Clocked Cell Cycle Clocks: Implications Toward Chronopharmacology and Aging

  • Leland N. EdmundsJr.
Part of the Advances in experimental medicine and biology book series (AEMB, volume 108)


Cell developmental and division cycles, comprising relatively discrete morphological and biochemical events that may be ordered sequentially or in a branching network, constitute “clocks” themselves in a general sense. Yet abundant evidence exists in both unicellular protistan and algal populations and in cultured mammalian cells that the cell division cycle (and perhaps other related cyclic events) may itself be modulated (or “clocked”) by a circadian oscillatory mechanism (an endogenous, self-sustaining oscillation) that at one level is conceptually and operationally distinct from the cell division cycle itself, but nevertheless, must ultimately be associated with, and generated by, basic cell cycle processes since the oscillatory mechanism(s) is itself replicated during each cell division cycle. A summary of the empirical evidence for these assertions is given in the first section of this paper.


Cell Cycle Cell Division Circadian Rhythm Generation Time Circadian Clock 
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Clocked Cell Cycle Clocks

  1. Barnett, A. Cell division: A second circadian clock system in Paramecium multimicronucleatum. Science 164: 1417–1419, 1969.PubMedCrossRefGoogle Scholar
  2. Bruce, V.G. The biological clock in Chlamydomonas reinhardi. J. Protozool. 17: 328–333, 1970.Google Scholar
  3. Cameron, I.L. and Padilla, G.M., eds. Cell Synchrony: Studies in Biosynthetic Regulation, Academic Press, New York and London, 392 pp., 1966.Google Scholar
  4. Cook, J.R. and James, T.W. Light-induced division synchrony in Euglena gracilis var. bacillaris. Exp. Cell Res. 21: 583–589, 1960.PubMedCrossRefGoogle Scholar
  5. Edmunds, L.N. Jr. Studies on synchronously dividing cultures of Euglena gracilis Klebs (strain Z). I. Attainment and characterization of cell division. J. Cell Comp. Physiol. 66: 147–158, 1965.CrossRefGoogle Scholar
  6. Edmunds, L.N. Jr: Studies on synchronously dividing cultures of Euglena gracilis Klebs (strain Z). III. Circadian components of cell division. J. Cell Physiol. 67: 35–44, 1966.PubMedCrossRefGoogle Scholar
  7. Edmunds, L.N. Jr: Persisting circadian rhythm of cell division in Euglena: Some theoretical considerations and the problem of intercellular communication. In: Biochronometry, M. Menaker, ed. Nat. Acad. Sci., Washington, D.C., pp 594–611, 1971.Google Scholar
  8. Edmunds, L.N. Jr: Circadian clock control of the cell developmental cycle in synchronized cultures of Euglena. In: Mechanisms of Regulation of Plant Growth, R.L. Bieleski, A.R. Ferguson and M.M. Cresswell, eds. Royal Society of New Zealand, Wellington, pp 287–297, Bull. 12, 1974.Google Scholar
  9. Edmunds, L.N. Jr: Temporal differentiation in Euglena: Circadian phenomena in non-dividing populations and in synchronously dividing cells. In: Les Cycles Cellularies et Leur Blocage chez Plusieurs Protistes. Colloques Int. C.N.R.S., n° 240. Centre National de la Recherche Scientifique, Paris, pp 53–67, 1975.Google Scholar
