Somatic Cell Genetics in the Analysis of in Vitro Senescence

  • Thomas H. Norwood


The limited replicative life span, or “senescence,” of cultured human diploid somatic cells is now well established (Hayflick and Moorhead, 1961). During the past decade, extensive investigations have resulted in detailed characterization of these cells; the mechanism or mechanisms that regulate their limited proliferative capabilities, however, remain unknown. Moreover, the relevance of such in vitro senescence to the aging of proliferating cell populations in vivo is controversial. Indeed, the relative contributions of proliferating cell populations and postmitotic cells to the aging process are also unknown. There is no information that clearly favors one or the other of the various hypotheses concerning the mechanism of senescence in the intact organism. Thus, while we are in this state of relative ignorance, it is important to analyze all potentially relevant model systems with a variety of experimental approaches.


Senescent Cell Sister Chromatid Exchange T98G Cell Xeroderma Pigmentosum Hybrid Clone 


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  1. Absher, P. M., Absher, R. G., and Barnes, W. D., 1974, Genealogies of clones of diploid fibroblasts, Exp. Cell Res. 88:95–104.PubMedGoogle Scholar
  2. Albertini, R. J., and DeMars, R., 1973, Somatic-cell mutation, detection and quantification of X-ray-induced mutation in cultured, diploid human fibroblasts, Mutat. Res. 18:199–224.PubMedGoogle Scholar
  3. Allen, J. W., and Latt, S. A., 1976, Analysis of sister chromatid exchange formation in vivo in mouse spermatogonia as a new test system for environmental mutagens, Nature (London) 260:449–451.Google Scholar
  4. Azzarone, B., Pedulla, D., and Romanzi, C. A., 1976, Spontaneous transformation of human skin fibroblasts derived from neoplastic patients, Nature (London) 202:74–75.Google Scholar
  5. Baker, R. M., Brunette, D., Mankovitz, R., Thompson, L. R., Whitmore, G. F., Siminovitch, L., and Till, J. E., 1974, Ouabain-resistant mutants of mouse and hamster cells in culture, Cell 1:9–21.Google Scholar
  6. Baserga, R., and Nemeroff, K., 1962, Two-emulsion radioautography, J. Histochem. Cyto-chem. 10:628–635.Google Scholar
  7. Beaudet, A. L., Roufa, D. J., and Caskey, C. T., 1973, Mutations affecting the structure of hydoxanthine: guanine phosphoribosyltransferase in cultured Chinese hamster cells, Proc. Natl. Acad. Sci. U.S.A. 70:320–324.PubMedGoogle Scholar
  8. Bjorksten, J., 1974, Theoretical aspects of aging, in: Symposium on the Theoretical Aspects of Aging (M. Rockstein, ed.), pp. 43–59, Academic Press, New York.Google Scholar
  9. Boone, C. W., 1975, Malignant hemangioendotheliomas produced by subcutaneous inoculation of BALB/3T3 cells attached to glass beads, Science 188:68–70.PubMedGoogle Scholar
  10. Boone, C. W., Takeichi, N., Paranjpe, M., and Gilden, R., 1976, Vasoformative sarcomas arising from BALB/3T3 cells attached to solid substrates, Cancer Res. 36:1625–1633.Google Scholar
  11. Bosmann, H. B., Gutheil, R. L., and Case, K. R., 1976, Loss of a critical neutral protease in ageing WI-38 cells, Nature (London) 261:499–501.Google Scholar
  12. Bowman, P. D., and Daniel, C. W., 1975, Characteristics of proliferative cells from young, old, and transformed WI-38 cultures, in: Cell Impairment in Aging and Development (V. J. Cristofalo and E. Holečkovâ, eds.), pp. 107–122, Plenum Press, New York.Google Scholar
  13. Bradley, M. O., Hayflick, L., and Schimke, R. T., 1976, Protein degradation in human fibroblasts (WI-38), J. Biol. Chem. 251:3521–3529.PubMedGoogle Scholar
  14. Brinster, R. L., 1974, The effect of cells transferred into the mouse plastocyst on subsequent development, J. Exp. Med. 140:1049–1056.PubMedGoogle Scholar
  15. Brock, M. A., and Hay, R. J., 1971, Comparative ultrastructure of chick fibroblasts in vitro at early and late stages during their growth span, J. Ultrastruct. Res. 36:291–311.PubMedGoogle Scholar
  16. Bunn, C. L., Wallace, D. C., and Eisenstadt, J. M., 1974, Cytoplasmic inheritance of chloramphenicol resistance in mouse tissue culture, Proc. Natl. Acad. Sci. U.S.A. 71:1681–1685.PubMedGoogle Scholar
  17. Burnet, F. M., 1974a, Intrinsic mutagenesis: A genetic basis of ageing, Pathology 6: 1.PubMedGoogle Scholar
  18. Burnet, F. M., 1974b, Intrinsic Mutagenesis: A Genetic Approach to Aging, John Wiley & Sons, New York.Google Scholar
  19. Burstin, S. J., Meiss, H. K., and Basilico, C., 1974, A temperature-sensitive cell cycle mtuant of the BHK cell line, J. Cell. Physiol. 84:397–408.PubMedGoogle Scholar
  20. Cameron, I. L., 1972, Cell proliferation and renewal in aging mice, J. Gerontol. 27:162–172.PubMedGoogle Scholar
  21. Capecchi, M. R., Capecchi, N. E., Hughes, S. H., and Wahl, G. M., 1974, Selective degradation of abnormal proteins in mammalian tissue culture cells, Proc. Natl. Acad. Sci. U.S.A. 71:4732–4736.PubMedGoogle Scholar
  22. Carrel, A., 1912, On the permanent life of tissues outside of the organism, J. Exp. Med. 15:516–528.PubMedGoogle Scholar
  23. Carter, S. B., 1967, Effects of cytochalasins on mammalian cells, Nature (London) 213:261–264.Google Scholar
  24. Chasin, L. A., and Urlaub, G., 1975, Chromosome-wide event accompanies the expression of recessive mutations in tetraploid cells, Science 187:1091–1092.PubMedGoogle Scholar
  25. Chen, T. R., and Ruddle, F. H., 1974, Chromosome changes revealed by the Q-band staining method during cell senescence, Proc. Soc. Exp. Biol. Med. 147:533–536.PubMedGoogle Scholar
  26. Chu, E. H. Y., and Giles, N. H., 1959, Human chromosome complements in normal somatic cells in culture, Am. J. Hum. Genet. 11:63–79.PubMedGoogle Scholar
  27. Clarkson, J. M., and Painter, R. B., 1974, Repair of X-ray damage in aging WI-38 cells, Mutat. Res. 23:107–112.PubMedGoogle Scholar
