The Stem Cell Hypothesis of Aging

Anna Meiliana, Andi Wijaya


BACKGROUND: There is probably no single way to age. Indeed, so far there is no single accepted explanation or mechanisms of aging (although more than 300 theories have been proposed). There is an overall decline in tissue regenerative potential with age, and the question arises as to whether this is due to the intrinsic aging of stem cells or rather to the impairment of stem cell function in the aged tissue environment.

CONTENT: Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16INK4a may also induce an unwanted consequence: a decline in the replicative function of certain stem cells types with advancing age. This decrease regenerative capacity appears to pointing to the stem cell hypothesis of aging.

SUMMARY: Recent evidence suggested that we grow old partly because of our stem cells grow old as a result of mechanisms that suppress the development of cancer over a lifetime. We believe that a further, more precise mechanistic understanding of this process will be required before this knowledge can be translated into human anti-aging therapies.

KEYWORDS: stem cells, senescence, telomere, DNA damage, epigenetic, aging

Full Text:



Frisard M, Ravussin E. Energy metabolism and oxidative stress: impact on the metabolic syndrome and the aging process. Endocrine. 2006; 29: 27-32, CrossRef.

Harman D. Aging: phenomena and theories. Ann NY Acad Sci. 1998; 854: 1-7, CrossRef.

Schlessinger D, Van Zant G. Does functional depletion of stem cells drive aging? Mech Aging Dev. 2001; 122: 1537-53, CrossRef.

Park Y, Gerson SL. DNA repair defects in stem cell function and aging. Annu Rev Med. 2005; 56: 495-508, CrossRef.

Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007; 447: 725-30, CrossRef.

Finkel TS, Holbrook NJ. Oxidants, oxidative stress and the biology of aging. Nature. 2000; 408: 239-47, CrossRef.

Lombard DB, Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell. 2005; 120: 497-512, CrossRef.

Brunet A, Rando TA. Aging: From stem to stern. Nature. 2007; 449: 288-91, CrossRef.

Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 2007; 8: 703-13, CrossRef.

Kirkwood TBL. Understanding the odd science of aging. Cell. 2005; 120: 437-47, CrossRef.

Karanjawala ZE, Lieber MR. DNA damage and aging. Mech Aging Dev. 2004; 125: 405-15, CrossRef.

Medvedev ZA. An attempt at a rational classifi cation of theories of aging. Bio Rev Camb Philos Soc. 1990; 65: 375-98, CrossRef.

Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996; 273: 59-63, CrossRef.

Ben-Porath I, Weinberg RA. When cells get stressed; an integrative view of cellular senescence. J Clin Invest. 2004; 113: 8-13, CrossRef.

Von Zglinicki T. Replicative senescence and the art of counting. Exp Gerontol. 2003; 38: 1259-64, CrossRef.

Krtolica A, Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol. 2002; 34: 1401-14, CrossRef.

Vijg J, Campisi J. Puzzles, promises and a cure for aging. Nature. 2008; 454: 1065-71, CrossRef.

Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1957; 2: 298-300, CrossRef.

McCord JM, Fridovich I. Superoxide dismutase. An enzymatic function for erythrocuperin (hemocuperin). J Biol Chem. 1969; 244: 6049-55, PMID.

Promislow DE. DNA repair and the evolution of longevity: a critical analysis. J Theor Biol. 1994; 170: 291-300, CrossRef.

Bürkle A. Physiology and patophysiology of poly(ADP-ribosyl) ation. Bioessays 2001; 23: 795-806, CrossRef.

Kim S, Kaminker P, Campisi J. Telomeres, aging and cancer: in search of a happy ending. Oncogene. 2002; 21: 503-11, CrossRef.

Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999; 283: 1482-8, CrossRef.

Müller-Höcker J. Cytochrome-c-oxidase defi cient cardiomyocytes in the human heart: An age-related phenomenon. A histochemical ultracytochemical study. Am J Pathol. 1989; 134: 1167-73, PMID.

