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Regulation of Life Span in Adult Stem Cells

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Adult Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

Unlike pluripotent stem cells in the early embryo, many types of somatic stem cells in the adult, such as hematopoietic, neural, and hair follicle stem cells, appear to have a limited life span. There are a number of different intrinsic and extrinsic factors that can affect the regulation of somatic stem cell life span, including the accumulation of DNA damage, oxidative stress from reactive oxygen species, the attrition of telomeres, aberrant changes in gene expression driven by age-related epigenetic shifts, and loss of function of the stem cell niche with age. There are also a number of potential events that define the end-point to stem cell life span, namely cell senescence, apoptosis, terminal differentiation, and tumorigenic transformation. The principal factors affecting the rate of aging in a somatic stem cell as well as the mechanism of life span termination are dependent on the type of stem cell. The development of new methods to extend or attenuate somatic stem cell life span holds substantial promise as effective means to treat the age-related or disease-specific decline in numbers of certain stem cells, or to eliminate cancer stem cells as an anticancer therapy, respectively.

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Abbreviations

Arf:

Alternative reading frame tumor suppressor

ATM:

Ataxia telangiectasia-mutated

ES:

Embryonic stem

G-CSF:

Granulocyte colony-stimulating factor

HDF:

Human diploid fibroblast

HSC:

Hematopoietic stem cell

iPS:

Induced pluripotent stem

NAC:

N-acetyl-l-cysteine

NSC:

Neural stem cell

PI3K:

Phosphoinositide-3 kinase

rDNA:

Extrachromosomal ribosomal DNA

ROS:

Reactive oxygen species

Tert:

Telomerase reverse transcriptase

TR:

Telomerase

References

  • Alcorta DA, Xiong Y, Phelps D et al (1996) Involvement of the cylin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA 93:13742–13747.

    Article  CAS  PubMed  Google Scholar 

  • Alexander P (1967) The role of DNA lesions in the processes leading to aging in mice. Symp Soc Exp Biol 21:29–50.

    CAS  PubMed  Google Scholar 

  • Allsopp RC, Vaziri H, Patterson C, Goldstein S et al (1992) Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89:10114–10118.

    Article  CAS  PubMed  Google Scholar 

  • Allsopp RC, Cheshier S, Weissman IL (2001) Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med 193:917–924.

    Article  CAS  PubMed  Google Scholar 

  • Allsopp RC, Morin GB, DePinho R et al (2003) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102:517–520.

    Article  CAS  PubMed  Google Scholar 

  • Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922.

    Article  CAS  PubMed  Google Scholar 

  • Artandi SE, Alson S, Tietze MK et al (2002) Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc Natl Acad Sci USA 99:8191–8196.

    Article  CAS  PubMed  Google Scholar 

  • Becker AJ, McCulloch EA, Till JE (1963) Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nautre 197:452–454.

    CAS  Google Scholar 

  • Best BP (2009) Nuvlear DNA damage as a direct cause of aging. Rejuvenation Res 12:199–208.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Calado RT, Regal JA, Kajigaya S et al (2009) Erosion of telomeric single-stranded overhang in patients with aplastic anaemia carrying telomerase complex mutations. Eur J Clin Invest 39:1025–1032.

    Article  CAS  PubMed  Google Scholar 

  • Chambers SM, Shaw CA, Gatza C et al (2007) Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5:e201.

    Article  PubMed  Google Scholar 

  • Chan SR, Blackburn EH (2004) Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci 359:109–121.

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Astle CM, Harrison DE (2000) Genetic regulation of primitive hematopoietic stem cell senescence. Exp Hematol 28:442–450.

    Article  CAS  PubMed  Google Scholar 

  • Cho RH, Sieburg HB, Muller-Sieburg CE (2008) A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood 111:5553–5561.

    Article  CAS  PubMed  Google Scholar 

  • Conboy IM, Conboy MJ, Smythe GM et al (2003) Notch-mediated restoration of regenerative potential to aged muscle. Science 302:1575–1577.

    Article  CAS  PubMed  Google Scholar 

  • Conboy IM, Conboy MJ, Wagers AJ et al (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760–764.

    Article  CAS  PubMed  Google Scholar 

  • Counter CM, Avilion AA, LeFeuvre CE et al (1992) Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11:1921–1929.

    CAS  PubMed  Google Scholar 

  • Cristofalo VJ, Pignolo RJ (1996) Molecular markers of senescence in fibroblast-like cultures. Exp Gerontol 31:111–123.

    Article  CAS  PubMed  Google Scholar 

  • Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367.

    Article  CAS  PubMed  Google Scholar 

  • Du HY, Pumbo E, Ivanovich J et al (2009) TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements. Blood 113:309–316.

    Article  CAS  PubMed  Google Scholar 

  • Dumble M, Moore L, Chambers SM et al (2007) The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood 109:1736–1742.

    Article  CAS  PubMed  Google Scholar 

  • Ertl RP, Chen J, Astle CM et al (2008) Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated. Blood 111:1709–1716.