  10. Edmunds, L.N. Jr., Chuang, L., Jarrett, R.M. and Terry O.W. Long-term persistence of free-running circadian rhythms of cell division in Euglena and the implication of autosynchrony. J. Interdisc. Cycle Res. 2: 121–132, 1971.CrossRefGoogle Scholar
  11. Edmunds, L.N. Jr. and Cirillo, V.P. On the interplay among cell cycle, biological clock and membrane transport control systems. Int. J. Chronobiol. 2: 233–246, 1974.PubMedGoogle Scholar
  12. Edmunds, L.N. Jr. and Funch, R. Effects of “skeleton” photoperiods and high frequency light-dark cycles on the rhythm of cell division in synchronized cultures of Euglena. Planta (Berlin) 87: 134–163, 1969a.CrossRefGoogle Scholar
  13. Edmunds, L.N. Jr. and Funch, R.R. Circadian rhythm of cell division in Euglena: Effects of a random illumination regimen. Science 165: 500–503, 1969b.PubMedCrossRefGoogle Scholar
  14. Edmunds, L.N. Jr. and Halberg, F. Circadian time structure of Euglena: A model system amenable to quantification. Chronobiologia (in press).Google Scholar
  15. Edmunds, L.N. Jr., Jay, M.E., Kohlmann, A., Liu, S.C., Merriam, V.H. and Sternberg, H. The coupling effects of some thiol and other sulfur-containing compounds on the circadian rhythm of cell division in photosynthetic mutants of Euglena. Arch. Microbiol. 108: 1–8, 1976.PubMedCrossRefGoogle Scholar
  16. Edmunds, L.N. Jr., Apter, R.I., Cirillo, V.P. and Woodward, J.R. Phasing and inhibitory effects of visible light on growth, cell division and transport in Saccharomyces cerevisiae. Fifth Annual Meeting, Amer. Soc. Photobiol., 12-16 May 1977, San Juan, Puerto Rico (abstracts).Google Scholar
  17. Ehret, C.F. and Dobra, K.W. The infradian eukaryotic cell: A circadian energy-reserve escapement. In: Proceedings of XII International Conference, International Society for Chrono-biology (Section on Cellular and Metabolic Mechanisms), Casa Editrice “Il Ponte”, Milano, pp 563–570, 1977.Google Scholar
  18. Ehret, C.F. and Wille, J.J. The photobiology of circadian rhythms in protozoa and other eukaryotic microorganisms. In: Photo-biology of Microorganisms, P. Halldal, ed. Wiley — Interscience, London, New York, Sydney and Toronto, pp 369–416, 1970.Google Scholar
  19. Ehret, C.F., Meinert, J.C., Groh, K.R. and Antipa, G.A. Circadian regulation: Growth kinetics of the infradian cell. In: Growth Kinetics and Biochemical Regulation of Normal and Malignant Cells, B. Drewinko and R.M. Humphrey, eds. Williams and Wilkins Co., Baltimore, pp 49–76, 1977.Google Scholar
  20. Engelberg, J. The decay of synchronization of cell division. Exp. Cell Res. 36: 647–662, 1964.PubMedCrossRefGoogle Scholar
  21. Halvorson, H.O., Carter, B.L.A. and Tauro, P. Synthesis of enzymes during the cell cycle. Advances in Microbial Physiology 6: 47–106, 1971.CrossRefGoogle Scholar
  22. Hartwell, L.H. Genetic control of the cell division cycle in yeast. II. Genes controlling DNA replication and its initiation. J. Molec. Biol. 59: 183–194, 1971.PubMedCrossRefGoogle Scholar
  23. Hartwell, L.H. Saccharomyces cerevisiae cell cycle. Bacteriol. Rev. 38: 164–198, 1974.PubMedGoogle Scholar
  24. Hartwell, L.H., Culotti, J. and Reid, B. Genetic control of the cell division cycle in yeast. Science 183: 46–51, 1974.PubMedCrossRefGoogle Scholar
