Abstract
Stem cells are responsible for tissue repair and maintenance and it is assumed that changes observed in the stem cell compartment with age underlie the concomitant decline in tissue function. Studies in murine models have highlighted the importance of intrinsic changes occurring in stem cells with age. They have also drawn the attention to other factors, such as changes in the local or systemic environment as the primary cause of stem cell dysfunction. Whilst knowledge in murine models has been advancing rapidly there has been little translation of these data to human aging. This is most likely due to the difficulties of testing the regenerative capacity of human stem cells in vivo and to substantial differences in the aging phenotype within humans. Here we summarize evidence to show how progeroid syndromes, integrated with other models, can be valuable tools in addressing questions about the role of stem cell aging in human degenerative diseases of older age and the molecular pathways involved.
Similar content being viewed by others
References
Ademokun A, Wu YC et al (2010) The ageing B cell population: composition and function. Biogerontology 11(2):125–137
Allsopp RC, Morin GB et al (2003) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102(2):517–520
Angelopoulou N, Matziari C et al (2000) Bone mineral density and muscle strength in young men with mental retardation (with and without Down syndrome). Calcif Tissue Int 66(3):176
Bahn S, Mimmack M et al (2002) Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down’s syndrome: a gene expression study. Lancet 359(9303):310–315
Barlow C, Hirotsune S et al (1996) Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86(1):159–171
Baxter MA, Wynn RF et al (2004) Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22(5):675–682
Beerman I, Bhattacharya D et al (2010) Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107(12):5465–5470
Bellantuono I, Keith WN (2007) Stem cell ageing: does it occur and can we intervene? Expert Rev Mol Med 9(31):1–20
Blackburn EH (2005) Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett 579(4):859–862
Blasco MA (2007) Telomere length, stem cells and aging. Nat Chem Biol 3(10):640–649
Bug G, Gul H et al (2005) Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells. Cancer Res 65(7):2537–2541
Cairney CJ, Sanguinetti G et al (2009) A systems biology approach to Down syndrome: identification of Notch/Wnt dysregulation in a model of stem cells aging. Biochim Biophys Acta 1792:353–363
Carmichael CL, Majewski IJ et al (2009) Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. Blood 113(9):1929–1937
Chakraborty S, Sun CL et al (2009) Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma. J Clin Oncol 27(5):791–798
Chen S, Do JT et al (2006) Self-renewal of embryonic stem cells by a small molecule. Proc Natl Acad Sci U S A 103(46):17266–17271
Cho RH, Sieburg HB et al (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(12):5553–5561
Choudhury AR, Ju Z et al (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39(1):99–105
Creutzig U, Ritter J et al (1996) Myelodysplasia and acute myelogenous leukemia in Down’s syndrome. A report of 40 children of the AML-BFM study group. Leukemia 10(11):1677–1686
De Felice L, Tatarelli C et al (2005) Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells. Cancer Res 65(4):1505–1513
de Lange T (2002) Protection of mammalian telomeres. Oncogene 21(4):532–540
Drachtman RA, Alter BP (1995) Dyskeratosis congenita. Dermatol Clin 13(1):33–39
Enwere E, Shingo T et al (2004) Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24(38):8354–8365
Epstein CJ, Hofmeister BG et al (1985) Stem cell deficiencies and thymic abnormalities in fetal mouse trisomy 16. J Exp Med 162(2):695–712
Ertl RP, Chen J et al (2008) Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated. Blood 111(3):1709–1716
Espada J, Varela I et al (2008) Nuclear envelope defects cause stem cell dysfunction in premature-aging mice. J Cell Biol 181(1):27–35
Ferron S, Mira H et al (2004) Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131(16):4059–4070
Flores I, Blasco MA (2010) The role of telomeres and telomerase in stem cell aging. FEBS Lett 584(17):3826–3830
Flores I, Cayuela ML et al (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309(5738):1253–1256
Flores I, Canela A et al (2008) The longest telomeres: a general signature of adult stem cell compartments. Genes Dev 22(5):654–667
Frasca D, Blomberg BB (2009) Effects of aging on B cell function. Curr Opin Immunol 21(4):425–430
Gambardella A, Nagaraju CK et al (2011) Glycogen synthase kinase-3alpha/beta inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage. J Bone Miner Res 26(4):811–821
Grolleau-Julius A, Ray D et al (2010) The role of epigenetics in aging and autoimmunity. Clin Rev Allergy Immunol 39(1):42–50
Harley CB, Futcher AB et al (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345(6274):458–460
Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
Haynes L, Maue AC (2009) Effects of aging on T cell function. Curr Opin Immunol 21(4):414–417
Herndon LA, Schmeissner PJ et al (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419(6909):808–814
Herrera E, Samper E et al (1999) Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J 18(11):2950–2960
Hilton MJ, Tu X et al (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14(3):306–314
Hofer AC, Tran RT et al (2005) Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging. J Gerontol A Biol Sci Med Sci 60(1):10–20
Holmes DK, Bates N et al (2006) Hematopoietic progenitor cell deficiency in fetuses and children affected by Down’s syndrome. Exp Hematol 34(12):1611–1615
Ikuta K, Kina T et al (1990) A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62(5):863–874
Jaskelioff M, Muller FL et al (2010) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469:102–106
Jawaheer D, Seldin MF et al (2003) Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum 48(4):906–916
Jiang H, Schiffer E et al (2008) Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc Natl Acad Sci U S A 105(32):11299–11304
Ju Z, Jiang H et al (2007) Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13(6):742–747
Kantor AB, Herzenberg LA (1993) Origin of murine B cell lineages. Annu Rev Immunol 11:501–538
Karlson EW, Chibnik LB et al (2009) Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis Rheum 60(3):641–652