Brierley EJ, Johnson MA, Lightowlers RN, James OF, Turnbull DM. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann Neurol. 1998; 43: 217-23, CrossRef.

Cottrell DA, Blakely EL, Johnson MA, Ince PG, Borthwick GM, Turnbull DM. Cytochrome c oxidase deficient cells accumulate in the hippocampus and choroid plexus with age. Neurobiol Aging. 2000; 22: 265-72, CrossRef.

Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, et al. Mitochondrial DNA mutations in human colonic crypt stem cells, J Clin Invest. 2003; 112: 1351-60, CrossRef.

Carrard G, Bulteau AL, Petropoulos I, Friguet B. Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol. 2002; 34: 1461-74, CrossRef.

Soti C, Csermely P. Aging and molecular chaperones. Exp Gerontol. 2003; 38: 1037-40, CrossRef.

Terman A, Brunk UT. Aging as a catabolic malfunction. Int J Biochem Cell Biol. 2004; 36: 2365-75, CrossRef.

Kirkwood TBL, Boys RJ, Gillespie CS, Proctor CJ, Shanley DP, Wilkinson DJ. Towards an e-biology of aging: integrating theory and data. Nat Rev Mol Cell Biol. 2003; 4: 243-9, CrossRef.

Kowald A, Kirkwood TBL. A network theory of aging: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the aging process. Mutat Res. 1996; 316: 209-36, CrossRef.

Giorgio M, Trinei M, Migliaccio E, Pellici PG. Hydrogen peroxide: a metabolic by-product or a common mediator of aging signals? Nat Rev Mol Cell Biol. 2007; 8: 722-8, CrossRef.

Stone JR, Yang S. Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal. 2006; 8: 243-70, CrossRef.

Finkel T. Redox-dependent signal transduction. Febs Lett. 2000; 476: 52-4, CrossRef.

Alexandrova AY, Kopnin PB, Vasiliev JM, Kopnin BP. ROS up-regulation mediates Ras-induced changes of cell morphology and motility. Exp Cell Res. 2006; 312: 2066-73, CrossRef.

Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell 2002; 9: 1031-44, CrossRef.

Schimmel M, Bauer G. Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fi broblasts. Oncogene. 2002; 21: 5886-96, CrossRef.

Giles GI. The redox regulation of thiol dependent signaling pathways in cancer. Curr Pharm Des. 2006; 12: 4427-43, CrossRef.

North S, Moenner M, Bikfalvi A. Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Lett. 2005; 218: 1-14, CrossRef.

Passos JF, Von Zglinicki T. Oxygen free radicals in cell senescence: are they signal transducers? Free Radic Res. 2006; 40: 1277-83, CrossRef.

Kowaltowski AJ, Castilho RF, Vercesi AE. Mitochondrial permeability transition and oxidative stress. FEBS Lett. 2001; 495: 12-5, CrossRef.

Landis GN, Tower J. Superoxide dismutase evolution and life span regulation. Mech Aging Dev. 2005; 126: 365-79, CrossRef.

Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005; 308: 1909-11, CrossRef.

Francia P, delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E, et al. Deletion of p66Shc gene protects against age-related endothelial dysfunction. Circulation. 2004; 110: 2889-95, CrossRef.

Menini S, Amadio L, Oddi G, Ricci C, Pesce C, Pugliese F, et al. Deletion of p66Shc longevity gene protects against experimental diabetic glomerulopathy by preventing diabetes-induced oxidative stress. Diabetes. 2006; 55: 1642-50, CrossRef.

Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, et al. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA. 2003; 18: 2112-6, CrossRef.

Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66Shc gene. Circ Res 2006; 99: 42-52, CrossRef.

Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, et al. The p66Shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999; 402: 309-13, CrossRef.

Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 3rd ed. Oxford: Oxford University Press; 1998, NLMID.

Sohal RS, Allen RG. Oxidative stress as a causal factor in differentiation and aging: a unifying hypothesis. Exp Gerontol. 1990; 25: 499-522, CrossRef.