  25. Hastings, J.W. and Sweeney, B.M. Phased cell division in the marine dinoflagellates. In: Synchrony in Cell Division and Growth, E. Zeuthen, ed. Wiley — Interscience, New York, Sydney and London, pp 307–321, 1964.Google Scholar
  26. Hesse, M. Endogene Rhythmik der Produktionsfähigkeit bei Chlorella und ihre Beeinflussung durch Licht. Z. Pflanzenphysiol. 67: 58–77, 1972.Google Scholar
  27. Howard, A. and Pelc, S.R. Synthesis of deoxyribonucleic acid in normal and irradiated cells and its relation to chromosome breakage. Heredity Suppl. 6: 261–273, 1953.Google Scholar
  28. Howell, S.H. and Naliboff, J.A. Conditional mutants in Chlamydomonas reinhardtii blocked in the vegetative cell cycle. I. An analysis of cell cycle block points. J. Cell. Biol. 57: 760–772, 1973.PubMedCrossRefGoogle Scholar
  29. Jarrett, R.M. and Edmunds, L.N. Jr. Persisting circadian rhythm of cell division in a photosynthetic mutant of Euglena. Science 167: 1730–1733, 1970.PubMedCrossRefGoogle Scholar
  30. Klevecz, R.R. Temporal order in mammalian cells. I. The periodic synthesis of lactate dehydrogenase in the cell cycle. J. Cell Biol. 43: 207–219, 1969a.PubMedCrossRefGoogle Scholar
  31. Klevecz, R.R. Temporal coordination of DNA replication with enzyme synthesis in diploid and heteroploid cells. Science 166: 1536–1538, 1969b.PubMedCrossRefGoogle Scholar
  32. Klevecz, R.R. Molecular manifestations of the cellular clock. In: The Cell Cycle in Malignancy and Immunity, 13th Annual Hanford Biology Symposium, J.C. Hampton, Chmn. ERDA Technical Info. Center, Oak Ridge, pp 1-19, 1975.Google Scholar
  33. Klevecz, R.R. Quantized generation time in mammalian cells as an expression of the cellular clock. Proc. Nat. Acad. Sci. USA 73: 4012–4016, 1976.PubMedCrossRefGoogle Scholar
  34. Mitchell, J.L.A. Photoinduced division synchrony in permanently bleached Euglena gracilis. Planta (Berlin) 100: 244–257, 1971.CrossRefGoogle Scholar
  35. Mitchison, J.M. The Biology of the Cell Cycle. Cambridge University Press, Cambridge, England, 313 pp, 1971.Google Scholar
  36. Padilla, G.M., Whitson, G.L. and Cameron, I.L., eds. The Cell Cycle: Gene-Enzyme Interactions. Academic Press, New York and London, 399 pp, 1969.Google Scholar
  37. Padilla, G.M., Cameron, I.L. and Zimmerman, A., eds. Cell Cycle Controls. Academic Press, New York, San Francisco and London, 370 pp, 1974.Google Scholar
  38. Pirson, A. and Lorenzen, H. Ein endogener Zeitfaktor bei der Teilung von Chlorella. Z. Bot. 46: 53–66, 1958.Google Scholar
  39. Pittendrigh, C.S. The circadian oscillation in Drosophila pseudoobscura pupae: A model for the photoperiodic clock. Z. Pflanzenphysiol. 54: 275–307, 1966.Google Scholar
  40. Pittendrigh, C.S. and Skopik, S.D. Circadian systems. V. The driving oscillation and the temporal sequence of development. Proc. Nat. Acad. Sci. USA 65: 500–507, 1970.PubMedCrossRefGoogle Scholar
  41. Prescott, D.M. Reproduction of Eukaryotic Cells, Academic Press, New York, San Francisco and London, 177 pp, 1976.Google Scholar
  42. Rensing, L. Tagesperiodik von Zellfunktionen und Strahlenempfindlichkeit in Normal-und Tumorgewebe. Naturwiss. Rdschau. 22: 390–396, 1969.Google Scholar
  43. Rensing, L. and Goedeke, K. Circadian rhythm and cell cycle: Possible entraining mechanisms. Chronobiologia 3: 53–65, 1976.Google Scholar
  44. Russell, G.K. and Lyman, H. Isolation of mutants of Euglena gracilis with impaired photosynthesis. Plant Physiol. 43: 1284–1290, 1968.PubMedCrossRefGoogle Scholar
  45. Scheving, L.E. and Pauly, J.E. Cellular mechanisms involving bio-rhythms with emphasis on those rhythms associated with the S and M stages of the cell cycle. Int. J. Chronobiol. 1: 269–286, 1973.PubMedGoogle Scholar
  46. Schwelitz, F.D., Dilley, R.A. and Crane, F.L. Biochemical and biophysical characteristics of a photosynthetic mutant of Euglena gracilis blocked in photosystem II. Plant Physiol. 50: 161–165, 1972.PubMedCrossRefGoogle Scholar
  47. Shields, R. Transition probability and the origin of variation in the cell cycle. Nature 267: 704–707, 1977.PubMedCrossRefGoogle Scholar
  48. Smith, J.A. and Martin, L. Do cells cycle? Proc. Natl. Acad. Sci. USA 70: 1263–1267, 1973.PubMedCrossRefGoogle Scholar
  49. Sweeney, B.M. and Hastings, J.W. Rhythmic cell division in populations of Gonyaulax polyedra. J. Protozool. 5: 217–244, 1958.Google Scholar
  50. Terry, O. and Edmunds, L.N. Jr. Semi-continuous culture and monitoring system for temperature-synchronized Euglena. Biotechnol. Bioeng. 11: 745–756, 1969.CrossRefGoogle Scholar
  51. Terry, O.W. and Edmunds, L.N. Jr. Phasing of cell division by temperature cycles in Euglena cultured autotrophically under continuous illumination. Planta (Berlin) 93: 106–127, 1970a.CrossRefGoogle Scholar
  52. Terry, O.W. and Edmunds, L.N. Jr. Rhythmic settling induced by temperature cycles in continuously-stirred autotrophic cultures of Euglena gracilis (Z strain). Planta (Berlin) 93: 128–142, 1970b.CrossRefGoogle Scholar
  53. Volm, M. Die Tagesperiodik der Zellteilung von Paramecium bursaria. Z. vergl. Physiol. 48: 157–180, 1964.CrossRefGoogle Scholar
  54. Wille, J.J. Jr. Light entrained circadian oscillations of growth rate in the yeast Candida utilis. In: Chronobiology, L.E. Scheving, F. Halberg and J.E. Pauly, eds. Igaku Shoin, Tokyo, pp 72–77, 1974.Google Scholar
  55. Wille, J.J. and Ehret, C.F. Light synchronization of an endogenous circadian rhythm of cell division in Tetrahymena. J. Protozool. 15: 785–788, 1968.PubMedGoogle Scholar
  56. Zeuthen, E., ed. Synchrony in Cell Division and Growth. Wiley — Interscience, New York, Sydney and London, 630 pp, 1964.Google Scholar
  57. Zeuthen, E. Recent developments in the synchronization of Tetrahymena cell cycle. In: Advances in Cell Biology, Vol. 2, D.M. Prescott, L. Goldstein and E. McConkey, eds. Appleton-Century-Crofts-Meredith, New York, pp 111–152, 1971.Google Scholar

Chronopharmacological Implications

  1. Baker, B.M. Undulant fever presenting the clinical syndrome of intermittent hydrarthrosis. Arch. Int. Med. 44: 128, 1929.CrossRefGoogle Scholar
  2. Baserga, R., ed. The Cell Cycle and Cancer. Marcel Dekker, New York, 481 pp, 1971.Google Scholar
  3. Burton, A.C. Cellular communication, contact inhibition, cell clocks, and cancer: The impact of the work and ideas of W.R. Loewenstein. Perspect. Biol. Med. 14: 301–318, 1971.PubMedGoogle Scholar
  4. Burton, A.C. The role of biochemical rhythms in contact inhibition of cellular division. In: Cellular Membranes and Tumor Cell Behavior, 28th Annual Symposium on Fundamental Cancer Research, Houston. Williams and Wilkins Co., Baltimore, pp 249–266, 1975.Google Scholar