Kerbauy DM, Lesnikov V et al (2004) Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-beta2-microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells. Blood 104(7):2202–2203
Kirkwood TB (2005) Understanding the odd science of aging. Cell 120(4):437–447
Kirkwood TB, Finch CE (2002) Ageing: the old worm turns more slowly. Nature 419(6909):794–795
Kirsammer G, Jilani S et al (2008) Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood 111(2):767–775
Kollman C, Howe CW et al (2001) Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98(7):2043–2051
Lafreniere D, Mann N (2009) Anosmia: loss of smell in the elderly. Otolaryngol Clin North Am 42(1):123–131 x
Lee HW, Blasco MA et al (1998) Essential role of mouse telomerase in highly proliferative organs. Nature 392(6676):569–574
Martin GM (2005) Genetic modulation of senescent phenotypes in Homo sapiens. Cell 120(4):523–532
Masi AT (1994) Incidence of rheumatoid arthritis: do the observed age-sex interaction patterns support a role of androgenic-anabolic steroid deficiency in its pathogenesis? Br J Rheumatol 33(8):697–699
Miller JP, Allman D (2003) The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 171(5):2326–2330
Min H, Montecino-Rodriguez E et al (2006) Effects of aging on the common lymphoid progenitor to pro-B cell transition. J Immunol 176(2):1007–1012
Molofsky AV, Slutsky SG et al (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443(7110):448–452
Morrison SJ, Prowse KR et al (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5(3):207–216
Naveiras O, Nardi V et al (2009) Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460(7252):259–263
Nespoli L, Burgio GR et al (1993) Immunological features of Down’s syndrome: a review. J Intellect Disabil Res 37(Pt 6):543–551
Nimer SD (2008) Myelodysplastic syndromes. Blood 111(10):4841–4851
Nishimura EK, Granter SR et al (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307(5710):720–724
Omidvar N, Kogan S et al (2007) BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia. Cancer Res 67(24):11657–11667
Ozgenc A, Loeb LA (2005) Current advances in unraveling the function of the Werner syndrome protein. Mutat Res 577(1–2):237–251
Pignolo RJ, Suda RK et al (2008) Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Aging Cell 7(1):23–31
Raaijmakers MH, Mukherjee S et al (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464(7290):852–857
Rauner M, Sipos W et al (2009) Inhibition of Lamin A/C attenuates osteoblast differentiation and enhances RANKL-dependent osteoclastogenesis. J Bone Miner Res 24(1):78–86
Rigolin GM, Porta MD et al (2004) Flow cytometric detection of accelerated telomere shortening in myelodysplastic syndromes: correlations with aetiological and clinical–biological findings. Eur J Haematol 73(5):351–358
Rossi DJ, Bryder D et al (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102(26):9194–9199
Rossi DJ, Jamieson CH et al (2008) Stems cells and the pathways to aging and cancer. Cell 132(4):681–696
Rudolph KL, Chang S et al (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96(5):701–712
Rumble B, Retallack R et al (1989) Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 320(22):1446–1452
Ruzankina Y, Pinzon-Guzman C 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(1):113–126
Sahin E, Depinho RA (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464(7288):520–528
Samper E, Flores JM et al (2001) Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep 2(9):800–807
Samper E, Fernandez P et al (2002) Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood 99(8):2767–2775
Sanguinetti G, Noirel J et al (2008) MMG: a probabilistic tool to identify submodules of metabolic pathways. Bioinformatics 24(8):1078–1084
Sato N, Meijer L et al (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10(1):55–63
Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312(5776):1059–1063
Scaffidi P, Misteli T (2008) Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat Cell Biol 10(4):452–459
Schonland SO, Lopez C et al (2003) Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci U S A 100(23):13471–13476
Sharpless NE, DePinho RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8(9):703–713
Sieburg HB, Cho RH et al (2006) The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood 107(6):2311–2316
Siegl-Cachedenier I, Flores I et al (2007) Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. J Cell Biol 179(2):277–290
Song Z, Wang J et al (2010) Alterations of the systemic environment are the primary cause of impaired B and T lymphopoiesis in telomere-dysfunctional mice. Blood 115(8):1481–1489
Strehler BL, Mildvan AS (1960) General theory of mortality and aging. Science 132:14–21
Testa NG, Hendry JH et al (1985) Long-term bone marrow damage in experimental systems and in patients after radiation or chemotherapy. Anticancer Res 5(1):101–110
Tomas-Loba A, Flores I et al (2008) Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135(4):609–622
Trowbridge JJ, Xenocostas A et al (2006) Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 12(1):89–98
Vaziri H, Dragowska W et al (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A 91(21):9857–9860
Vulliamy TJ, Dokal I (2008) Dyskeratosis congenita: the diverse clinical presentation of mutations in the telomerase complex. Biochimie 90(1):122–130
Wang Y, Schulte BA et al (2006) Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 107(1):358–366
Waterstrat A, Oakley E, Miller A, Swierski C, Liang Y, Van Zant G (2008) Mechanisms of stem cell aging. In: Rudolph KL (ed) Telomeres and telomerase in ageing, disease, and cancer, Springer, pp 111–140
Wong KK, Maser RS et al (2003) Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421(6923):643–648
Xu Y, Ashley T et al (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10(19):2411–2422
Zhao C, Deng W et al (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4):645–660
Acknowledgments
Research in the authors labs is supported by Cancer Research UK, European Community grants LSHC-CT-2004-502943, Health-F2-2007-200950, Glasgow University and Strategic Promotion of Ageing Research Capacity.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bellantuono, I., Sanguinetti, G. & Keith, W.N. Progeroid syndromes: models for stem cell aging?. Biogerontology 13, 63–75 (2012). https://doi.org/10.1007/s10522-011-9347-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-011-9347-2