Progeroid syndromes: role of accelerated fibroblast senescence and p38 activation

Davis, Terence ORCID: https://orcid.org/0000-0003-2780-0262 2014. Progeroid syndromes: role of accelerated fibroblast senescence and p38 activation. Hayat, M. A., ed. Tumor Dormancy and Cellular Quiescence and Senescence, Volume 3: Aging, Cancer, and Noncancer Pathologies, Berlin: Springer Verlag, pp. 25-39. (10.1007/978-94-017-9325-4_3)

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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.

Item Type:	Book Section
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Springer Verlag
ISBN:	9789401793247
Last Modified:	14 Dec 2022 02:18
URI:	https://orca.cardiff.ac.uk/id/eprint/83964

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