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Werner Syndrome, Telomeres, and Stress Signaling: Implications for Future Therapies?

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Telomeres and Telomerase in Ageing, Disease, and Cancer

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Werner syndrome (WS) is a premature ageing disorder used as a model of normal human ageing. WS individuals have several characteristics of normal ageing, such as cataracts, hair greying, and skin ageing, but manifest these at an early age. Additionally, WS individuals have high levels of infl ammatory diseases such as atherosclerosis and type II diabetes. The in vivo ageing in WS is associated with premature ageing of fi broblasts in culture, and it is thought that WS is a disease of accelerated cell ageing. Normal fi broblasts senesce as a result of telomere erosion and WRNp is known to play a role in telomere maintenance. However, telomeres in WS cells do not appear to show accelerated rates of erosion. Thus the cause of the accelerated senescence is not understood. Several features of WS cells suggest that they are growing under conditions of stress, and low oxygen conditions and antioxidant treatment revert some of the accelerated senescence phenotype. In addition, WS cells have significant levels of genomic instability. Oxidative stress and genomic instability result in the activation of stress kinases such as p38, and the p38-specifi c inhibitor SB203580 essentially prevents the accelerated senescence seen in WS fi broblasts. The recent development of p38 inhibitors with different binding properties, specifi cities, and oral bioavailability, and of new potent and selective inhibitors of other stress kinases such as 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 refl ective of WS ageing in vivo, these kinase inhibitors may well form the basis of anti-ageing therapeutics for individuals with WS.

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  1. Department of Pathology, School of Medicine, Cardiff University, CF14 4XN, Heath Park, Cardiff, UK

    Terence Davis & David Kipling

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  1. Terence Davis
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  1. University of Ulm, Albert-Einstein-Allee 11, 89091, Ulm, Germany

    K. Lenhard Rudolph

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Davis, T., Kipling, D. (2008). Werner Syndrome, Telomeres, and Stress Signaling: Implications for Future Therapies?. In: Rudolph, K.L. (eds) Telomeres and Telomerase in Ageing, Disease, and Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73709-4_14

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