Abstract
Human ageing studies are problematic due to their complex nature so genetic progeroid syndromes that manifest a subset of ageing phenotypes are used as proxies to dissect out specific ageing processes. Many such processes are believed to involve cellular senescence, as senescent cells gradually build-up during life. Two forms of cellular senescence exist; replicative due to telomere dysfunction and stress-induced via activation of p38 MAP kinase. As progeroid syndromes show premature ageing, they are useful for cell ageing studies that may provide support for the linkage between cellular senescence and ageing. For several progeroid syndromes, notably Werner, ATR-Seckel, Hutchinson-Gilford, Ataxia-Telangiectasia, Nijmegen Breakage and Dyskeratosis congenita, there is clear evidence that fibroblasts undergo rapid or premature ageing. For other syndromes such as Cockayne, Rothmund-Thomson and Bloom there is no such clear evidence. In addition, no clear relationship between the severity of ageing features and premature fibroblast senescence is seen. However, as some of these syndromes result in early death from non-age related causes, it may be that insufficient lifespan is available for significant premature ageing to occur. For example in Nijmegen Breakage syndrome, fibroblasts age rapidly but the progeroid features are slight, possibly due to early death from cancer. In addition, it may be that premature cell senescence occurs in cell types other than fibroblasts. The accelerated cell ageing that does occur results from accelerated telomere dysfunction in some syndromes, activation of p38 in others, or a mix of both mechanisms. In this chapter, I provide a summation of the evidence for accelerated cellular senescence in progeroid syndromes and attempt to relate this to the severity and tissue specificity of the progeroid phenotypes. Finally, I discuss a model that may underlie the accelerated ageing in a subset of these syndromes that may be relevant to normal ageing processes.
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Notes
- 1.
Note: due to the reference limitations imposed in this chapter (a maximum of 35 permitted), an exhaustive review of the literature is not possible. Therefore I have predominantly cited papers that review the information quoted (many of which are my own works) rather than the primary source. This does not denigrate the primary sources in any way whatsoever (these are listed in the cited references), nor does it imply any form of priority or enhanced importance of the cited references, and sincere apologies are herein expressed for all the authors of the primary literature that I have been unable to cite due to these limitations. If readers wish further information on any of the topics discussed I recommend that they read the original sources that can be found in the cited references.
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Acknowledgements
I would like to acknowledge the long-term collaborations of Prof David Kipling of Cardiff University and Prof Mark Bagley of Sussex University, and the invaluable help of the various Post-Docs, Students, and Research Techs who have done much of the laboratory work over the years. In addition, I would like to thank Prof Joanna Latimer of Cardiff University for giving me an appreciation of the wider Social Science and Policy aspects of human ageing processes. My research programmes have been funded for the last 14 years by the UK Research Councils, including the MRC (Medical Research Council), BBSRC (Biology and Biotechnology Research Council), EPSRC (Engineering and Physical Research Council), and ESRC (Economics and Social Science Research Council).
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Davis, T. (2014). Progeroid Syndromes: Role of Accelerated Fibroblast Senescence and p38 Activation. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Vol. 3. Tumor Dormancy and Cellular Quiescence and Senescence, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9325-4_3
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DOI: https://doi.org/10.1007/978-94-017-9325-4_3
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