME, Zambetti GP, Gage FH, Xu Y (2010) Puma is required for p53-induced depletion of adult stem cells. Nat Cell Biol 12(10):993–998. doi:10.1038/ncb2100

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005) DNA repair, genome stability, and aging. Cell 120(4):497–512. doi:10.1016/j.cell.2005.01.028

    CAS  PubMed  Google Scholar 

  • Lopez-Garcia C, Klein AM, Simons BD, Winton DJ (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330(6005):822–825. doi:10.1126/science.1196236

    CAS  PubMed  Google Scholar 

  • Lorenz E, Uphoff D, Reid TR, Shelton E (1951) Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst 12(1):197–201

    CAS  PubMed  Google Scholar 

  • Majumdar AP, Du J (2006) Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging. Am J Physiol Gastrointest Liver Physiol 290(1):G49–G55. doi:10.1152/ajpgi.00106.2005

    CAS  PubMed  Google Scholar 

  • Maringele L, Lydall D (2002) EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Delta mutants. Genes Dev 16(15):1919–1933. doi:10.1101/gad.225102

    CAS  PubMed Central  PubMed  Google Scholar 

  • Martin K, Kirkwood TB, Potten CS (1998a) Age changes in stem cells of murine small intestinal crypts. Exp Cell Res 241(2):316–323. doi:10.1006/excr.1998.4001

    CAS  PubMed  Google Scholar 

  • Martin K, Potten CS, Roberts SA, Kirkwood TB (1998b) Altered stem cell regeneration in irradiated intestinal crypts of senescent mice. J Cell Sci 111(Pt 16):2297–2303

    CAS  PubMed  Google Scholar 

  • Martinez P, Siegl-Cachedenier I, Flores JM, Blasco MA (2009) MSH2 deficiency abolishes the anticancer and pro-aging activity of short telomeres. Aging Cell 8(1):2–17. doi:10.1111/j.1474-9726.2008.00441.x

    CAS  PubMed  Google Scholar 

  • Maryanovich M, Oberkovitz G, Niv H, Vorobiyov L, Zaltsman Y, Brenner O, Lapidot T, Jung S, Gross A (2012) The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells. Nat Cell Biol 14(5):535–541. doi:10.1038/ncb2468

    CAS  PubMed  Google Scholar 

  • Maser RS, Wong KK, Sahin E, Xia H, Naylor M, Hedberg HM, Artandi SE, DePinho RA (2007) DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol Cell Biol 27(6):2253–2265. doi:10.1128/MCB.01354-06

    CAS  PubMed Central  PubMed  Google Scholar 

  • Merritt AJ, Potten CS, Kemp CJ, Hickman JA, Balmain A, Lane DP, Hall PA (1994) The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res 54(3):614–617

    CAS  PubMed  Google Scholar 

  • Merritt AJ, Potten CS, Watson AJ, Loh DY, Nakayama K, Hickman JA (1995) Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J Cell Sci 108(Pt 6):2261–2271

    CAS  PubMed  Google Scholar 

  • Merritt AJ, Allen TD, Potten CS, Hickman JA (1997) Apoptosis in small intestinal epithelial from p53-null mice: evidence for a delayed, p53-independent G2/M-associated cell death after gamma-irradiation. Oncogene 14(23):2759–2766. doi:10.1038/sj.onc.1201126

    CAS  PubMed  Google Scholar 

  • Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE, Baffour-Awuah NY, Ambruzs DM, Fogli LK, Algra S, Breault DT (2011) Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci U S A 108(1):179–184. doi:10.1073/pnas.1013004108

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murga M, Bunting S, Montana MF, Soria R, Mulero F, Canamero M, Lee Y, McKinnon PJ, Nussenzweig A, Fernandez-Capetillo O (2009) A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nat Genet 41(8):891–898. doi:10.1038/ng.420

    CAS  PubMed Central  PubMed  Google Scholar 

  • Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, van Leeuwen W, Theil AF, Vermeulen W, van der Horst GT, Meinecke P, Kleijer WJ, Vijg J, Jaspers NG, Hoeijmakers JH (2006) A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444(7122):1038–1043. doi:10.1038/nature05456

