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      Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

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          Abstract

          Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future.

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          Inflamm-aging. An evolutionary perspective on immunosenescence.

          In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
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            Extension of life-span by introduction of telomerase into normal human cells.

            Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.
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              Cytokine pathways and joint inflammation in rheumatoid arthritis.

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                Author and article information

                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                04 June 2010
                June 2010
                : 3
                : 6
                : 1842-1872
                Affiliations
                [1 ]School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
                [2 ]Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mails: Bagleymc@ 123456cardiff.ac.uk (M.C.B.); KiplingD@ 123456cardiff.ac.uk (D.K.); wpttd@ 123456cardiff.ac.uk (T.D.)
                Article
                pharmaceuticals-03-01842
                10.3390/ph3061842
                4033955
                27713332
                d9a450fe-db27-4f21-85b3-024b7543a244
                © 2010 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 31 March 2010
                : 13 May 2010
                : 26 May 2010
                Categories
                Review

                accelerated ageing,inflammation,microwave-assisted synthesis,p38 mapk,progeroid syndrome,werner syndrome

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