Prevention of Accelerated Cell Aging in Werner Syndrome Using a p38 Mitogen-Activated Protein Kinase Inhibitor

Davis, Terence; Baird, Duncan Martin; Haughton, Michele Fleur; Jones, Christopher J.; Kipling, David

doi:10.1093/gerona/60.11.1386

Cited by 85 publications

(159 citation statements)

References 36 publications

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“…We first examined p38 activation, as this marker was also shown to be involved in senescence of WS fibroblasts (51). A proportional increase in p38 expression and phosphorylation levels was noted in the liver of Wrn Δhel/Δhel animals compared to WT mice, but ascorbate had no effect on these changes (Fig.…”

Section: Vitamin C Normalizes Several Wrn δHel/δhel Mouse Liver Stresmentioning

confidence: 99%

Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

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Section: Vitamin C Normalizes Several Wrn δHel/δhel Mouse Liver Stresmentioning

confidence: 99%

Vitamin C restores healthy aging in a mouse model for Werner syndrome

et al. 2009

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“…The AT and WS fibroblasts early in their replicative lifespan are reported to show an altered, enlarged, cellular morphology due to the presence of extensive networks of F-actin stress-fibres (Davis et al 2005;McKinnon and Burgoyne 1985), and resemble normal fibroblasts that have undergone stress-induced premature senescence (SIPS) as a result of oncogenic ras expression or arsenite treatment (Deng et al 2004;Guay et al 1997;Huot et al 1997;Wang et al 2002). These features of SIPS can result from activation of the stress-associated p38a MAP kinase as the use of the p38 selective inhibitor SB203580 prevents ras-induced senescence in human BJ fibroblasts (Deng et al 2004;Wang et al 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Recent work has shown that WS fibroblasts have a normal lifespan and cellular morphology when treated with the p38 inhibitor SB203580; in effect SB203580 prevents the accelerated ageing that is a hallmark of WS cells (Davis et al 2005). Thus, the accelerated ageing is thought to be due to SIPS, and the p38 signalling pathway is activated in cultures of young WS cells.…”

Section: Introductionmentioning

confidence: 99%

Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of Ataxia Telangiectasia and Werner syndrome fibroblasts

Davis

Kipling

2008

Biogerontology

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The premature ageing Ataxia Telangiectasia (AT) and Werner syndromes (WS) are associated with accelerated cellular ageing. Young WS fibroblasts have an aged appearance and activated p38 MAP kinase, and treatment with the p38 inhibitor SB230580 extends their lifespan to within the normal range. SB203580 also extends the replicative lifespan of normal adult dermal fibroblasts, however, the effect is much reduced when compared to WS cells, suggesting that WS fibroblasts undergo a form of stress-induced premature senescence (SIPS). A small lifespan extension is seen in AT cells, which is not significant compared to normal fibroblasts, and the majority of young AT cells do not have an aged appearance and lack p38 activation, suggesting that the premature ageing does not result from SIPS. The lack of p38 activation is supported by the clinical manifestation, since AT is not associated with inflammatory disease, whereas WS individuals are predisposed to atherosclerosis, type II diabetes and osteoporosis, conditions known to be associated with p38 activation.

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“…It has been shown that the p38MAPK gene product is activated in fibroblasts from Werner syndrome patients (Davis et al, 2005). However, it is unclear what role p38MAPK may play in adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The implication is that Wrn is involved in modulating p38MAPK activity. This concept is of interest since a recent study by Davis et al, (2005) showed that treatment of human WS cells with a p38MAPK inhibitor could reverse this senescent phenotype.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet

Moore

Knoblaugh

Gollahon

et al. 2008

Mechanisms of Ageing and Development

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Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner gene (Wrn). WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four month old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during four months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia were characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.

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Prevention of Accelerated Cell Aging in Werner Syndrome Using a p38 Mitogen-Activated Protein Kinase Inhibitor

Cited by 85 publications

References 36 publications

Vitamin C restores healthy aging in a mouse model for Werner syndrome

Vitamin C restores healthy aging in a mouse model for Werner syndrome

Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of Ataxia Telangiectasia and Werner syndrome fibroblasts

Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet

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