  28. Cleaver, J. E., and Bootsma, D., 1975, Xeroderma pigmentosum: Biochemical and genetic characteristics, Annu. Rev. Genet. 9:19–38.PubMedGoogle Scholar
  29. Cox, R., and Masson, W. K., 1974, X-ray dose response for mutation to fructose utilization in cultured diploid human fibroblasts, Nature (London) 252:308–310.Google Scholar
  30. Cristofalo, V. J., 1970, Metabolic aspects of aging in diploid human cells, in: Aging in Cell and Tissue Culture (E. Holečkovâ and V. J. Cristofalo, eds.), pp. 83–119, Plenum Press, New York.Google Scholar
  31. Cristofalo, V. J., 1972, Animal cell cultures as a model system for the study of aging, Adv. Gerontol. 4:45–79.Google Scholar
  32. Cristofalo, V. J., and Kritchevsky, D., 1969, Cell size and nucleic acid content in the diploid human cell line WI-38 during aging, Med. Exp. (Basel) 19:313–320.Google Scholar
  33. Cristofalo, V. J., and Sharf, B. B., 1973, Cellular senescence and DNA synthesis, Exp. Cell Res. 76:419–427.PubMedGoogle Scholar
  34. Croce, C. M., and Koprowski, H., 1973, Enucleation of cells made simple and rescue of SV40 by enucleated cells made even simpler, Virology 51:227–229.PubMedGoogle Scholar
  35. Croce, C. M., and Koprowski, H., 1974, Positive control of transformed phenotype in hybrids between SV-40-transformed and normal human cells, Science 184:1288–1289.PubMedGoogle Scholar
  36. Danes, B. S., 1971, Progeria: A cell culture study on aging, J. Clin. Invest. 50:2000–2003.PubMedGoogle Scholar
  37. Daniel, C. W., deOme, K. B., Young, J. R., Blair, P. B., and Faulkin, L. J., 1968, The in vivo lifespan of normal and preneoplastic mouse mammary glands: A serial transplantation study, Proc. Natl. Acad. Sci. U.S.A. 61:53–59.PubMedGoogle Scholar
  38. Davidson, R., and Ephrussi, B., 1970, Factors influencing the “effective mating rate” of mammalian cells, Exp. Cell Res. 61:222–226.PubMedGoogle Scholar
  39. Davidson, R. L., and Gerald, P. S., 1976, Improved techniques for the induction of mammalian cell hybridization by polyethylene glycol, Somat. Cell Genet. 2:165–176.PubMedGoogle Scholar
  40. Davidson, R. L., O’Malley, K. A., and Wheeler, T. B., 1976, Polyethylene glycol-induced mammalian cell hybridization: Effect of polyethylene glycol molecular weight and concentration, Somat. Cell Genet. 2:271–280.PubMedGoogle Scholar
  41. Davis, F. M., and Adelberg, E. A., 1973, Use of somatic cell hybrids for analysis of the differentiated state, Bacteriol. Rev. 37:197–214.PubMedGoogle Scholar
  42. Deal, D. R., Gerber, P., and Chisari, F. V., 1971, Heterotransplantation of two human lymphoid cell lines transformed in vitro by Epstein-Barr virus, J. Natl. Cancer Inst. 47:771–780.PubMedGoogle Scholar
  43. Dunn, G. R., and Stevens, L. C., 1970, Determination of sex of teratomas derived from early mouse embryos, J. Natl. Cancer Inst. 44:99–105.PubMedGoogle Scholar
  44. Elmore, E., and Swift, M., 1975, Growth of cultured cells from patients with Fanconi anemia, J. Cell. Physiol. 87:229–234.PubMedGoogle Scholar
  45. Elmore, E., and Swift, M., 1976, Growth of cultured cells from patients with ataxia-telangiec-tasia, J. Cell. Physiol. 89:429–432.PubMedGoogle Scholar
  46. Epstein, C. J., Martin, G. M., Schultz, A. S., and Motulsky, A. G., 1966, Werner’s syndrome: A review of its symptomatology, natural history, pathology features, genetics, and relationships to the aging process, Medicine (Baltimore) 45:177–221.Google Scholar
  47. Epstein, C. J., Williams, J. R., and Little, J. B., 1974, Rate of DNA repair in progeric and normal human fibroblasts, Biochem. Biophys. Res. Commun. 59:850–857.PubMedGoogle Scholar
  48. Fox, B. W., and Prusoff, W. H., 1965, The comparative uptake of I125-labeled 5-iodo-2′-deoxyuridine and thymidine-H3 into tissues of mice bearing hepatoma-129, Cancer Res. 25:234–240.PubMedGoogle Scholar
  49. Fujiwara, Y., and Tatsumi, M., 1975, Repair of mitomycin C damage to DNA in mammalian cells and its impairment in Fanconi’s anemia cells, Biochem. Biophys. Res. Commun. 66:592–595.PubMedGoogle Scholar
  50. Gey, G. O., and Gey, M. K., 1938, The maintenance of human normal cells and tumor cells in continuous culture, Am. J. Cancer 27:45–76.Google Scholar
  51. Goldberg, A. L., 1972, Degradation of abnormal proteins in Escherichia coli, Proc. Natl. Acad. Sci. U.S.A. 69:422–426.Google Scholar
  52. Goldstein, S., 1969, Lifespan of cultured cells in progeria, Lancet 1:424.PubMedGoogle Scholar
  53. Goldstein, S., 1971, The role of DNA repair in aging of cultured fibroblasts from xeroderma pigmentosum and normals, Proc. Soc. Exp. Biol. Med. 137:730–734.Google Scholar
  54. Goldstein, S., 1974, Aging in vitro, growth of cultured cells from the Galapagos tortoise, Exp. Cell Res. 83:297–302.Google Scholar
  55. Goldstein, S., and Lin, C. C., 1972, Rescue of senescent human fibroblasts by hybridization with hamster cells in vitro, Exp. Cell Res. 70:436–439.PubMedGoogle Scholar
  56. Goldstein, S., and Moerman, E. J., 1976, Defective proteins in normal and abnormal human fibroblasts during aging in vitro, Interdiscip. Top. Gerontol. 10:28–43.Google Scholar
  57. Goldstein, S., Littlefield, J. W., and Soeldner, J. S., 1969, Diabetes mellitus and aging: Diminished plating efficiency of cultured human fibroblasts, Proc. Natl. Acad. Sci. U.S.A. 64:155–160.PubMedGoogle Scholar
  58. Goldstein, S., Niewiarowski, S., and Singal, D. P., 1975, Pathological implications of cell aging in vitro, Fed. Proc. Fed. Am. Soc. Exp. Biol. 34:56–63.Google Scholar
  59. Good, P. I., and Smith, J. R., 1974, Age distribution of human diploid fibroblasts, Biophys. J. 14:811–823.PubMedGoogle Scholar
  60. Grove, G. L., Kress, E. D., and Cristofalo, V. J., 1976, The cell cycle and thymidine incorporation during aging in vitro, J. Cell Biol. 70: 133a (abstract).Google Scholar
