The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging.
Werner syndrome (WS) is a premature aging disorder used as a model of normal human aging. WS individuals have several characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. Additionally, WS individuals have high levels of inflammatory diseases, such as atherosclerosis and type 2 diabetes. The in vivo aging in WS is associated with accelerated aging of fibroblasts in culture. The cause of the accelerated senescence is not understood, but may be due to the genomic instability that is a hallmark of WS. Genome instability results in activation of stress kinases, such as p38, and the p38-specific inhibitor SB203580, prevents the accelerated senescence seen in WS fibroblasts. However, oxidative damage plays a role, as low oxygen conditions and antioxidant treatment revert some of the accelerated senescence phenotype. The effects of oxidative stress appear to be suppressible by SB203580; however, it does not appear to be transduced by p38. As SB203580 is known to inhibit other kinases in addition to p38, this suggests that more than one kinase pathway is involved. The recent development of p38 inhibitors with different binding properties, specificities, and oral bioavailability, and of new potent and selective inhibitors of JNK and MK2, will make it possible to dissect the roles of various kinase pathways in the accelerated senescence of WS cells. If this accelerated senescence is reflective of WS aging in vivo, these kinase inhibitors may well form the basis of antiaging therapies for individuals with WS.
Davis
Terence
T
Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. kiplingd@cardiff.ac.uk
Wyllie
Fiona S
FS
Rokicki
Michal J
MJ
Bagley
Mark C
MC
Kipling
David
D
D000199:Actins / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D016922:Cellular Senescence; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D007249:Inflammation; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D016615:Telomere; D013997:Time Factors; D014898:Werner Syndrome / Q000378:metabolism* / Q000473:pathology*
D000199:Actins; D000975:Antioxidants; D004791:Enzyme Inhibitors; D010100:Oxygen