  5. Burton, A.C. and Canham, P.B. The behavior of coupled biochemical oscillators as a model of contact inhibition of cellular division. J. Theoret. Biol. 39: 555–580, 1973.CrossRefGoogle Scholar
  6. Cardoso, S.S., Scheving, L.E. and Halberg, F. Mortality of mice as influenced by the hour of the day of drug (ara-C) administration. Pharmacologist 12: 302, 1970.Google Scholar
  7. Focan, C., Barbason, H. and Betz, E.H. Use of synchronization induced by cyclophosphamide in a methylcholanthrene sarcoma with circadian proliferation to rationalize sequential chemotherapy. Biomedicine 23: 230–235, 1975.PubMedGoogle Scholar
  8. Halberg, F. When to treat. Indian J. Cancer 12: 1–20, 1975.PubMedGoogle Scholar
  9. Halberg, F., Haus, E., Cardoso, S.S., Scheving, L.E., Kühl, J.F.W., Shiotsuka, R., Rosene, G., Pauly, J.E., Runge, W., Spalding, J.F., Lee, J.K. and Good, R.J. Toward a chronotherapy of neoplasia: Tolerance of treatment depends upon host rhythms. Experientia 29: 909–934, 1973.PubMedCrossRefGoogle Scholar
  10. Hastings, J.W. and Schweiger, H.G., eds. The Molecular Basis of Circadian Rhythms. Dahlem Konferenzen, Berlin, 462 pp, 1976.Google Scholar
  11. Haus, E., Halberg, F., Scheving, L.E., Pauly, J.E., Cardoso, S., Kühl, J.F.W., Sothern, R.B., Shiotsuka, R.N. and Shong, H.D. Increased tolerance of leukemic mice to arabinosyl cytosine with schedule adjusted to circadian system. Science 177: 80–82, 1972.PubMedCrossRefGoogle Scholar
  12. Haus, E., Halberg, F., Kiihl, J.F.W. and Lakatua, D.J. Chrono-pharmacology in animals. Chronobiologia 1 (Suppl. 1): 122–156, 1974.PubMedGoogle Scholar
  13. Hill, B.T. and Baserga, R. The cell cycle and its significance for cancer treatment. Cancer Treatment Rev. 2: 159–175, 1975.CrossRefGoogle Scholar
  14. Kauffman, S.A. and Wille, J.J. The mitotic oscillator in Physarum polycephalum. J. Theoret. Biol. 55: 47–54, 1975.CrossRefGoogle Scholar
  15. Klein, B. Compartmental model for study of diurnal rhythms in cell proliferation. J. Theoret. Biol. 64: 27–42, 1977.CrossRefGoogle Scholar
  16. Kühl, J.F.W., Haus, E., Halberg, F., Scheving, L., Pauly, J., Cardoso, S. and Rosene, G. Experimental chronotherapy with ara-C: Comparison of murine ara-C tolerance on differently timed treatment schedules. Chronobiologia (in press).Google Scholar
  17. Loewenstein, W.R. Intercellular communication in normal and neo-plastic tissues. In: Cellular Membranes and Tumor Cell Behavior, 28th Annual Symposium on Fundamental Cancer Research. Williams and Wilkins Co., Baltimore, pp 239–248, 1975.Google Scholar
  18. Madoc-Jones, H. and Mauro, F. Site of action of cytotoxic agents in the cell life cycle. In: Handbook of Experimental Pharmacology, Vol. 38/1, Antineoplastic and Immunosuppressive Agents. Springer Verlag, Berlin, pp 205–219, 1974.CrossRefGoogle Scholar
  19. Reinberg, A. Chronopharmacology in man. Chronobiologia 1 (Suppl. 1): 157–185, 1974.PubMedGoogle Scholar
  20. Reinberg, A. Advances in human chronopharmacology. Chronobiologia 3: 151–166, 1976.PubMedGoogle Scholar
  21. Reinberg, A. and Halberg, F. Circadian chronopharmacology. Ann. Rev. Pharmacol. 11: 455–492, 1971.PubMedCrossRefGoogle Scholar