  61. Gurdon, J. P., and Woodland, H. R., 1970, On the long term control of nuclear activity during cell differentiation, Curr. Top. Dev. Biol. 5:39–70.PubMedGoogle Scholar
  62. Hahn, G. M., King, D., and Yang, S., 1971, Quantitative changes in unscheduled DNA synthesis in rat muscle cells after differentiation, Nature (London) 230:242–244.Google Scholar
  63. Hamilton, E., 1976, Aging and the proliferative capacity of mouse colon cells in vivo, J. Cell Biol. 70: 27a (abstract).Google Scholar
  64. Hand, R., and German, J., 1975, A retarded rate of DNA chain growth in Bloom’s syndrome, Proc. Natl. Acad. Sci. U.S.A. 72:758–762.PubMedGoogle Scholar
  65. Harman, D., 1956, Aging: A theory based on free-radical and radiation chemistry, J. Gerontol. 11:298–300.PubMedGoogle Scholar
  66. Harman, D., 1961, Prolongation of the normal lifespan and inhibition of spontaneous cancer by antioxidants, J. Gerontol. 16:247–254.PubMedGoogle Scholar
  67. Harnden, D. G., Benn, P. A., Oxford, J. M., Taylor, A. M. R., and Webb, T. P., 1976, Cytogenetically marked clones in human fibroblasts cultured from normal subjects Somat. Cell Genet. 2:55–62.PubMedGoogle Scholar
  68. Harris, H., 1967, The reactivation of the red cell nucleus, J. Cell Sci. 2:23–32.PubMedGoogle Scholar
  69. Harris, H., and Hopkinson, D. A., 1972, Average heterozygosity per locus in man: An estimate based on the incidence of enzyme polymorphisms, Ann. Hum. Genet. 36:9–38.PubMedGoogle Scholar
  70. Harris, H., and Watkins, J. F., 1965, Hybrid cells derived from mouse and man: Artificial heterokaryons of mammalian cells from different species, Nature (London) 205:640–646.Google Scholar
  71. Harris, H., Watkins, J. F., and Schoefl, G. L., 1966, Artificial heterokaryons of animal cells from different species, J. Cell Sci. 1:1–30.PubMedGoogle Scholar
  72. Harris, H., Sidebottom, E., Grace, D. M., and Bramwell, M. E., 1969, The expression of genetic information: A study with hybrid animal cells, J. Cell Sci. 4:499–525.PubMedGoogle Scholar
  73. Harris, M., 1971, Mutation rates in cells at different ploidy levels, J. Cell. Physiol. 78:177–184.PubMedGoogle Scholar
  74. Harris, M., 1974, Comparative frequency of dominant and recessive markers for drug resistance in Chinese hamster cells, J. Natl. Cancer Inst. 52:1811–1816.PubMedGoogle Scholar
  75. Harrison, D. E., 1973, Normal production of erythrocytes by mouse marrow continuous for 73 months, Proc. Natl. Acad. Sci. U.S.A. 70:3184–3188.PubMedGoogle Scholar
  76. Hart, R. W., and Setlow, R. B., 1974, Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species, Proc. Natl. Acad. Sci. U.S.A. 71:2169–2173.PubMedGoogle Scholar
  77. Hart, R. W., and Setlow, R. B., 1976, DNA repair in late-passage human cells, Mech. Ageing Dev. 5:67–77.PubMedGoogle Scholar
  78. Hatzfeld, J., and Buttlin, G., 1975, Temperature-sensitive cell cycle mutants: A Chinese hamster cell line with a reversible block in cytokinesis, Cell 5:123–129.PubMedGoogle Scholar
  79. Hay, R. J., and Strehler, B. L., 1967, The limited growth span of cell strains isolated from the chick embryo, Exp. Gerontol. 2:123–135.Google Scholar
  80. Hayflick, L., 1965, The limited in vitro lifetime of human diploid cell strains, Exp. Cell Res. 37:614–636.PubMedGoogle Scholar
  81. Hayflick, L., 1970, Aging under glass, Exp. Gerontol. 5:291.PubMedGoogle Scholar
  82. Hayflick, L., 1974, The longevity of cultured human cells, J. Am. Geriatr. Soc. 22:1–12.PubMedGoogle Scholar
  83. Hayflick, L., 1976, The cell biology of human aging, N. Engl. J. Med. 295:1302–1309.PubMedGoogle Scholar
  84. Hayflick, L., and Moorhead, P. S., 1961, The serial cultivation of human diploid cell strains, Exp. Cell Res. 25:585–621.Google Scholar
  85. Hendil, K. B., 1976, Degradation of abnormal proteins in HeLa cells, J. Cell. Physiol. 87:289–296.PubMedGoogle Scholar
  86. Hershko, A., Mamont, P., Shields, R., and Tomkins, G. M., 1971, Pleiotypic response, Nature (London) New Biol. 232:206–211.Google Scholar
  87. Hoehn, H., and Martin, G. M., 1972, Heritable alteration of human constitutive heterochromatin induced by mitomycin C, Exp. Cell Res. 75:275–278.PubMedGoogle Scholar
  88. Hoehn, H., Bryant, E. M., Au, K., Norwood, T. H., Boman, H., and Martin, G. M., 1975a, Variegated translocation mosaicism in human skin fibroblast cultures, Cytogenet. Cell Genet. 15: 282–298.PubMedGoogle Scholar
  89. Hoehn, H., Bryant, E. M., Johnston, P., Norwood, T. H., and Martin, G. M., 1975b, Nonselective isolation, stability and longevity of hybrids between normal human somatic cells, Nature (London) 258:608–610.Google Scholar
  90. Hogan, B. L. M., 1976, Changes in the behavior of teratocarcinoma cells cultivated in vitro, Nature (London) 263:136–137.Google Scholar
  91. Holland, J. J., Kohne, D., and Doyle, M. V., 1973, Analysis of virus replication in ageing human fibroblast cultures, Nature (London) 245:316–319.Google Scholar
  92. Holliday, R., and Porterfield, J. S., 1974, Premature ageing and occurrence of altered enzyme in Werner’s syndrome fibroblasts, Nature (London) 248:762–763.Google Scholar
  93. Holliday, R., and Tarrant, G. M., 1972, Altered enzymes in ageing human fibroblasts, Nature (London) 238:26–30.Google Scholar
  94. Iyer, V. N., and Szybalski, W., 1963, A molecular mechanism of mitomycin action: Linking of complementary DNA strands, Proc. Natl. Acad. Sci. U.S.A. 50:355–362.PubMedGoogle Scholar
  95. Iyer, V. N., and Szybalski, W., 1964, Mitomycins and porfiromycin: Chemical mechanism of activation and cross-linking of DNA, Science 145:55–58.PubMedGoogle Scholar
  96. Kaback, M. M., and Bernstein, L. H., 1970, Biologic studies of trisomic cells growing in vitro, Ann. N. Y. Acad. Sci. 171:526–536.Google Scholar
