Abstract
Werner Syndrome (WS) is a human segmental progeria resulting from mutations in a DNA helicase. WS fibroblasts have a shortened replicative capacity, an aged appearance, and activated p38 MAPK, features that can be modulated by inhibition of the p38 pathway. Loss of the WRNp RecQ helicase has been shown to result in replicative stress, suggesting that a link between faulty DNA repair and stress-induced premature cellular senescence may lead to premature ageing in WS. Other progeroid syndromes that share overlapping pathophysiological features with WS also show defects in DNA processing, raising the possibility that faulty DNA repair, leading to replicative stress and premature cellular senescence, might be a more widespread feature of premature ageing syndromes. We therefore analysed replicative capacity, cellular morphology and p38 activation, and the effects of p38 inhibition, in fibroblasts from a range of progeroid syndromes. In general, populations of young fibroblasts from non-WS progeroid syndromes do not have a high level of cells with an enlarged morphology and F-actin stress fibres, unlike young WS cells, although this varies between strains. p38 activation and phosphorylated HSP27 levels generally correlate well with cellular morphology, and treatment with the p38 inhibitor SB203580 effects cellular morphology only in strains with enlarged cells and phosphorylated HSP27. For some syndromes fibroblast replicative capacity was within the normal range, whereas for others it was significantly shorter (e.g. HGPS and DKC). However, although in most cases SB203580 extended replicative capacity, with the exception of WS and DKC the magnitude of the effect was not significantly different from normal dermal fibroblasts. This suggests that stress-induced premature cellular senescence via p38 activation is restricted to a small subset of progeroid syndromes.Electronic supplementary materialThe online version of this article (doi:10.1007/s10522-012-9407-2) contains supplementary material, which is available to authorized users.
Highlights
Much remains to be discovered regarding the pathophysiology of human senescence (PuzianowskaKuznicka and Kuznicki 2005), a complex process involving genetic and environmental factors affecting several physiological pathways
Replicative senescence can contribute to agerelated degenerations in division competent tissues as a result of reduced proliferative capacity in organs where cell division is central to normal function or repair, or from the observation that senescent cells display deleterious biochemical features as a result of patterns of gene expression that differ markedly from their dividing counterparts (Ostler et al 2002; Kipling et al 2004; Burton 2009; Faragher et al 2009)
This increase in experimental replicative capacity for these normal strains is 29.7 ± 11.6 % (Table 1; Fig. 1). This compares to a replicative capacity extension seen in Werner Syndrome (WS) and AT fibroblasts of 158.7 ± 61 % (p \ 0.00016) and 43.8 ± 16.8 % (p [ 0.14) respectively
Summary
Much remains to be discovered regarding the pathophysiology of human senescence (PuzianowskaKuznicka and Kuznicki 2005), a complex process involving genetic and environmental factors affecting several physiological pathways. One mechanism commonly postulated as underlying human ageing is replicative cellular senescence, or the observation that many normal human somatic cells are capable of only a finite number of divisions (Campisi 1996; Ostler et al 2002; Burton 2009; Faragher et al 2009). Replicative senescence can contribute to agerelated degenerations in division competent tissues as a result of reduced proliferative capacity in organs where cell division is central to normal function or repair (e.g. small intestine, immune system, skin), or from the observation that senescent cells display deleterious biochemical features as a result of patterns of gene expression that differ markedly from their dividing counterparts (Ostler et al 2002; Kipling et al 2004; Burton 2009; Faragher et al 2009). Senescent cells secrete inflammatory cytokines such as IL-1 and tumour necrosis factor (TNFa) (Kumar et al 1993; Parrinello et al 2005), and express cell surface molecules such as ICAM-1 that are involved in the recruitment of leukocytes during inflammation (Gorgoulis et al 2005)
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