  22. Richter, C.P. Biological clocks in medicine and psychiatry: Shock-phase hypothesis. Proc. Nat. Acad. Sci. USA 46: 1506–1530, 1960.PubMedCrossRefGoogle Scholar
  23. Richter, C.P. Biological Clocks in Medicine and Psychiatry. Charles C. Thomas, Springfield, 109 pp, 1965.Google Scholar
  24. Rosene, G.L. Suppression of mitoses in mouse mammary tumor cells following administration of circadian designed chemotherapy regimens. In: Chronobiology, L.E. Scheving, F. Halberg and J.E. Pauly, eds. Igaku Shoin, Tokyo, pp 306–310, 1974.Google Scholar
  25. Rosene, G., Lee, J.K., Kühl, J.F.W., Halberg, F. and Grage, T.B. Circadian chronotherapeutic index: Product of adriamycin-associated mouse breast-cancer-shrinkage and survival time augmentation. Int. J. Chronobiol. 1: 354–355, 1973.Google Scholar
  26. Sachsenmaier, W., Remy, H. and Plattner-Schobel, R. Initiation of synchronous mitosis in Physarum polycephalum; a model of the control of cell division in eukaryotes. Exp. Cell Res. 73: 41–48, 1972.PubMedCrossRefGoogle Scholar
  27. Scheving, L.E., Mayersbach, H. von and Pauly, J.E. An overview of chronopharmacology. Europ. J. Toxicol. 7: 203–227, 1974a.Google Scholar
  28. Scheving, L.E., Cardoso, S.S., Pauly, J.E., Halberg, F. and Haus, E. Variation in susceptibility of mice to the carcinostatic agent arabinosyl cytosine. In: Chronobiology, L.E. Scheving, F. Halberg and J. E. Pauly, eds. Igaku Shoin, Tokyo, pp 213–217, 1974b.Google Scholar
  29. Skipper, H.E. The cell cycle and chemotherapy of cancer. In: The Cell Cycle and Cancer, R. Baserga, ed. Marcel Dekker, New York, pp 358–387, 1971.Google Scholar
  30. Skipper, H.E., Schabel, E.M. Jr. and Wilcox, W.S. Experimental evaluation of potential anticancer agents. XII. Scheduling of arabinosyl cytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemotherapy Rpts. 51: 125–165, 1967.Google Scholar
  31. Urquahart, J. and Yates, F.E., eds. Temporal Aspects of Therapeutics. Plenum Press, New York and London, 213 pp, 1973.Google Scholar
  32. Van Putten, L.M., Keizer, H.J. and Mulder, J.H. Perspectives in cancer research: Synchronization in tumor chemotherapy. Europ. J. Cancer 12: 79–85, 1976.Google Scholar

Implication Towards Senescence and Aging: Cell Cycle and Life Cycle Clocks

  1. Aschoff, J. Desynchronization and resynchronization of human circadian rhythms. Aerospace Med. 40: 844–849, 1969.PubMedGoogle Scholar
  2. Aschoff, J., Saint-Paul, E. v. and Wever, R. Die Lebensdauer von Fliegen unter dem Einfluss von Zeit-Verschiebungen. Naturwiss. 58: 574, 1971.PubMedCrossRefGoogle Scholar
  3. Brock, M.A. and Hay, R.J. Comparative ultrastructure of chick fibroblasts in vitro at early and late stages during their growth span. J. Ultrastruct. Res. 36: 291–311, 1971.PubMedCrossRefGoogle Scholar
  4. Burnet, M. Intrinsic Mutagenesis: A Genetic Approach to Ageing. John Wiley and Sons, New York and Toronto, 244 pp, 1974.CrossRefGoogle Scholar
  5. Choe, B.-K. and Rose, N.R. In vitro senescence of mammalian cells. Gerontology 22: 89–108, 1976.PubMedCrossRefGoogle Scholar
  6. Cristofalo, V.J. Animal cell cultures as a model system for the study of aging. Adv. Geront. Res. 4: 45–79, 1972.Google Scholar
  7. Cristofalo, V.J. Thymidine labelling index as a criterion of aging in vitro. Gerontology 22: 9–27, 1976.PubMedCrossRefGoogle Scholar