  97. Kahan, B. W., and Ephrussi, B., 1970, Developmental potentialities of clonal in vitro cultures of mouse testicular teratoma, J. Natl. Canc. Inst. 44:1015–1029.Google Scholar
  98. Kato, H., 1974, Induction of sister chromatid exchanges by chemical mutagens and its possible relevance to DNA repair, Exp. Cell Res. 85:239–247.PubMedGoogle Scholar
  99. Kohn, R. R., 1975, Aging and cell division, Science 188:203–204.PubMedGoogle Scholar
  100. Krohn, P. L., 1966, Transplantation and aging, in: Topics in the Biology of Aging (P. L. Krohn, ed), p. 133, John Wiley & Sons, New York.Google Scholar
  101. Krooth, R. S., Darlington, G. A., and Velazques, I. A. A., 1968, The genetics of cultured mammalian cells, Annu. Rev. Genet. 2:141–164.Google Scholar
  102. Kuliev, A. M., Kukharenko, V. I., Grinberg, K. N., Terskikh, V. V., Tamarkina, A. D., Bogomazov, E. A., Redkin, P. S., and Vasileysky, S. S., 1974, Investigation of a cell strain with trisomy 14 from a spontaneously aborted fetus, Humangenetik 21:1–12.PubMedGoogle Scholar
  103. Latt, S. A., 1973, Microfluorometric detection of deoxyribonucleic acid replication in human metaphase chromosomes, Proc. Natl. Acad. Sci. 70:3395–3399.PubMedGoogle Scholar
  104. Latt, S. A., 1974, Sister chromatid exchanges, indices of human chromosome damage and repair: Detection by fluorescence and induction by mitomycin C, Proc. Natl. Acad. Sci. U.S.A. 71:3162–3166.PubMedGoogle Scholar
  105. Lefford, F., 1964, The effect of donor age on the emigration of cells from chick embryo expiants in vitro, Exp. Cell Res. 35:557–571.PubMedGoogle Scholar
  106. Lehman, J. M., Speers, W. C., Swartzendruber, D. E., and Pierce, G. B., 1974, Neoplastic differentiation: Characteristics of cell lines derived from a murine teratocarcinoma, J. Cell. Physiol. 84:13–28.PubMedGoogle Scholar
  107. Lesher, S., and Sacher, G. A., 1968, Effects of age on cell proliferation in mouse duodenal cysts, Exp. Gerontol. 3:211–217.PubMedGoogle Scholar
  108. Lewis, C. H., and Tarrant, G. M., 1972, Error theory and ageing in human diploid fibroblasts, Nature (London) 239:316–318.Google Scholar
  109. Lima, L., and Macieira-Coelho, A., 1972, Parameters of aging in chicken embryo fibroblasts cultivated in vitro, Exp. Cell Res. 70:279–284.PubMedGoogle Scholar
  110. Lipetz, J., and Cristofalo, V. J., 1972, Ultrastructural changes accompanying the aging of human diploid cells in culture, J. Ultrastruct. Res. 39:43–56.PubMedGoogle Scholar
  111. Liskay, M. R., 1974, A mammalian somatic “cell cycle” mutant defective in G1, J. Cell. Physiol. 84:49–56.PubMedGoogle Scholar
  112. Little, J. B., 1976, Relationship between DNA repair capacity and cellular aging, Gerontology 22:28–55.PubMedGoogle Scholar
  113. Littlefield, J. W., 1964, Selection of hybrids from matings of fibroblasts in vitro and their presumed recombinants, Science 145:709–710.PubMedGoogle Scholar
  114. Littlefield, J. W., 1973, Attempted hybridizations with senescent human fibroblasts, J. Cell. Physiol. 82:129–132.PubMedGoogle Scholar
  115. Littlefield, J. W., 1976, Variation, Senescence, and Neoplasia in Cultured Somatic Cells, Harvard University Press, Cambridge, Massachusetts.Google Scholar
  116. Littlefield, L. G., and Mailhes, J. B., 1975, Observations of de novo clones of cytogenetically aberrant cells in primary fibroblast cell strains from phenotypically normal women, Am. J. Hum. Genet. 27:190–197.PubMedGoogle Scholar
  117. Litwin, J., 1972, Human diploid cell response to variations in relative amino acid concentrations in Eagle medium, Exp. Cell Res. 72:566–568.PubMedGoogle Scholar
  118. Lukas, J. J., Szekely, E., and Kates, J. R., 1976, The regeneration and division of mouse L-cell karyoplasts, Cell 7:115–122.Google Scholar
  119. Lyons, L. B., Cox, R. P., and Dancis, J., 1973, Complementation analysis of maple syrup urine diseases in heterokaryons derived from cultured human fibroblasts, Nature (London) 243:533–535.Google Scholar
  120. Macieira-Coelho, A., 1974, Are non-dividing cells present in ageing cell cultures?, Nature (London) 248:421–422.Google Scholar
  121. Macieira-Coelho, A., Pontén, J., and Philipson, L., 1966, The division cycle and RNA synthesis in diploid human cells at different passages levels in vitro, Exp. Cell Res. 42:673–684.PubMedGoogle Scholar
  122. Mankovitz, R., Buchwald, M., and Baker, R. M., 1974, Isolation of ouabain-resistant human diploid fibroblasts, Cell 3:221–226.PubMedGoogle Scholar
  123. Martin, G. M., 1977, Cellular Aging—Part I. Clonal senescence, Part II. Postreplicative cells, Am. J. Pathol. 89:484–530.PubMedGoogle Scholar
  124. Martin, G. M., 1978a, Genetic syndromes in man with potential relevance to the pathobiology of aging, in: Genetic Effects on Aging, Birth Defects: Orig. Artic. Ser. (D. Bergsma and D. E. Harrison, eds.), The National Foundation-March of Dimes, New York (in press).Google Scholar
  125. Martin, G. M., 1978b, Summary discussion, in: Genetic Effects on Aging, Birth Defects: Orig. Artic. Ser. (D. Bergsma and D. E. Harrison, eds.), The National Foundation-March of Dimes, New York (in press).Google Scholar
  126. Martin, G. M., and Sprague, C. A., 1973, Symposium on in vitro studies related to atherogenesis: Life histories of hyperplastoid cell lines from aorta and skin, Exp. Mol. Pathol. 18:125–141.PubMedGoogle Scholar
  127. Martin, G. M., Sprague, C. A., and Epstein, C. J., 1970, Replicative life-span of cultivated human cells: Effects of donor’s age, tissue, and genotype, Lab. Invest. 23:86–92.PubMedGoogle Scholar
  128. Martin, G. M., Sprague, C. A., Norwood, T. H., and Pendergrass, W. R., 1974, Clonal selection, attenuation and differentiation in an in vitro model of hyperplasia, Am. J. Pathol. 74:137–154.PubMedGoogle Scholar
  129. Martin, G. M., Sprague, C. A., Norwood, T. H., Pendergrass, W. R., Bornstein, P., Hoehn, H., and Arend, W. P., 1975, Do hyperplastoid cell lines differentiate themselves to death?, Adv. Exp. Med. Biol. 53:67–90.PubMedGoogle Scholar
