title: Absence of premature senescence in Werner's syndrome keratinocytes.
abstract: Werner's syndrome (WS) is an autosomal recessive genetic disorder caused by loss of function mutation in wrn and is a useful model of premature in vivo ageing. Cellular senescence is a plausible causal mechanism of mammalian ageing and, at the cellular level, WS fibroblasts show premature senescence resulting from a combination of telomeric attrition and replication fork stalling. Over 90% of WS fibroblast cultures achieve <20 population doublings (PD) in vitro compared to wild type human fibroblast cultures. It has been proposed that some cell types, capable of proliferation, will fail to show a premature senescence phenotype in response to wrn mutations. To test this hypothesis, human dermal keratinocytes (derived from both WS and wild type patients) were cultured long term. WS Keratinocytes showed a replicative lifespan in excess of 100 population doublings but maintained functional growth arrest mechanisms based on p16 and p53. The karyotype of the cells was superficially normal and the cultures retained markers characteristic of keratinocyte holoclones (stem cells) including p63 expression and telomerase activity. Accordingly we conclude that, in contrast to WS fibroblasts, WS keratinocytes do not demonstrate slow growth rates or features of premature senescence. These findings suggest that the epidermis is among the tissue types that do not display symptoms of premature ageing caused by loss of function of wrn. This is in support that Werner's syndrome is a segmental progeroid syndrome.
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: badr_ibrahim@ymail.com.
authors: Badr
authors: B
authors: Ibrahim
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: a.n.sheerin@brighton.ac.uk.
authors: Angela N
authors: AN
authors: Sheerin
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: katrin@jennert.com.
authors: Katrin
authors: K
authors: Jennert-Burston
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: J.Bird3@Bradford.ac.uk.
authors: Joe L E
authors: JL
authors: Bird
authors: Department of Dermatology, University of Sassari, Viale S Pietro No 43, 09100 Sassari, Italy, Department of Human and Hereditary Pathology, Section of General Biology and Medical Genetics, University of Pavia, Pavia.
authors: M V
authors: MV
authors: Massala
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: m.Illsley@brighton.ac.uk.
authors: Matthew
authors: M
authors: Illsley
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: S.E.james@brighton.ac.uk.
authors: S Elizabeth
authors: SE
authors: James
authors: School of Pharmacy and biomolecular sciences, stress, ageing and diseases research group, College of life, health and physical sciences, University of Brighton, Cockcroft Building, Brighton, BN149HJ, England. Electronic address: R.G.A.Faragher@brighton.ac.uk.
authors: Richard G A
authors: RG
authors: Faragher
mesh_terms: D015415:Biomarkers / Q000032:analysis; D002478:Cells, Cultured; D016922:Cellular Senescence; D004261:DNA Replication; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D010641:Phenotype; D019098:Telomerase; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase / Q000235:genetics*
chemical_list: D015415:Biomarkers; D019098:Telomerase; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
keywords: Ageing; Cellular senescence; Fibroblasts; Keratinocytes; Werner's syndrome; p53; p63