  8. Cutler, R.G., ed. Cellular Ageing: Concepts and Mechanisms (Inter-disc. Topics in Gerontology, Vols. 9, 10), S, Karger, Basel, München, Paris, London, New York and Sydney, 218 + 129 pp, 1976.Google Scholar
  9. Danielli, J.F. and Muggleton, A.L. Some alternative states of amoebae with special reference to life span. Gerontologia 3: 76, 1959.PubMedCrossRefGoogle Scholar
  10. Duchesne, J. A unifying biochemical theory of cancer, senescence and maximal life span. J. Theoret. Biol. 66: 137–145, 1977.CrossRefGoogle Scholar
  11. Franks, L.M. Ageing in differentiated cells. Gerontologia 20: 51–62, 1974.PubMedCrossRefGoogle Scholar
  12. Gelfant, S. and Smith, J.G. Jr. Aging: Noncycling cells an explanation. Science 178: 357–361, 1972.PubMedCrossRefGoogle Scholar
  13. Gomez, M.P. and Harris, J.B. Ultrastructural cytochemistry of Euglena gracilis ‘Z’ from aging cultures. J. Protozool. 20: 515 (abstract 72), 1973.Google Scholar
  14. Gomez, M.P. and Walne, P.L. The fine structure of intranuclear changes related to aging in Euglena gracilis Klebs strain ‘Z’. J. Protozool. 21: 443 (abstract 109), 1974.Google Scholar
  15. Hay, R.J. and Strehler, B.L. The limited growth span of cell strains isolated from the chick embryo. Exp. Gerontol. 2: 123–135, 1967.CrossRefGoogle Scholar
  16. Hay, R.J., Menzies, R.A., Morgan, H.P. and Strehlerr, B.L. The division potential of cells in continuous growth as compared to cells subcultivated after maintenance in stationary phase. Exp. Gerontol. 3: 35–44, 1968.PubMedCrossRefGoogle Scholar
  17. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37: 614–636, 1965.PubMedCrossRefGoogle Scholar
  18. Hayflick, L. Cell culture and the aging phenomenon. In: Topics in the Biology of Aging, Symposium, Salk Institute for Biological Studies, San Diego, 1965, P.L. Krohn, ed. Wiley — Interscience, New York, London and Sydney, pp 83–100, 1966.Google Scholar
  19. Hayflick, L. Cytogerontology. In: Theoretical Aspects of Aging, M. Rockstein, M.L. Sussman, and J. Chesky, eds. Academic Press, New York, San Francisco and London, pp 83–103, 1974.Google Scholar
  20. Hayflick, L. The cell biology of human aging. New Eng. J. Med. 295: 1302–1308, 1976.PubMedCrossRefGoogle Scholar
  21. Hayflick, L. and Moorhead, P.S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25: 585–621, 1961.PubMedCrossRefGoogle Scholar
  22. Highkin, H.R. and Hanson, J.B. Possible interaction between light-dark cycles and endogenous daily rhythms on the growth of tomato plants. Plant Physiol. 29: 301–302, 1954.PubMedCrossRefGoogle Scholar
  23. Hillman, W.S. Injury of tomato plants by continuous light and unfavorable photoperiodic cycles. Amer. J. Bot. 43: 89–96, 1956.CrossRefGoogle Scholar
  24. Holliday, R. Growth and death of diploid and transformed human fibroblasts. Fed. Proc. Fed. Am. Socs. Exp. Biol. 34: 51–55, 1975.Google Scholar
  25. Ketellapper, H.J. Interaction of endogenous and environmental periods in plant growth. Plant Physiol. 35: 238–241, 1960.PubMedCrossRefGoogle Scholar
  26. Krohn, P.L., ed. Topics in the Biology of Aging (Symposium, Salk Institute for Biological Studies, San Diego, 1965. Wiley — Interscience, New York, London and Sydney, 177 pp, 1966.Google Scholar