  130. Martin, G. M., Norwood, T. H., and Hoehn, H., 1977, Somatic cell genetic investigations of clonal senescence, in: The Molecular Biology of the Mammalian Genetic Apparatus (P. O. P. Ts’o, ed.), Chapt. 23, pp. 289–302, Elsevier-Exerpta Medica, Holland.Google Scholar
  131. Martin, G. M., Ogburn, C. E., and Sprague, C. A., 1978, Effects of age on cell division capacity, in: Le Vierllissement: Un Défi à la Science et a la Politique Sociale (M. Marois and D. Danor, eds.), Elsevier-Exerpta Medica, Holland.Google Scholar
  132. Mayne, R., Vail M. S., Mayne, P. M., and Miller, E. J., 1976, Changes in type of collagen synthesized as clones of chick chondrocytes grow and eventually lose division capability, Proc. Natl. Acad. Sci. U.S.A. 73:1674–1678.PubMedGoogle Scholar
  133. McBurney, M. W., 1976, Clonal lines of teratocarcinoma cells in vitro: Differentiation and cytogenetic characteristics, J. Cell. Physiol. 89:441–456.PubMedGoogle Scholar
  134. Merz, G. S., and Ross, J. D., 1969, Viability of human diploid cells as a function of in vitro age, J. Cell. Physiol. 74:219–222.PubMedGoogle Scholar
  135. Mezger-Freed, L., 1971, Puromycin resistance in haploid and heteroploid frog cells: Gene or membrane determined?, J. Cell Biol. 51:742–751.PubMedGoogle Scholar
  136. Mezger-Freed, L., 1972, Effect of ploidy and mutagens on bromodeoxyuridine resistance in haploid and diploid frogs, Nature (London) New Biol. 235:245–246.Google Scholar
  137. Migeon, B. R., Norum, R. A., and Corsaro, C. M., 1974, Isolation and analysis of somatic hybrids derived from two human diploid cells, Proc. Natl. Acad. Sci. U.S.A. 71:937–941.PubMedGoogle Scholar
  138. Mintz, B., and Illmensee, K., 1975, Normal genetically mosaic mice produced from malignant teratocarcinoma cells, Proc. Natl. Acad. Sci. U.S.A. 72:3585–3589.PubMedGoogle Scholar
  139. Mitsui, Y., and Schneider, E. L., 1976a, Relationship between cell replication and volume in senescent human diploid fibroblasts, Mech. Ageing Dev. 5: 45–56.PubMedGoogle Scholar
  140. Mitsui, Y., and Schneider, E. L., 1976b, Increased nuclear sizes in senescent human diploid fibroblast cultures, Exp. Cell Res. 100: 147–152.PubMedGoogle Scholar
  141. Muggleton-Harris, A., and Hayflick, L., 1976, Cellular aging studied by the reconstruction of replicating cells from nuclei and cytoplasms isolated from normal human diploid cells, Exp. Cell Res. 103:321–330.PubMedGoogle Scholar
  142. Nadler, H. L., Chacko, C. M., and Rachmeler, M., 1970, Interallelic complementation in hybrid cells derived from human diploid strains deficient in galactose-1-phosphate uridyl transferase activity, Proc. Natl. Acad. Sci. U.S.A. 67:976–982.PubMedGoogle Scholar
  143. Norwood, T. H., Pendergrass, W. R., Sprague, C. A., and Martin, G. M., 1974, Dominance of the senescent phenotype in heterokaryons between replicative and post-replicative human fibroblast-like cells, Proc. Natl. Acad. Sci. U.S.A. 71:223–236.Google Scholar
  144. Norwood, T. H., Pendergrass, W. R., and Martin, G. M., 1975, Reinitiation of DNA synthesis in senescent human fibroblasts upon fusion with cells of unlimited growth potential, J. Cell Biol. 64:551.PubMedGoogle Scholar
  145. Norwood, T. H., Zeigler, C. J., and Martin, G. M., 1976, Dimethyl sulfoxide enhances polyethylene glycol mediated somatic cell fusion, Somat. Cell Genet. 2:263–270.PubMedGoogle Scholar
  146. Norwood, T. H., Hoehn, H., Martinez, A. O., and Martin, G. M., 1978a, Synkaryon and heterokaryon analyses of clonal senescence, in: Cellular Senescence and Somatic Cell Genetics, Vol 2, Senescence: Dominant or Recessive in Somatic Cell Crosses (W. Nichols and D. Murphy, eds.), Plenum Press, New York (in press).Google Scholar
  147. Norwood, T. H., Pendergrass, W., Bornstein, P., and Martin, G. M., 19786, Behavior of chemically injured cells in heterokaryons and its relevance to clonal senescence (in prep.).Google Scholar
  148. Orgel, L. E., 1963, The maintenance of the accuracy of protein synthesis and its relevance to ageing, Proc. Natl. Acad. Sci. U.S.A. 49:517–521.PubMedGoogle Scholar
  149. Orgel, L. E., 1973, Ageing of clones of mammalian cells, Nature (London) 243:441–445.Google Scholar
  150. Painter, R. B., Clarkson, J. M., and Young, B. R., 1973, Ultraviolet-induced repair replication in aging diploid human cells WI-38, Radiat. Res. 56:560–564.PubMedGoogle Scholar
  151. Papaioannou, V. E., McBurney, M. W., Gardner, R. L., and Evans, M. J., 1975, Fate of teratocarcinoma cells injected into early mouse embryos, Nature (London) 258:70–73.Google Scholar
  152. Paterson, M. C., Smith, B. P., Lohman, P. H. M., Anderson, A. K., and Fishman, L., 1976, Defective excision repair of X-ray-damaged DNA in human (ataxia-telangiectasia) fibroblasts, Nature (London) 260:444–447.Google Scholar
  153. Pendergrass, W. R., Martin, G. M., and Bornstein, P., 1976, Evidence contrary to the protein error hypothesis for in vitro senescence, J. Cell. Physiol. 87:3.PubMedGoogle Scholar
  154. Perry, P. E., and Evans, H. J., 1975, Cytological detection of mutagen-carcinogen exposure by sister chromatid exchange, Nature (London) 258:121–125.Google Scholar
  155. Perry, P., and Wolff, S., 1974, New Giemsa method for the differential staining of sister chromatids, Nature (London) 251:156–158.Google Scholar
  156. Petes, T. D., Farber, R. A., Tarrant, G. M., and Holliday, R., 1974, Altered rate of DNA synthesis in aging fibroblast cultures, Nature (London) 251:434–436.Google Scholar
  157. Pitha, J., Stork, E., and Wimmer, E., 1975, Protein synthesis during aging of human cells in culture, Exp. Cell Res. 94:310–314.PubMedGoogle Scholar