    Article  CAS  PubMed  Google Scholar 

  • Falconer E, Chavez EA, Henderson A et al (2010) Identification of sister chromatids by DNA template strand sequences. Nature 463:93–97.

    Article  CAS  PubMed  Google Scholar 

  • Fauce SR, Jamieson BD, Chin AC et al (2008) Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol 181:7400–7406.

    CAS  PubMed  Google Scholar 

  • Feng J, Funk WD, Wang SS et al (1995) The RNA component of human telomerase. Science 269:1236–1241.

    Article  CAS  PubMed  Google Scholar 

  • Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309:1253–1256.

    Article  CAS  PubMed  Google Scholar 

  • Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609.

    Article  CAS  PubMed  Google Scholar 

  • Geiger H, True JM, de Haan G et al (2001) Age- and stage-specific regulation patterns in the hematopoietic stem cell hierarchy. Blood 98:2966–2972.

    Article  CAS  PubMed  Google Scholar 

  • Goldstein S (1990) Replicative senescence: the human fibroblast comes of age. Science 249:1129–1134.

    Article  CAS  PubMed  Google Scholar 

  • González-Suárez E, Samper E, Ramírez A et al (2001) Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J 20:2619–2630.

    Article  PubMed  Google Scholar 

  • Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–337.

    Article  CAS  PubMed  Google Scholar 

  • Harley CB (2002) Telomerase is not an oncogene. Oncogene 21:494–502.

    Article  CAS  PubMed  Google Scholar 

  • Harley CB (2008) Telomerase and cancer therapeutics. Nat Rev Cancer 8:167–179.

    Article  CAS  PubMed  Google Scholar 

  • Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nautre 345:458–460.

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Harman D (1972) The biological clock: the mitochondria? J Am Geriatr Soc 20:145–147.

    CAS  PubMed  Google Scholar 

  • Harrison DE, Astle CM (1982) Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med 156:1767–1779.

    Article  CAS  PubMed  Google Scholar 

  • Hastie ND, Dempster M, Dunlop MG et al (1990) Telomere reduction in human colorectal carcinoma and with ageing. Nature 346:866–868.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  • Inomata K, Aoto T, Binh NT et al (2009) Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137:1088–1099.

    Article  CAS  PubMed  Google Scholar 

  • Itahana K, Zou Y, Itahana Y et al (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 23:389–401.

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Hirao A, Arai F et al (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431:997–1002.

    Article  CAS  PubMed  Google Scholar 

  • Iwama A, Oguro H, Negishi M et al (2004) Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21:843–851.

    Article  CAS  PubMed  Google Scholar 

  • Janzen V, Forkert R, Fleming HE et al (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443:421–426.

    CAS  PubMed  Google Scholar 

  • Ju Z, Jiang H, Jaworski M et al (2007) Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13:742–747.

    Article  CAS  PubMed  Google Scholar 

  • Kaeberlein M, Kirkland KT, Fields S et al (2004) Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol 2:E296.

    Article  PubMed  Google Scholar 

  • Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015.

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Jung KJ, Yu BP et al (2002) Modulation of redox-sensitive transcription factors by calorie restriction during aging. Mech Ageing Dev 123:1589–1595.

    Article  CAS  PubMed  Google Scholar 

  • Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033.

    CAS  PubMed  Google Scholar 

  • Kujoth GC, Hiona A, Pugh TD et al (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484.

    Article  CAS  PubMed  Google Scholar 

  • Labrie III JE, Sah AP, Allman DM et al (2004) Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. J Exp Med 200:411–423.

    Article  CAS  PubMed  Google Scholar 

  • Lee HW, Blasco MA, Gottlieb GJ et al (1998) Essential role of mouse telomerase in highly proliferative organs. Nature 392:569–574.

    Article  CAS  PubMed  Google Scholar 

  • Lee CK, Weindruch R, Prolla TA (2000) Gene expression profile of the aging brain in mice. Nat Genet 25:294–297.

    Article  CAS  PubMed  Google Scholar 

  • Liang Y, Van Zant G, Szilvassy SJ (2005) Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106:1479–1487.

    Article  CAS  PubMed  Google Scholar 

  • Lindsey J, McGill NI, Lindsey LA et al (1991) In vivo loss of telomeric repeats with age in humans. Mutat Res 256:45–48.

    CAS  PubMed  Google Scholar 

  • Lu T, Pan Y, Kao SY et al (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891.

    Article  CAS  PubMed  Google Scholar 

  • Marion RM, Strati K, Li H et al (2009) Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell 4:141–154.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Maslov AY, Barone TA, Plunkett RJ et al (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24:1726–1733.

    Article  CAS  PubMed  Google Scholar 

  • Matheu A, Maraver A, Klatt P et al (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:375–379.

    Article  CAS  PubMed  Google Scholar 

  • Migliaccio E, Giorgio M, Mele S et al (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309–313.

    Article  CAS  PubMed  Google Scholar 

  • Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402:551–555.

    Article  CAS  PubMed  Google Scholar 

  • Mitsui A, Hamuro J, Nakamura H et al (2002) Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal 4:693–696.