Russel SJ, Kahn CR. Endocrine regulation of aging. Nat Rev Mol Cell Biol. 2007; 8: 681-91, CrossRef.

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling aging. Nature. 1997; 390: 45-51, CrossRef.

Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309: 1829-33, CrossRef.

Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 2004; 565: 143-7, CrossRef.

Kirkwood TB, Cremer T. Cytogerontology since 1881: a reappraisal of August Weismann and a review of modern progress. Hum Genet. 1982; 60: 101-21, CrossRef.

Guarente L, Kenyon C. Genetic pathways that regulate aging in model organisms. Nature. 2000; 408: 255-62, CrossRef.

Partridge L, Gems D. Mechanisms of aging: public or private? Nat Rev Genet. 2002; 3: 165-75, CrossRef.

Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell. 2005; 120: 449-60, CrossRef.

De Bont R, van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis. 2004; 19: 169-85, CrossRef.

Garinis GA, van der Horst GTJ, Vijg J, Hoeijmakers HJ. DNA damage and aging: new-age ideas for an age-old problem. Nat Cell Biol. 2008; 11: 1241-7, CrossRef.

Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics. 2003; 16: 29-37, CrossRef.

Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006; 444: 1038-43, CrossRef.

Bahar R. Increased cell-to-cell variation in gene expression in aging mouse heart. Nature. 2006; 441: 1011-4, CrossRef.

Cheutin T, McNairn AJ, Jenuwein T, Gilbert DM, Singh PB, Misteli T. Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science. 2003; 299: 721-5, CrossRef.

Grewal SI, Jia S. Heterochromatin revisited. Nature Rev Gene. 2007; 8: 35-46, CrossRef.

Villeponteau B. The heterochromatin loss model of aging. Exp Gerontol. 1997; 32: 383-94, CrossRef.

Imai S, Kitano H. Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Exp Gerontol.1998; 33: 555-70, PMID.

Goldstein S. Replicative senescence: the human fibroblast comes of age. Science. 1990; 249: 1129-33, CrossRef.

Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120: 513-22, CrossRef.

Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and aging. Nat Rev Mol Cell Biol. 2007; 8: 692-702, CrossRef.

Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 2006; 140: 2603-24, CrossRef.

Narita M, Nuñez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113: 703-16, CrossRef.

Scaffi di P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science. 2006; 312: 1059-63, CrossRef.

Imai S, Nishibayashi S, Takao K, Tomifuji M, Fujino T, Hasegawa M, et al. Dissociation of Oct-1 from the nuclear peripheral structure induces the cellular aging-associated collagenase gene expression. Mol Biol Cell. 1997; 8: 2407-19, CrossRef.

Malins DC, Anderson KM, Jaruga P, Ramsey CR, Gilman NK, Green VM, et al. Oxidative changes in the DNA of stroma and epithelium from the female breast: potential implications for breast cancer. Cell Cycle. 2006; 5: 1629-32, CrossRef.

Packer L, Fuehr K. Low oxygen concentration extends the lifespan of cultured human diploid cells. Nature 1977; 267: 423-5, CrossRef.

von Zglinicki T, Saretzki G, Docke W, Lotze C. Mild hyperoxia shortens telomeres and inhibits proliferation of fi broblasts: a model for senescence? Exp Cell Res. 1995; 220: 186-93, CrossRef.

Chen Q, Ames B N. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fi broblast F65 cells. Proc Natl Acad Sci USA. 1994; 91: 4130-4, CrossRef.

Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells, Biogerontology. 2004; 5: 1-10, CrossRef.

Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997; 91: 649-59, CrossRef.

Stein GH, Drullinger LF, Soulard A, Dulic V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 1999; 19: 2109-17, CrossRef.

Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclindependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA. 1996; 93: 13742-7, CrossRef.

Campisi J. Suppressing cancer: the importance of being senescent. Science. 2005; 309: 886-7, CrossRef.

Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006; 127: 265-75, CrossRef.

Sone H, Kagawa Y. Pancreatic β cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat dietinduced diabetic mice. Diabetologia. 2005; 48: 58-67, CrossRef.

Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114: 1299-307, CrossRef.

Edwards MG, Anderson RM, Yuan M, Kendziorski CM, Weindruch R, Prolla TA. Gene expression profiling ofaging reveals activation of a p53-mediated transcriptional program. BMC Genomics. 2007; 8: e80, CrossRef.

Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, et al. Stem-cell aging modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006; 443: 421-6, CrossRef.

Chen J, Astle CM, Harrison DE. Hematopoietic senescence is postponed and hematopoietic stem cell function is enhanced by dietary restriction. Exp Hematol. 2003; 31: 1097-103, CrossRef.

Campisi J. Between Scylla and Charybdis: p53 links tumor suppression and aging. Mech Aging Dev. 2002; 123: 567-73, CrossRef.

Hornsby PJ. Cellular senescence and tissue aging in vivo. J Gerontol A Biol Sci Med Sci. 2002; 57A: B251-6, CrossRef.

Kirkwood TB, Austad SN. Why do we age? Nature. 2000; 408: 233-8, CrossRef.

Serrano M, Blasco MA. Cancer and aging: convergent and divergent mechanisms. Nat Rev Mol Cell Biol. 2007; 8: 715-21, CrossRef.

Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445: 656-60, CrossRef.

Kirkwood TL, Kapahi P, Shanley DP. Evolution, stress, and longevity. J Anat. 2000; 197: 587-90, CrossRef.

Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004; 113: 160-8, CrossRef.

Wright WE, Shay JW. Historical claims and current interpretations of replicative aging. Nat Biotechnol. 2002; 20: 682-8, CrossRef.

Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 2001; 11: S27-31, CrossRef.

Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 2003; 424: 223-8, CrossRef.

Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer. 2002; 2: 910-7, CrossRef.

Vousden KH. p53: death star. Cell. 2000; 103: 691-4, CrossRef.

Sharpless NE, DePinho RA. p53: good cop/bad cop. Cell. 2002; 110: 9-12, CrossRef.

Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997; 88: 323-31, CrossRef.

Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell. 1998; 92: 713-23, CrossRef.

Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998; 12: 2424-33, CrossRef.

de Stanchina E, McCurrach ME, Zindy F, Shieh S-Y, Ferbeyre G, Samuelson AV, et al. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 1998; 12: 2434-42, CrossRef.

Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998; 92: 725-34, CrossRef.

Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998; 17: 5001-14, CrossRef.

Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 1998; 95: 8292-7, CrossRef.

Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998; 12: 2997-3007, CrossRef.

Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88: 593-602, CrossRef.

Zindy F, Quelle DE, Roussel MF, Sherr CJ. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene. 1997; 15: 203-11, CrossRef.

Pelicci PG. Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence? J Clin Invest. 2004; 113: 4-7, CrossRef.

Park IK, Morrison SJ, Clarke MF. Bmi-1, stem cells, and senescence regulation. J Clin Invest 2004; 113: 175-9, CrossRef.

Kahlem P, Dörken B, Schmitt CA. Cellular senescence in cancer treatment: friend or foe? J Clin Invest 2004; 113: 169-74, CrossRef.

Ju Z, Jiang H, Jaworsky M, Rathinam C, Gompf A, Klein C, et al. Telomere dysfunction induces environmental alterations limiting hemaotopoeitic stem cell function and engraftment. Nat Med. 2007; 13: 742-7, CrossRef.

Lieber MR, Karanjawala ZE. Aging, repetitive genomes and DNA damage. Nat Rev Mol Cell Biol. 2004; 5: 69-75, CrossRef.

d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003; 426: 194-8, CrossRef.

Vaziri H, Benchimol S. From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging. Exp Gerontol. 1996; 31: 295-301, CrossRef.