  158. Pontecorvo, G., 1975, Production of mammalian somatic cell hybrids by means of polyethylene glycol treatment, Somat. Cell Genet. 1:397–400.PubMedGoogle Scholar
  159. Pontén, J., 1970, The growth capacity of normal and Rous-virus-transformed chicken fibroblasts in vitro, Int. J. Cancer 6:323–332.PubMedGoogle Scholar
  160. Poon, P. K., O’Brian, R. L., and Parlear, J. W., 1974, Defective DNA repair in Fanconi’s anemia, Nature (London) 250:223–225.Google Scholar
  161. Povey, S., Gardiner, S. E., Watson, B., Mowbray, S., and Harris, H., 1973, Genetic studies on human lymphoblastoid lines: Isozyme analysis on cell lines from forty-one different individuals and on mutants produced following exposure to a chemical mutagen, Ann. Hum. Genet. 36:247–266.PubMedGoogle Scholar
  162. Prescott, D. M., and Kirkpatrick, J. B., 1973, Mass enucleation of cultured animal cells, Methods Cell Biol. 7:189–202.PubMedGoogle Scholar
  163. Prickett, M. S., Coultrip, L., Patterson, M. K., and Morrow, J., 1975, Effect of ploidy on spontaneous mutation rate to asparagine non-requirement in cultured cells, J. Cell Physiol. 85:621–626.PubMedGoogle Scholar
  164. Prouty, W. F., and Goldberg, A. L., 1972, Effects of protease inhibitors on protein breakdown in Escherichia coli, J. Biol. Chem. 247:3341–3352.Google Scholar
  165. Puck, T. T., Cieciura, S. J., and Fisher, H. W., 1957, Clonal growth in vitro of human cells with fibroblastic morphology: Comparison of growth and genetic characteristics of single epithelioid and fibroblast-like cells from a variety of human organs, J. Exp. Med. 106:145–157.PubMedGoogle Scholar
  166. Puck, T. T., Cieciura, S. J., and Robinson, A., 1958, Genetics of somatic mammalian cells. III. Long-term cultivation of euploid cells from human and animal subjects, J. Exp. Med. 108:945–955.PubMedGoogle Scholar
  167. Rao, M. V. N., 1975, Reactivation of chicken erythrocyte nucleus in young and senescent WI-38 cells, J. Cell Biol. 67: 352a (abstract).Google Scholar
  168. Rao, P. N., and Johnson, R. T., 1970, Mammalian cell fusion: Studies on the regulation of DNA synthesis and mitosis, Nature (London) 255:159–164.Google Scholar
  169. Rao, P. N., and Johnson, R. T., 1972, Cell fusion and its application to studies on the regulation of the cell cycle, Methods Cell Physiol. 5:76–122.Google Scholar
  170. Regan, J. D., and Setlow, R. B., 1974, DNA repair in human progeroid cells, Biochem. Biophys. Res. Commun. 59:858–864.PubMedGoogle Scholar
  171. Robbins, E., Levine, E. M., and Eagle, H., 1970, Morphologic changes accompanying senescence of cultured human diploid cells, J. Exp. Med. 131:1211–1221.PubMedGoogle Scholar
  172. Rogers, N. G., Basnight, M., Gibbs, C. J., and Gajdusek, D. C., 1967, Latent viruses in chimpanzees with experimental Kuru, Nature (London) 216:446–449.Google Scholar
  173. Roscoe, D. H., Robinson, H., and Carbonelli, A. W., 1973, DNA synthesis and mitosis in a temperature sensitive Chinese hamster cell line, J. Cell. Physiol. 82:333–338.PubMedGoogle Scholar
  174. Rosenbloom, A. L., Goldstein, S., and Yip, C. C., 1976, Insulin binding to cultured human fibroblasts increases with normal and precocious aging, Science 193:412–414.PubMedGoogle Scholar
  175. Rothfels, K. H., Kupelwieser, E. B., and Parker, R. C., 1963, Effects of X-irradiated feeder layers on mitotic activity and development of aneuploidy in mouse-embryo cells in vitro, Can. Cancer Conf. 5:191–223.PubMedGoogle Scholar
  176. Ruddle, F. H., and Creagan, R. P., 1975, Parasexual approaches to the genetics of man, Annu. Rev. Genet. 9:407–486.PubMedGoogle Scholar
  177. Ryan, J. M., Duda, G., and Cristofalo, V. J., 1974, Error accumulation and aging in human diploid cells, J. Gerontol. 29:616–621.PubMedGoogle Scholar
  178. Saksela, E., and Moorhead, P. S., 1963, Aneuploidy in the degenerative phase of serial cultivation of human cell strains, Proc. Natl. Acad. Sci. U.S.A. 50:390–395.PubMedGoogle Scholar
  179. Sasaki, M. S., 1975, Is Fanconi’s anaemia defective in a process essential to the repair of DNA crosslinks?, Nature (London) 257:501–503.Google Scholar
  180. Scheffler, I. E., and Buttin, G., 1975, Conditional lethal mutations in Chinese hamster cells: Isolation of a temperature-sensitive line and its investigation by cell cycle studies, J. Cell. Physiol. 81:199–216.Google Scholar
  181. Schneider, E. L., and Epstein, C. J., 1972, Replication rate and lifespan of cultured fibroblasts in Down’s syndrome, Proc. Soc. Exp. Biol. Med. 141:1092–1094.PubMedGoogle Scholar
  182. Schneider, E. L., and Fowlkes, B. J., 1976, Measurement of DNA content and cell volume in senescent human fibroblasts utilizing flow multiparameter single cell analysis, Exp. Cell Res. 98:298–302.PubMedGoogle Scholar
  183. Schneider, E. L., and Mitsui, Y. 1976, The relationship between in vitro cellular aging and in vivo human age, Proc. Natl. Acad. Sci. U.S.A. 73:3584–3588.PubMedGoogle Scholar
  184. Schneider, E. L., Stanbridge, E. J., Epstein, C. J., Golbus, M., Abbo-Halbasch, G., and Rodgers, G., 1974, Mycoplasma contamination of cultured amniotic fluid cells: Potential hazard to prenatal chromosomal diagnosis, Science 184:477–480.PubMedGoogle Scholar
  185. Schwartz, A. G., 1975, Correlation between species lifespan and capacity to activate 7,12-dimethylbenz(a)anthracene to a form mutagenic to a mammalian cell, Exp. Cell Res. 94:445–447.PubMedGoogle Scholar
  186. Segal, D. J., and McCoy, E. E., 1974, Studies on Down’s syndrome in tissue culture. 1. Growth rates and protein contents of fibroblast cultures, J. Cell. Physiol. 83:85–90.PubMedGoogle Scholar
  187. Schaeffer, J. R., 1973, Structure and synthesis of the unstable hemoglobin sabine (α2β2 91LeuPro), J. Biol. Chem. 248:7473–7480.Google Scholar
  188. Sharp, J. D., Capecchi, N. E., and Capecchi, M. R., 1973, Altered enzymes in drug-resistant variants of mammalian tissue culture cells, Proc. Natl. Acad. Sci. U.S.A. 70:3145–3149.PubMedGoogle Scholar