  27. Landahl, H.D. Biological periodicities, mathematical biology, and aging. In: Handbook of Aging and the Individual, J.E. Birren, ed. University of Chicago Press, Chicago and London, pp 81–115, 1959.Google Scholar
  28. Lipetz, J. and Cristofalo, V.J. Ultrastructural changes accompanying the aging of human diploid cells in culture. J. Ultra-struct. Res. 39: 43–56, 1972.CrossRefGoogle Scholar
  29. Mohan, C. and Radha, E. Circadian rhythm in acetyl cholinesterase activity during aging of the central nervous system. Life Sci. 15: 231–237, 1974.PubMedCrossRefGoogle Scholar
  30. Muggleton, A.L. and Danielli, J.F. Ageing of Amoeba proteus and A. discoides cells. Nature 181: 1738, 1958.CrossRefGoogle Scholar
  31. Orgel, L.E. The maintenance of the accuracy of protein synthesis and the relevance to aging. Proc. Nat. Acad. Sci. USA 49: 517–521, 1963.PubMedCrossRefGoogle Scholar
  32. Palisano, J.R. and Walne, P.L. Acid phosphatase activity and ultrastructure of aged cells of Euglena granulata. J. Phycology. 8: 81–88, 1972.Google Scholar
  33. Pittendrigh, C.S. Circadian rhythms and the circadian organization of living systems. In: Biological Clocks, Cold Spring Harbor Symposium, A. Chovnick, ed. Quant. Biol. Vol. 25. Long Island Biological Association, Cold Spring Harbor, pp 93-125, 1960.Google Scholar
  34. Pittendrigh, C.S. Circadian oscillations in cells and the circadian organization of multicellular systems. In: The Neurosciences, Third Study Program, F.O. Schmitt and F.G. Worden, eds. The MIT Press, Cambridge, Mass. and London, pp 437-458, 1974.Google Scholar
  35. Pittendrigh, C.S. and Minis, D.H. Circadian systems: Longevity as a function of circadian resonance in Drosophila melanogaster. Proc. Nat. Acad. Sci. USA 69: 1537–1539, 1972.PubMedCrossRefGoogle Scholar
  36. Rockstein, M., Sussman, M.L. and Chesky, J., eds. Theoretical Aspects of Aging. Academic Press, New York, San Francisco and London, 1974.Google Scholar
  37. Samis, H.V. Aging: the loss of temporal organization. Perspect. Biol. Med. 12: 95–102, 1968.PubMedGoogle Scholar
  38. Saunders, D.S. Circadian control of larval growth rate in Sarcophaga argyrostoma. Proc. Nat. Acad. Sci. USA 69: 2738–2740, 1972.PubMedCrossRefGoogle Scholar
  39. Schneider, E.L. and Mitsui, Y. The relationship between in vitro cellular aging and in vivo human age. Proc. Nat. Acad. Sci. USA 73: 3584–3588, 1976.PubMedCrossRefGoogle Scholar
  40. Strehler, B.L., Ebert, J.D., Glass, H.B. and Shock, N.W. The Biology of Aging. Amer. Inst. Biol. Sci., Washington, D.C., 364 pp, 1960.Google Scholar
  41. Went, F.W. The periodic aspect of photoperiodism and photo-periodicity. In: Photoperiodism and Related Phenomena in Plants and Animals, R.B. Withrow, ed. Amer. Assoc. Advanc. Sci., Washington, D.C., pp 551–564, 1959.Google Scholar
  42. Wilson, D.L. The programmed theory of aging. In: Theoretical Aspects of Aging, M. Rockstein, M.L. Sussman and J. Chesky, eds. Academic Press, New York, San Francisco and London, pp 11–21, 1974.Google Scholar

Copyright information

© Springer Science+Business Media New York 1978

Authors and Affiliations

  • Leland N. EdmundsJr.
    • 1
  1. 1.Division of Biological SciencesState University of New YorkStony BrookUSA

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