Abstract
Almost 40 years ago, Leonard Hayflick discovered that cultured normal human cells have limited capacity to divide, after which they become senescent — a phenomenon now known as the ‘Hayflick limit’. Hayflick's findings were strongly challenged at the time, and continue to be questioned in a few circles, but his achievements have enabled others to make considerable progress towards understanding and manipulating the molecular mechanisms of ageing.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Weismann, A. Collected Essays upon Heredity and Kindred Biological Problems (ed. Poulton, E. B.) (Clarendon, Oxford, 1889).
Carrel, A. & Ebeling, A. H. Age and multiplication of fibroblasts . J. Exp. Med. 34, 599– 606 (1921).
Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).
Witkowski, J. A. Dr. Carrel's immortal cells. Med. Hist. 24, 129–142 (1980).
Witkowski, J. A. The myth of cell immortality. Trends Biochem. Sci. 10, 258–260 (1985).
Rubin, H. Telomerase and cellular lifespan: ending the debate? Nature Biotechnol. 16, 396–397 ( 1998).
Burnett, M. Intrinsic Mutagenesis (Medical and Technical Publishing Co., Lancaster, 1974).
Garfield, E. Current Comments. Curr. Contents 15, 5– 8 (1983).
Hayflick, L. The coming of age of WI-38. Adv. Cell Cult. 3, 303–316 (1984).
Hayflick, L. How and why we age. Exp. Gerontol. 33, 639 –653 (1998).
Wright, W. E. & Hayflick, L. Nuclear control of cellular ageing demonstrated by hybridization of anucleate and whole cultured normal human fibroblasts. Exp. Cell Res. 96, 113– 121 (1975).
Watson, J. D. Origin of concatemeric T7 DNA. Nature New Biol. 239 , 197–201 (1972).
Olovnikov, A. M. Telomeres, telomerase and aging: Origin of the theory. Exp. Gerontol. 31, 443–448 ( 1996).
Olovnikov, A. M. Principles of marginotomy in template synthesis of polynucleotides. Dokl. Akad. Nauk S.S.S.R. 201, 1496– 1499 (1971).
Olovnikov, A. M. A theory of marginotomy: The incomplete copying of template margin in enzyme synthesis of polynucleotides and biological significance of the problem. J. Theor. Biol. 41, 181–190 (1973).
Muller, H. J. in Studies of Genetics: The Selected Papers of H. J. Muller 384– 408 (Indiana Univ. Press, Bloomington, 1962).
McClintock, B. The stability of broken ends of chromosomes in Zea mays. Genetics 26, 234–282 ( 1941).
Blackburn, E. H. & Gall, J. G. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 120, 33– 53 (1978).
Moyzis, R. K. et al. A highly conserved repetitive DNA sequence (TTAGGG)n, present at the telomeres of human chromosomes. Proc. Natl Acad. Sci. USA 85, 6622–6626 ( 1988).
Cooke, H. J. & Smith, B. A. Variability at the telomeres of human X/Y pseudoautosomal regions. Cold Spring Harb. Symp. Quant. Biol. 51, 213–219 ( 1986).
Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts . Nature 345, 458–460 (1990).
Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866– 868 (1990).
DeLange, T. et al. Structure and variability of human chromosome ends. Mol. Cell Biol. 10, 518–527 (1990).
Lindsey, J., McGill, N. I., LinDsey, L. A., Green, D. K. & Cooke, H. J. In vivo loss of telomere repeats with age in humans. Mutat. Res. 256, 45–48 (1991).
Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase enzyme with two kinds of primer specificity. Cell 51, 405– 413 (1985).
Morin, G. B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521 –529 (1989).
Kim, N.-W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011– 2015 (1994).
Feng, F. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).
Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and humans. Science 277, 955– 959 (1997).
Bodnar, A. G. et al. Extension of life span by introduction of telomerase into normal human cells. Science 279, 349– 352 (1998).
Shay, J. W. & Wright, W. E. The use of telomerized cells for tissue engineering. Nature Biotechnol. 18, 22–23 (2000).
Shay, J. W. & Gazdar, A. F. Telomerase in the early detection of cancer. J. Clin. Path. 50, 106– 109 (1997).
Herbert, B.-S. et al. Inhibition of telomerase leads to eroded telomeres, reduced proliferation, and apoptosis. Proc. Natl Acad. Sci. USA 96, 14276–14281 (1999).
Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in ageing skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).
Shay, J. W. & Wright, W. E. in Ageing Vulnerability: Causes and Interventions (Novartis Foundation Proceedings, in the press).
Hayflick, L. A brief overview of the discovery of cell mortality and immortality and of its influence on concepts about ageing and cancer. Pathol. Biol. 47, 1094–1104 ( 1999).
Wright, W. E. & Shay, J. W. Telomere dynamics in cancer progression and prevention: Fundamental differences in human and mouse telomere biology . Nature Med. 6, 849–851 (2000).
Hayflick, L. The biology of human aging. Am. J. Med. Sci. 265, 433–445 (1973).
Namba, M. et al. in Monograph on Cancer Research Vol. 27, 221–230 (Tokyo Univ. Press, Tokyo, 1981).
Shiels, P. G. et al. Analysis of telomere lengths in cloned sheep. Nature 399, 316–317 ( 1999).
Lanza, R. P. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 88, 665–669 (2000).
Shay, J. W. Telomerase in cancer — diagnostic, prognostic and therapeutic implications . Sci. Am. 4, S26–S34 (1998).
Hayflick, L., Plotkin, S. A., Norton, T. W. & Koprowski, H. Preparation of poliovirus vaccines in a human fetal diploid cell strain. Am. J. Hyg. 75, 240–258 (1962).
Hayflick, L., Moorhead, P., Pomerat, C. M. & Hsu, T. C. Choice of a cell system for vaccine production. Science 140, 760–763 (1963).
Fletcher, M. A., Hessel, L. & Plotkin, S. A. in Developments in Biological Standardization Vol. 93, 97–107 (Basel, Kargert, 1998).
Chanock, R. M., Hayflick, L. & Barille, M. F. Growth on artificial medium of an agent associated with atypical pneumonia and its identification as a PPLO. Proc. Natl Acad. Sci. USA 48, 41–49 (1962).
Hayflick, L. Tissue cultures and mycoplasmas. Texas Rep. Biol. Med. 23, 285–303 (1965).
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
ENCYCLOPEDIA OF LIFE SCIENCES
FURTHER INFORMATION
Rights and permissions
About this article
Cite this article
Shay, J., Wright, W. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol 1, 72–76 (2000). https://doi.org/10.1038/35036093
Issue Date:
DOI: https://doi.org/10.1038/35036093
This article is cited by
-
Germline specific genes increase DNA double-strand break repair and radioresistance in lung adenocarcinoma cells
Cell Death & Disease (2024)
-
First continuous marine sponge cell line established
Scientific Reports (2023)
-
Conformational plasticity and allosteric communication networks explain Shelterin protein TPP1 binding to human telomerase
Communications Chemistry (2023)
-
Gut-specific telomerase expression counteracts systemic aging in telomerase-deficient zebrafish
Nature Aging (2023)
-
Chromosome ends and the theory of marginotomy: implications for reproduction
Biogerontology (2023)