    CAS  PubMed  Google Scholar 

  • Omae T, Goto M, Shimomura M, Masuda S, Ito K, Okuda M, Inui K (2005) Transient up-regulation of P-glycoprotein reduces tacrolimus absorption after ischemia-reperfusion injury in rat ileum. Biochem Pharmacol 69(4):561–568

    CAS  PubMed  Google Scholar 

  • O’Sullivan RJ, Karlseder J (2010) Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 11(3):171–181. doi:10.1038/nrm2848

    PubMed Central  PubMed  Google Scholar 

  • O’Sullivan JN, Bronner MP, Brentnall TA, Finley JC, Shen WT, Emerson S, Emond MJ, Gollahon KA, Moskovitz AH, Crispin DA, Potter JD, Rabinovitch PS (2002) Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32(2):280–284. doi:10.1038/ng989

    PubMed  Google Scholar 

  • Potten CS (1977) Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature 269(5628):518–521

    CAS  PubMed  Google Scholar 

  • Potten CS, Hume WJ, Reid P, Cairns J (1978) The segregation of DNA in epithelial stem cells. Cell 15(3):899–906

    CAS  PubMed  Google Scholar 

  • Potten CS, Owen G, Booth D (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115(Pt 11):2381–2388

    CAS  PubMed  Google Scholar 

  • Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ (2012) The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149(1):146–158. doi:10.1016/j.cell.2012.02.042

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pritchard DM, Potten CS, Korsmeyer SJ, Roberts S, Hickman JA (1999) Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene 18(51):7287–7293. doi:10.1038/sj.onc.1203150

    CAS  PubMed  Google Scholar 

  • Pritchard DM, Print C, O’Reilly L, Adams JM, Potten CS, Hickman JA (2000) Bcl-w is an important determinant of damage-induced apoptosis in epithelia of small and large intestine. Oncogene 19(34):3955–3959. doi:10.1038/sj.onc.1203729

    CAS  PubMed  Google Scholar 

  • Qiu W, Carson-Walter EB, Liu H, Epperly M, Greenberger JS, Zambetti GP, Zhang L, Yu J (2008) PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell 2(6):576–583. doi:10.1016/j.stem.2008.03.009

    CAS  PubMed Central  PubMed  Google Scholar 

  • Quyn AJ, Appleton PL, Carey FA, Steele RJ, Barker N, Clevers H, Ridgway RA, Sansom OJ, Nathke IS (2010) Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell 6(2):175–181. doi:10.1016/j.stem.2009.12.007

    CAS  PubMed  Google Scholar 

  • Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, Strobl LJ, Honjo T, Clevers H, Radtke F (2008) Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 9(4):377–383

    CAS  PubMed Central  PubMed  Google Scholar 

  • Roberts SB, Fuss P, Heyman MB, Evans WJ, Tsay R, Rasmussen H, Fiatarone M, Cortiella J, Dallal GE, Young VR (1994) Control of food intake in older men. JAMA 272(20):1601–1606

    CAS  PubMed  Google Scholar 

  • Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL (2007) Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447(7145):725–729

    CAS  PubMed  Google Scholar 

  • Rube CE, Fricke A, Widmann TA, Furst T, Madry H, Pfreundschuh M, Rube C (2011) Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PLoS One 6(3), e17487. doi:10.1371/journal.pone.0017487

    PubMed Central  PubMed  Google Scholar 

  • 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(5):701–712

    CAS  PubMed  Google Scholar 

  • Rudolph KL, Millard M, Bosenberg MW, DePinho RA (2001) Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 28(2):155–159

    CAS  PubMed  Google Scholar 

  • Rujano MA, Bosveld F, Salomons FA, Dijk F, van Waarde MA, van der Want JJ, de Vos RA, Brunt ER, Sibon OC, Kampinga HH (2006) Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS Biol 4(12), e417

    PubMed Central  PubMed  Google Scholar 

  • Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Brown EJ (2007) Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1(1):113–126