Djojosubroto MW, Choi YS, Lee HW, Rudolph KL. Telomeres and telomerase in aging, regeneration and cancer. Mol Cells. 2003; 15: 164-75, PMID.

Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet. 2004; 36: 447-9, CrossRef.

Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA. Longevity, stress response, and cancer in aging telomerase defi cient mice. Cell. 1999; 96: 701-12, CrossRef.

Herrera E, Samper E, Martín-Caballero J, Flores JM, Lee HW, Blasco MA. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 1999; 18: 2950-60, CrossRef.

Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood. 2003; 102: 517-20, CrossRef.

Conboy IM, Rando TA. Aging, stem cells and tissue regeneration. Cell Cycle. 2005; 4: 407-10, CrossRef.

Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue specific stem cell. Am J Pathol. 2006; 169: 338-46, CrossRef.

Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006; 441: 1068-74, CrossRef.

Hodgson GS, Bradley TR. In vivo kinetic status of hematopoietic stem and progenitor cells as inferred from labeling with bromodeoxyuridine. Exp Hematol. 1984; 12: 683-7, PMID.

Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005; 202: 1599-611, CrossRef.

Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc NatlAcad Sci USA. 2005; 102: 9194-9, CrossRef.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414: 105-11, CrossRef.

Campisi J. Cancer and aging: rival demons? Nature Rev Cancer. 2003; 3: 339-49, CrossRef.

Pearce DJ, Anjos-Afonso F, Ridler CM, Eddaoudi A, Bonnet D. Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding the mechanisms of aging. Stem Cells. 2007; 25: 828-35, CrossRef.

Xing Z, Ryan MA, Daria D. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006; 108: 2190-7, CrossRef.

Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nature Med. 1996; 2: 1011-6, CrossRef.

Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000; 192: 1273-80, CrossRef.

Liang Y, Van Zan, G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood. 2005; 106: 1479-87, CrossRef.

Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower L, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. Plos Biol. 2007; 5: 1750-62, CrossRef.

Navarro S, Meza NW, Quintana-Bustamante O, Casado JA, Jacome A, McAllister K, et al. Hematopoietic dysfunction in amouse model for Fanconi anemia group D1. Mol Ther. 2006; 14: 525-35, CrossRef.

Reese JS, Liu L, Gerson SL. Repopulating defect of mismatch repair-deficient hematopoietic stem cells. Blood. 2003; 102: 1626-33, CrossRef.

Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JHJ, Touw IP, et al. Reduced hematopoietic reserves in DNA interstrand crosslink repair-defi cient Ercc1–/– mice. EMBO J. 2005; 24: 861-71, CrossRef.

Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, et al. DNA repair is limiting for haematopoietic stem cells during aging. Nature. 2007; 447: 686-90, CrossRef.

Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 2007; 39: 99-105, CrossRef.

Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, et al. p53 mutant mice that display early aging-associated phenotypes. Nature. 2002; 415: 45-53, CrossRef.

Maier B, Gluba W, Bernier B. Modulation of mammalian life span by the short isoform of p53. Genes Dev 2004; 18: 306-19, CrossRef.

Orsted DD, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population. J Exp Med. 2007; 204: 1295-301, CrossRef.

Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000; 287: 1804-8, CrossRef.

Morgan JE, Partridge TA. Muscle satellite cells. Int J Biochem Cell Biol. 2003; 35: 1151-6, CrossRef.

Sigal SH, Brill S, Fiorino AS, Reid LM. The liver as a stem cell and lineage system. Am J Physiol. 1992; 263: G139-48, PMID.

Oh SH, Hatch HM, Petersen BE. Hepatic oval ‘stem’ cell in liver regeneration. Semin Cell Dev Biol 2002; 13: 405-9, CrossRef.

Gage FH. Stem cells of the central nervous system. Curr Opin Neurobiol. 1998; 8: 671-6, PMID.

Leri A, Kajstura J, Anversa P. Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev. 2005; 85: 1373-416, CrossRef.


Indexed by:






The Prodia Education and Research Institute