  189. Sheinin, R., 1976, Preliminary characterization of temperature sensitive defect in DNA separation in the mouse L cell, Cell 7:49–57.PubMedGoogle Scholar
  190. Shimada, H., Shibuta, H., and Yoshikawa, M., 1976, Transformation of tissue-cultured xeroderma pigmentosum fibroblast by treatment with N-methyl-N-nitro-N-nitrosoguan-idine, Nature (London) 264:547–548.Google Scholar
  191. Shin, S., 1974, Nature of mutations conferring resistance to 8-azaguanine in mouse cell lines, J. Cell Sci. 14:235–251.PubMedGoogle Scholar
  192. Shiomi, T., and Sato, K., 1976, A temperature-sensitive mutant defective in mitosis and cytokinesis, Exp. Cell Res. 100:297–302.PubMedGoogle Scholar
  193. Siminovitch, L., 1976, On the nature of hereditable variation in cultured somatic cells, Cell 7:1–11.PubMedGoogle Scholar
  194. Simons, J. W. I. M., 1967, The use of frequency distribution of cell diameters to characterize cell populations in tissue culture, Exp. Cell Res. 45:336–350.PubMedGoogle Scholar
  195. Singal, D. P., and Goldstein, S., 1973, Absence of detectable HL-A antigens on cultured fibroblasts in progeria, J. Clin. Invest. 52:2259–2263.PubMedGoogle Scholar
  196. Siniscalco, M., Klinger, H. P., Eagle, H., Koprowski, H., Fujimoto, R. Y., and Seegmiller, J. E., 1969, Evidence for intergenic complementation in hybrid cells, derived from two human diploid strains, each carrying an X-linked mutation, Proc. Natl. Acad. Sci. U.S.A. 62:793–799.PubMedGoogle Scholar
  197. Smith, B. J., and Wigglesworth, N. M., 1973, A temperature-sensitive function in a Chinese hamster line affecting DNA synthesis, J. Cell. Physiol. 82:339–348.PubMedGoogle Scholar
  198. Smith, D. B., and Chu, E. H. Y., 1973, Isolation and characterization of temperature-sensitive mutants in a Chinese hamster cell line, Mutat. Res. 17:113–138.PubMedGoogle Scholar
  199. Smith, J. R., and Hayflick, L., 1974, Variation in the life-span of clones drived from human diploid cell strains, J. Cell Biol. 62:48–53.PubMedGoogle Scholar
  200. Smith, J. R., Pereira-Smith, O. M., and Good, P. I., 1977, Colony size distribution as a measure of age in cultured human cells, Mech. Ageing Dev. 6:283–286.PubMedGoogle Scholar
  201. Soukupovâ, M., Holečkovâ, E., and Hněvkovský, P., 1970, Changes of the latent period of explanted tissues during ontogenesis, in: Aging in Cell and Tissue Culture (E. Holečkovâ and V. J. Cristofalo, eds.), pp. 41–56, Plenum Press, New York.Google Scholar
  202. Spolsky, C. M., and Eisenstadt, J. M., 1972, Chloramphenicol-resistant mutants of human HeLa cells, FEBS Lett. 25:319–324.PubMedGoogle Scholar
  203. Sprague, C. A., Hoehn, H., and Martin, G. M., 1974, Ploidy of living clones of human somatic cells determined by mensuration at metaphase, J. Cell Biol. 60:781–784.PubMedGoogle Scholar
  204. Stanbridge, E. J., 1976, Suppression of malignancy in human cells, Nature (London) 260:17–20.Google Scholar
  205. Stanley, J. F., Pye, D., and MacGregor, A., 1975, Comparison of doubling numbers attained by cultured animal cells with life span of species, Nature (London) 255:158–159.Google Scholar
  206. Steel, C. M., McBeath, S., and O’Riordan, M. L., 1971, Human lymphoblastoid cell lines. II. Cytogenetic studies, J. Natl. Cancer Inst. 47:1203–1214.PubMedGoogle Scholar
  207. Stein, G. H., 1976, Characterization of T98: A polyploid human tumor cell line showing normal regulation in vitro, J. Cell Biol. 70: 24a.Google Scholar
  208. Stein, G. H., and Yanishevsky, R., 1976 (personal communication).Google Scholar
  209. Stetten, G., Latt, S. A., and Davidson, R. L., 1976, 33258 Hoechst enhancement of the photosensitivity of bromodeoxyuridine-substituted cells, Somat. Cell Genet. 2:285–290.PubMedGoogle Scholar
  210. Stevens, L. C., 1967, The biology of teratomas, Adv. Morphol. 6:1–31.Google Scholar
  211. Stevens, L. C., 1970, The development of transplantable teratocarcinomas from intratesticular grafts of pre-and postimplantation mouse embryos, Dev. Biol. 21:364–382.PubMedGoogle Scholar
  212. Stich, H. F., and San, R. H. C., 1970, DNA repair and chromatid anomalies in mammalian cells exposed to 4-nitroquinoline 1-oxide, Mutat. Res. 10:389.PubMedGoogle Scholar
  213. Stockdale, F. E., 1971, DNA synthesis in differentiating skeletal muscle cells: Initiation by ultraviolet light, Science 71:1145–1147.Google Scholar
  214. Subak-Sharpe, H., 1965, Biochemically marked variants of the Syrian hamster fibroblast cell line: BHK21 and its derivatives, Exp. Cell Res. 38:106–118.PubMedGoogle Scholar
  215. Swim, H. E., and Parker, R. F., 1957, Culture characteristics of human fibroblasts propagated serially, Am. J. Hyg. 66:235–243.PubMedGoogle Scholar
  216. Szybalska, E. H., and Szybalski, W., 1962, Genetics of human cell lines. IV. DNA-mediated heritable transformation of a biochemical trait, Proc. Natl. Acad. Sci. U.S.A. 48:2026–2034.PubMedGoogle Scholar
  217. Taylor, A. M. R., Metcalfe, J. A., Oxford, J. M., and Harden, D. G., 1976, Is chromatid-type damage in ataxia telangiectasia after irradiation at G0 a consequence of defective repair?, Nature (London) 260:441–443.Google Scholar
  218. Thomas, G. H., Taylor, H. A., Miller, C. S., Axelman, J., and Migeon, B. R., 1974, Genetic complementation after fusion of Tay-Sachs and Sandhoff cells, Nature (London) 250:580–582.Google Scholar
  219. Thomopoulos, P., Roth, J., Lovelace, E., and Pastan, I., 1976, Insulin receptors in normal and transformed fibroblasts: Relationship to growth and transformation, Cell 8:417–423.PubMedGoogle Scholar
  220. Thompson, K. V. A., and Holliday, R., 1975, Chromosome changes during the in vitro ageing of MRC-5 human fibroblasts, Exp. Cell Res. 96:1–6.PubMedGoogle Scholar