    CAS  PubMed Central  PubMed  Google Scholar 

  • Salles N (2007) Basic mechanisms of the aging gastrointestinal tract. Digest Dis (Basel, Switzerland) 25(2):112–117

    CAS  Google Scholar 

  • Samuel S, Walsh R, Webb J, Robins A, Potten C, Mahida YR (2009) Characterization of putative stem cells in isolated human colonic crypt epithelial cells and their interactions with myofibroblasts. Am J Physiol Cell Physiol 296(2):C296–C305. doi:10.1152/ajpcell.00383.2008

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40(7):915–920

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL (2007) Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130(5):863–877

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schepers AG, Vries R, van den Born M, van de Wetering M, Clevers H (2011) Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J 30(6):1104–1109. doi:10.1038/emboj.2011.26

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JM, Fibbe WE, Borst P (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 94(8):4028–4033

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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(1):33–39

    CAS  PubMed  Google Scholar 

  • Shcheprova Z, Baldi S, Frei SB, Gonnet G, Barral Y (2008) A mechanism for asymmetric segregation of age during yeast budding. Nature 454(7205):728–734

    CAS  PubMed  Google Scholar 

  • Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3(3):155–168. doi:10.1038/nrc1011

    CAS  PubMed  Google Scholar 

  • Siegl-Cachedenier I, Munoz P, Flores JM, Klatt P, Blasco MA (2007) Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres. Genes Dev 21(17):2234–2247. doi:10.1101/gad.430107

    CAS  PubMed Central  PubMed  Google Scholar 

  • Smilenov LB, Morgan SE, Mellado W, Sawant SG, Kastan MB, Pandita TK (1997) Influence of ATM function on telomere metabolism. Oncogene 15(22):2659–2665. doi:10.1038/sj.onc.1201449

    CAS  PubMed  Google Scholar 

  • Snippert HJ, Clevers H (2011) Tracking adult stem cells. EMBO Rep 12(2):113–122. doi:10.1038/embor.2010.216

    CAS  PubMed Central  PubMed  Google Scholar 

  • Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143(1):134–144. doi:10.1016/j.cell.2010.09.016

    CAS  PubMed  Google Scholar 

  • Sperka T, Song Z, Morita Y, Nalapareddy K, Guachalla LM, Lechel A, Begus-Nahrmann Y, Burkhalter MD, Mach M, Schlaudraff F, Liss B, Ju Z, Speicher MR, Rudolph KL (2012a) Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction. Nat Cell Biol 14(1):73–79. doi:10.1038/ncb2388

    CAS  Google Scholar 

  • Sperka T, Wang J, Rudolph KL (2012b) DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol 13(9):579–590. doi:10.1038/nrm3420

    CAS  PubMed  Google Scholar 

  • Stamatakos M, Douzinas E, Stefanaki C, Petropoulou C, Arampatzi H, Safioleas C, Giannopoulos G, Chatziconstantinou C, Xiromeritis C, Safioleas M (2009) Ischemic colitis: surging waves of update. Tohoku J Exp Med 218(2):83–92

    PubMed  Google Scholar 

  • Steinhauser ML, Bailey AP, Senyo SE, Guillermier C, Perlstein TS, Gould AP, Lee RT, Lechene CP (2012) Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. Nature 481(7382):516–519. doi:10.1038/nature10734

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stiff T, Walker SA, Cerosaletti K, Goodarzi AA, Petermann E, Concannon P, O’Driscoll M, Jeggo PA (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J 25(24):5775–5782. doi:10.1038/sj.emboj.7601446

    CAS  PubMed Central  PubMed  Google Scholar 

  • Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA (2011) Interconversion between intestinal stem cell populations in distinct niches. Science (New York, NY) 334(6061):1420–1424. doi:10.1126/science.1213214

    CAS  Google Scholar 

  • Tian H, Biehs B, Warming S, Leong KG, Rangell L, Klein OD, de Sauvage FJ (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478(7368):255–259. doi:10.1038/nature10408

