Telomere length predicts replicative capacity of human fibroblasts.
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Journal: 1992/December - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
PUBMED: 1438199
Abstract:
When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.
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Proc Natl Acad Sci U S A 89(21): 10114-10118
PMID: 1438199

Telomere length predicts replicative capacity of human fibroblasts.

Abstract

When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.

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Selected References

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  • HAYFLICK L, MOORHEAD PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961 Dec;25:585–621. [PubMed] [Google Scholar]
  • Martin GM, Sprague CA, Epstein CJ. Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype. Lab Invest. 1970 Jul;23(1):86–92. [PubMed] [Google Scholar]
  • Goldstein S, Moerman EJ, Soeldner JS, Gleason RE, Barnett DM. Chronologic and physiologic age affect replicative life-span of fibroblasts from diabetic, prediabetic, and normal donors. Science. 1978 Feb 17;199(4330):781–782. [PubMed] [Google Scholar]
  • Soldstein S. Aging in vitro. Growth of cultured cells from the Galapagos tortoise. Exp Cell Res. 1974 Feb;83(2):297–302. [PubMed] [Google Scholar]
  • Röhme D. Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5009–5013.[PMC free article] [PubMed] [Google Scholar]
  • Walton J. The role of limited cell replicative capacity in pathological age change. A review. Mech Ageing Dev. 1982 Jul;19(3):217–244. [PubMed] [Google Scholar]
  • Stanulis-Praeger BM. Cellular senescence revisited: a review. Mech Ageing Dev. 1987 Mar;38(1):1–48. [PubMed] [Google Scholar]
  • Goldstein S. Replicative senescence: the human fibroblast comes of age. Science. 1990 Sep 7;249(4973):1129–1133. [PubMed] [Google Scholar]
  • Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973 Sep 14;41(1):181–190. [PubMed] [Google Scholar]
  • Watson JD. Origin of concatemeric T7 DNA. Nat New Biol. 1972 Oct 18;239(94):197–201. [PubMed] [Google Scholar]
  • Blackburn EH. Structure and function of telomeres. Nature. 1991 Apr 18;350(6319):569–573. [PubMed] [Google Scholar]
  • Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991 Mar-Nov;256(2-6):271–282. [PubMed] [Google Scholar]
  • McClintock B. The Stability of Broken Ends of Chromosomes in Zea Mays. Genetics. 1941 Mar;26(2):234–282.[PMC free article] [PubMed] [Google Scholar]
  • Orr-Weaver TL, Szostak JW, Rothstein RJ. Yeast transformation: a model system for the study of recombination. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6354–6358.[PMC free article] [PubMed] [Google Scholar]
  • Haber JE, Thorburn PC. Healing of broken linear dicentric chromosomes in yeast. Genetics. 1984 Feb;106(2):207–226.[PMC free article] [PubMed] [Google Scholar]
  • Agard DA, Sedat JW. Three-dimensional architecture of a polytene nucleus. Nature. 1983 Apr 21;302(5910):676–681. [PubMed] [Google Scholar]
  • Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6622–6626.[PMC free article] [PubMed] [Google Scholar]
  • Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985 Dec;43(2 Pt 1):405–413. [PubMed] [Google Scholar]
  • Greider CW. Telomeres, telomerase and senescence. Bioessays. 1990 Aug;12(8):363–369. [PubMed] [Google Scholar]
  • Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990 May 31;345(6274):458–460. [PubMed] [Google Scholar]
  • Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ. In vivo loss of telomeric repeats with age in humans. Mutat Res. 1991 Jan;256(1):45–48. [PubMed] [Google Scholar]
  • Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC. Telomere reduction in human colorectal carcinoma and with ageing. Nature. 1990 Aug 30;346(6287):866–868. [PubMed] [Google Scholar]
  • Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol. 1992 Jun 20;225(4):951–960. [PubMed] [Google Scholar]
  • Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 1992 May;11(5):1921–1929.[PMC free article] [PubMed] [Google Scholar]
  • SAKSELA E, MOORHEAD PS. ANEUPLOIDY IN THE DEGENERATIVE PHASE OF SERIAL CULTIVATION OF HUMAN CELL STRAINS. Proc Natl Acad Sci U S A. 1963 Aug;50:390–395.[PMC free article] [PubMed] [Google Scholar]
  • Benn PA. Specific chromosome aberrations in senescent fibroblast cell lines derived from human embryos. Am J Hum Genet. 1976 Sep;28(5):465–473.[PMC free article] [PubMed] [Google Scholar]
  • Sherwood SW, Rush D, Ellsworth JL, Schimke RT. Defining cellular senescence in IMR-90 cells: a flow cytometric analysis. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9086–9090.[PMC free article] [PubMed] [Google Scholar]
  • Morin GB. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989 Nov 3;59(3):521–529. [PubMed] [Google Scholar]
  • Cooke HJ, Smith BA. Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):213–219. [PubMed] [Google Scholar]
  • Allshire RC, Dempster M, Hastie ND. Human telomeres contain at least three types of G-rich repeat distributed non-randomly. Nucleic Acids Res. 1989 Jun 26;17(12):4611–4627.[PMC free article] [PubMed] [Google Scholar]
  • de Lange T. Human telomeres are attached to the nuclear matrix. EMBO J. 1992 Feb;11(2):717–724.[PMC free article] [PubMed] [Google Scholar]
  • Mills RG, Weiss AS. Does progeria provide the best model of accelerated ageing in humans? Gerontology. 1990;36(2):84–98. [PubMed] [Google Scholar]
  • Mather MW. Base composition-independent hybridization in dried agarose gels: screening and recovery for cloning of genomic DNA fragments. Biotechniques. 1988 May;6(5):444–447. [PubMed] [Google Scholar]
  • Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. Nature. 1990 Sep 27;347(6291):400–402. [PubMed] [Google Scholar]
  • Starling JA, Maule J, Hastie ND, Allshire RC. Extensive telomere repeat arrays in mouse are hypervariable. Nucleic Acids Res. 1990 Dec 11;18(23):6881–6888.[PMC free article] [PubMed] [Google Scholar]
  • Lundblad V, Szostak JW. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989 May 19;57(4):633–643. [PubMed] [Google Scholar]
  • Levis RW. Viable deletions of a telomere from a Drosophila chromosome. Cell. 1989 Aug 25;58(4):791–801. [PubMed] [Google Scholar]
  • Biessmann H, Mason JM. Progressive loss of DNA sequences from terminal chromosome deficiencies in Drosophila melanogaster. EMBO J. 1988 Apr;7(4):1081–1086.[PMC free article] [PubMed] [Google Scholar]
  • Biessmann H, Carter SB, Mason JM. Chromosome ends in Drosophila without telomeric DNA sequences. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1758–1761.[PMC free article] [PubMed] [Google Scholar]
  • Wright WE, Pereira-Smith OM, Shay JW. Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts. Mol Cell Biol. 1989 Jul;9(7):3088–3092.[PMC free article] [PubMed] [Google Scholar]
  • Pereira-Smith OM, Smith JR. Evidence for the recessive nature of cellular immortality. Science. 1983 Sep 2;221(4614):964–966. [PubMed] [Google Scholar]
  • Pereira-Smith OM, Smith JR. Genetic analysis of indefinite division in human cells: identification of four complementation groups. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6042–6046.[PMC free article] [PubMed] [Google Scholar]
Department of Biochemistry, McMaster University, Hamilton, ON, Canada.
Department of Biochemistry, McMaster University, Hamilton, ON, Canada.
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Abstract
When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.
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