  221. Thompson, L. H., and Baker, R. M., 1972, Isolation of mutants of cultured mammalian cells, Methods Cell Biol. 7:209–281.Google Scholar
  222. Thompson, L. H., and Lindl, P. A., 1976, A CHO-cell mutant with a defect in cytokinesis, Somat. Cell Genet. 2:387–400.PubMedGoogle Scholar
  223. Thompson, L. H., Mankovitz, R., Baker, R. M., Till, J. E., Siminovitch, L., and Whitmore, G. F., 1970, Isolation of temperature-sensitive mutants of L-cells, Proc. Natl. Acad. Sci. U.S.A. 66:377–384.PubMedGoogle Scholar
  224. Thompson, L. H., Harkins, J. L., and Stanners, C. P., 1973, A mammalian cell mutant with a temperature-sensitive leucyl-transfer RNA synthetase, Proc. Natl. Acad. Sci. U.S.A. 70:3094–3098.PubMedGoogle Scholar
  225. Thrasher, J. D., 1971, Age and the cell cycle of the mouse esophageal epithelium, Exp. Gerontol. 6:19–24.PubMedGoogle Scholar
  226. Thrasher, J. D., and Greulich, R. C., 1968, The duodenal progenitor population. I. Age related increase in the duration of the crystal progenitor cycle, J. Exp. Zool. 159:39–46.Google Scholar
  227. Tice, R., Chaillet, J., and Schneider, E. L., 1976, Demonstration of spontaneous sister chromatid exchanges in vivo, Exp. Cell Res. 102:426–428.PubMedGoogle Scholar
  228. Till, J. E., McCulloch, E. A., and Siminovitch, L., 1964, A stochastic model of stem cell proliferation based on the growth of spleen colony-forming cells, Proc. Natl. Acad. Sci. U.S.A. 51:29–36.PubMedGoogle Scholar
  229. Tjio, J. H., and Puck, T. T., 1958, Genetics of somatic mammalian cells, J. Exp. Med. 108:259–268.PubMedGoogle Scholar
  230. Todaro, G. J., and Green, H., 1963, Quantitative studies of the growth of mouse embryo cells in culture, and their development into established lines, J. Cell Biol. 17:299–313.PubMedGoogle Scholar
  231. Tomkins, G. A., Stanbridge, E. J., and Hayflick, L., 1974, Viral probes of aging in the human diploid cell strain WI-38 (38110), Proc. Soc. Exp. Biol. Med. 146:385–390.PubMedGoogle Scholar
  232. Toniolo, D., Meiss, H. K., and Basilico, C., 1973, A temperature sensitive mutation affecting 28 S ribosomal RNA production in mammalian cells, Proc. Natl. Acad. Sci. U.S.A. 70:1273–1277.PubMedGoogle Scholar
  233. Veomett, G., Shay, J., Hough, P. V. C., and Prescott, D. M., 1976, Large-scale enucleation of mammalian cells, Methods Cell Biol. 13:1–6.PubMedGoogle Scholar
  234. Vogel, W., and Bauknecht, T., 1976, Differential chromatid staining by in vivo treatment as a mutagenicity test system, Nature (London) 260:448–449.Google Scholar
  235. Vracko, R., and Benditt, E. P., 1975, Restricted replicative life-span of diabetic fibroblasts in vitro: Its relationship to microangiopathy, Fed. Proc. Fed. Am. Soc. Exp. Biol. 34:68–70.Google Scholar
  236. Wang, R. J., 1974, Temperature-sensitive mammalian cell line blocked in mitosis, Nature (London) 248:76–78.Google Scholar
  237. Wang, R. J., 1976, A novel temperature-sensitive defective prophase progression, Cell 8:257–261.PubMedGoogle Scholar
  238. Waters, H., and Walford, R. L., 1970, Latent period for outgrowth of human skin explants as a function of age, J. Gerontol. 25:381–383.PubMedGoogle Scholar
  239. Waters, H., and Watford, R. L., 1971, A non-enzymatic method for subculturing monolayer cell cultures, Proc. Soc. Exp. Biol. Med. 137:523–525.Google Scholar
  240. Weiner, F., Klein, G., and Harris, H., 1974, The analysis of malignancy by cell fusion. V. Further evidence of the ability of normal diploid cells to suppress malignancy, J. Cell Sci. 15:177–183.Google Scholar
  241. Whitaker, A. M., Gould, J., and Smith, E. M., 1974, The effect of repeated subcultivations and of a serum with an unusual property, Exp. Cell Res. 87:55–62.PubMedGoogle Scholar
  242. Wise, G. E., and Prescott, D. M., 1973, Ultrastructure of enucleated mammalian cells in culture, Exp. Cell Res. 81:63–72.PubMedGoogle Scholar
  243. Wolff, S., 1972, The repair of X-ray-induced chromosome aberrations in stimulated and unstimulated human lymphocytes, Mutat. Res. 15:435–444.PubMedGoogle Scholar
  244. Wright, W. E., 1973, The production of mass populations of anucleate cytoplasms, in: Methods in Cell Biology (D. M. Prescott, ed.), Vol. 8, Chapt. 10, pp. 203–210, Academic Press, New York.Google Scholar
  245. Wright, W. E., and Hayflick, L., 1975a, Use of biochemical lesions for selection of human cells with hybrid cytoplasms, Proc. Natl. Acad. Sci. U.S.A. 72: 1812–1816.PubMedGoogle Scholar
  246. Wright, W. E., and Hayflick, L., 1975b, The regulation of cellular aging by nuclear events in cultured normal human fibroblasts (WI-38), Adv. Exp. Med. Biol. 61: 39–55.PubMedGoogle Scholar
  247. Wright, W. E., and Hayflick, L., 1975c, Contributions of cytoplasmic factors to in vitro cellular senescence, Fed. Proc. Fed. Am. Soc. Exp. Biol. 34: 76–79.Google Scholar
  248. Wright, W. E., and Hayflick, L., 1975c, Nuclear control of cellular aging demonstrated by hybridization of anucleate and whole cultured normal human fibroblasts, Exp. Cell Res. 96: 113–121.PubMedGoogle Scholar
  249. Yanishevsky, R., and Carrano, A. V., 1975, Prematurely condensed chromosomes of dividing and non-dividing cells in aging human cell cultures, Exp. Cell Res. 90:169–174.PubMedGoogle Scholar
  250. Yanishevsky, R., Mendelsohn, M. L., Mayall, B. H., and Cristofalo, V. J., 1974, Proliferative capacity and DNA content of aging human diploid cells in culture: A cytophotometric and autoradiographic analysis, J. Cell. Physiol. 84:165–170.PubMedGoogle Scholar
  251. Yoshida, M. C., and Makino, S., 1963, A chromosome study of non-treated and an irradiated human in vitro cell line, Jpn. J. Hum. Genet. 8:39–45.Google Scholar

Copyright information

© Plenum Press, New York 1978

Authors and Affiliations

  • Thomas H. Norwood
    • 1
  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA

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