    CAS  PubMed Central  PubMed  Google Scholar 

  • van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260

    PubMed  Google Scholar 

  • van Es JH, Sato T, van de Wetering M, Lyubimova A, Nee AN, Gregorieff A, Sasaki N, Zeinstra L, van den Born M, Korving J, Martens AC, Barker N, van Oudenaarden A, Clevers H (2012) Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14(10):1099–1104. doi:10.1038/ncb2581

    PubMed Central  PubMed  Google Scholar 

  • Verdun RE, Karlseder J (2007) Replication and protection of telomeres. Nature 447(7147):924–931. doi:10.1038/nature05976

    CAS  PubMed  Google Scholar 

  • Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8(10):755–768. doi:10.1038/nrc2499

    CAS  PubMed  Google Scholar 

  • Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T (2009) DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8(3):311–323. doi:10.1111/j.1474-9726.2009.00481.x

    CAS  PubMed  Google Scholar 

  • Wei K, Clark AB, Wong E, Kane MF, Mazur DJ, Parris T, Kolas NK, Russell R, Hou H Jr, Kneitz B, Yang G, Kunkel TA, Kolodner RD, Cohen PE, Edelmann W (2003) Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes Dev 17(5):603–614. doi:10.1101/gad.1060603

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38(7):787–793. doi:10.1038/ng1834

    CAS  PubMed  Google Scholar 

  • Wilson JW, Pritchard DM, Hickman JA, Potten CS (1998) Radiation-induced p53 and p21WAF-1/CIP1 expression in the murine intestinal epithelium: apoptosis and cell cycle arrest. Am J Pathol 153(3):899–909. doi:10.1016/S0002-9440(10)65631-3

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y, Alt FW, DePinho RA (2003) Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421(6923):643–648

    CAS  PubMed  Google Scholar 

  • Wong KK, Maser RS, Sahin E, Bailey ST, Xia H, Ji H, McNamara K, Naylor M, Bronson RT, Ghosh S, Welsh R, DePinho RA (2007) Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres. Oncogene 26(20):2815–2821. doi:10.1038/sj.onc.1210099

    CAS  PubMed  Google Scholar 

  • Wong VW, Stange DE, Page ME, Buczacki S, Wabik A, Itami S, van de Wetering M, Poulsom R, Wright NA, Trotter MW, Watt FM, Winton DJ, Clevers H, Jensen KB (2012) Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat Cell Biol 14(4):401–408. doi:10.1038/ncb2464

    CAS  PubMed Central  PubMed  Google Scholar 

  • Woudstra T, Thomson AB (2002) Nutrient absorption and intestinal adaptation with ageing. Best Pract Res 16(1):1–15

    Google Scholar 

  • Xiao ZQ, Moragoda L, Jaszewski R, Hatfield JA, Fligiel SE, Majumdar AP (2001) Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa. Mech Ageing Dev 122(15):1849–1864

    CAS  PubMed  Google Scholar 

  • Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ (2012) The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci U S A 109(2):466–471. doi:10.1073/pnas.1118857109

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yatabe Y, Tavare S, Shibata D (2001) Investigating stem cells in human colon by using methylation patterns. Proc Natl Acad Sci U S A 98(19):10839–10844. doi:10.1073/pnas.191225998

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Stem cell aging, Leibniz Institute for Age Research, Fritz Lipmann Institute e.V. (FLI), Beutenbergstr. 11, Jena, 07745, Germany

    Tobias Sperka & Lenhard Rudolph

Authors
  1. Tobias Sperka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lenhard Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lenhard Rudolph .

Editor information

Editors and Affiliations

  1. Dermatology and Allergic Diseases, Ulm University, Ulm, Germany

    Hartmut Geiger

  2. Department of Biology, University of Rochester, Rochester, New York, USA

    Heinrich Jasper

  3. Dermatology and Allergic Diseases, Ulm University, Ulm, Germany

    Maria Carolina Florian

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Wien

About this chapter

Cite this chapter

Sperka, T., Rudolph, L. (2015). Aging of Mammalian Intestinal Stem Cells. In: Geiger, H., Jasper, H., Florian, M. (eds) Stem Cell Aging: Mechanisms, Consequences, Rejuvenation. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1232-8_9

Download citation

Publish with us

Policies and ethics

Search

Navigation