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto K, Araki KY, Naka K et al (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1:101–112.

    Article  CAS  PubMed  Google Scholar 

  • Molofsky AV, Slutsky SG, Joseph NM et al (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452.

    Article  CAS  PubMed  Google Scholar 

  • Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132:598–611.

    Article  CAS  PubMed  Google Scholar 

  • Morrison SJ, Wandycz AM, Akashi K et al (1996) The aging of hematopoietic stem cells. Nat Med 2:1011–1016.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura TM, Morin GB, Chapman KB et al (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959.

    Article  CAS  PubMed  Google Scholar 

  • Navarro S, Meza NW, Quintana-Bustamante O et al (2006) Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1. Mol Ther 14:525–535.

    Article  CAS  PubMed  Google Scholar 

  • Niida H, Matsumoto T, Satoh H et al (1998) Severe growth defect in mouse cells lacking the telomerase RNA component. Nat Genet 19:203–206.

    Article  CAS  PubMed  Google Scholar 

  • Nishimura EK, Granter SR, Fisher DE (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307:720–724.

    Article  CAS  PubMed  Google Scholar 

  • Olovnikov AM (1971) Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201:1496–1499.

    CAS  PubMed  Google Scholar 

  • Orgel LE (1963) The maintenance of the accuracy of protein synthesis and its relevance to ageing. Proc Natl Acad Sci USA 49:517–521.

    Article  CAS  PubMed  Google Scholar 

  • Orr WC, Sohal RS (1994) Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263:1128–1130.

    Article  CAS  PubMed  Google Scholar 

  • Park IK, Qian D, Kiel M et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–305.

    Article  CAS  PubMed  Google Scholar 

  • Parmar K, Mauch P, Vergilio JA et al (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104:5431–5436.

    Article  CAS  PubMed  Google Scholar 

  • Rando TA (2007) The immortal strand hypothesis: segregation and reconstruction. Cell 129:1239–1243.

    Article  CAS  PubMed  Google Scholar 

  • Rossi DJ, Bryder D, Zahn JM et al (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA 102:9194–9199.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ruzankina Y, Pinzon-Guzman C, Asare A et al (2007) Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1:113–126.

    Article  CAS  PubMed  Google Scholar 

  • Samper E, Fernandez P, Eguia R et al (2002) Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood 99:2767–2775.

    Article  CAS  PubMed  Google Scholar 

  • Schriner SE, Linford NJ, Martin GM et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911.

    Article  CAS  PubMed  Google Scholar 

  • Shefer G, Van de Mark DP, Richardson JB et al (2006) Satellite-cell pool size does matter: defining the myogenic potency of aging skeletal muscle. Dev Biol 294:50–66.

    Article  CAS  PubMed  Google Scholar 

  • Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles–a cause of aging in yeast. Cell 26:1033–1042.

    Article  Google Scholar 

  • Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 271:59–63.

    Article  Google Scholar 

  • Stanulis-Praeger BM (1987) Cellular senescence revisited: a review. Mech Ageing Dev 38:1–48.

    Article  CAS  PubMed  Google Scholar 

  • Stephan RP, Reilly CR, Witte PL (1998) Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood 91:75–88.

    CAS  PubMed  Google Scholar 

  • Szilard L (1959) On the nature of aging process. Proc Nati Acad Sci USA 45:30–35.

    Article  CAS  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676.

    Article  CAS  PubMed  Google Scholar 

  • Tomás-Loba A, Flores I, Fernández-Marcos PJ et al (2008) Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135:609–622.

    Article  PubMed  Google Scholar 

  • Tothova Z, Kollipara R, Huntly BJ et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128:325–339.

    Article  CAS  PubMed  Google Scholar 

  • Vaziri H, Dragowska W, Allsopp RC et al (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 91:9857–9860.

    Article  CAS  PubMed  Google Scholar 

  • Vermulst M, Bielas JH, Kujoth GC et al (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39:540–543.

    Article  CAS  PubMed  Google Scholar 

  • West MD, Shay JW, Wright WE et al (1996) Altered expression of plasminogen activator and plasminogen activator inhibitor during cellular senescence. Exp Gerontol 31:175–193.

    Article  CAS  PubMed  Google Scholar 

  • Williams W, Beutler E, Erslev A, Ma L, Eds. (1983) Hematology. 3rd edition. New York, NY: McGraw-Hill.

    Google Scholar 

  • Wong H, Riabowol K (1996) Differential CDK-inhibitor gene expression in aging human diploid fibroblasts. Exp Gerontol 31:311–325.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute for Biogenesis Research, John A Burns School of Medicine, University of Hawaii, 651 Ilalo Street, BSB Room 163B, Honolulu, HI, 96813, USA

    Rich Allsopp

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  1. Philip Davy
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Correspondence to Rich Allsopp .

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  1. , Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps Way, Jupiter, 33458, Florida, USA

    Donald G. Phinney

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Davy, P., Allsopp, R. (2011). Regulation of Life Span in Adult Stem Cells. In: Phinney, D. (eds) Adult Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-61779-002-7_9

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