From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing.
Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.
Cox
L S
LS
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Faragher
R G A
RG
D000375:Aging; D019588:Aging, Premature / Q000209:etiology / Q000235:genetics*; D016922:Cellular Senescence; D005090:Exodeoxyribonucleases; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D011371:Progeria / Q000209:etiology / Q000235:genetics*; D053484:RecQ Helicases / Q000235:genetics; D014898:Werner Syndrome / Q000209:etiology / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D034904:Lamin Type A; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase