title: Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes.
abstract: Ageing is thought to be a polygenic and stochastic process in which multiple mechanisms operate at the same time. At the level of the individual organism ageing is associated with a progressive deterioration of health and quality of life, sharing common features such as: alopecia and grey hair, loss of audition, macular degeneration, neurodegeneration, cardiovascular diseases, osteoporosis, cataract formation, type-2 diabetes, lipodystrophies; a generally increased susceptibility to infection, autoimmune disorders and diseases such as cancer; and an impaired ability to cope with stress. Recent studies of mechanisms involved in the ageing process are contributing to the identification of genes involved in longevity. Monogenic heritable disorders causing premature ageing, and animal models have contributed to the understanding of some of the characteristic organism-level features associated with human ageing. Werner syndrome and Hutchinson-Gilford progeria syndrome are the best characterized human disorders. Werner syndrome patients have a median life expectancy of 47 years with clinical conditions from the second decade of life. Hutchinson-Gilford progeria syndrome patients die at a median age of 11-13 years with clinical conditions appearing soon after birth. In both syndromes, alterations in specific genes have been identified, with mutations in the WRN and LMNA genes respectively being the most closely associated with each syndrome. Results from molecular studies strongly suggest an increase in DNA damage and cell senescence as the underlying mechanism of pathological premature ageing in these two human syndromes. The same general mechanism has also been observed in human cells undergoing the normal ageing process. In the present article the molecular mechanisms currently proposed for explaining these two syndromes, which may also partly explain the normal ageing process, are reviewed.
authors.affiliation: Unidade de Enfermedades Tiroideas e Metabólicas (UETeM), Departamento de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, Spain. ml.dominguez.gerpe@usc.es
authors.forename: Lourdes
authors.initials: L
authors.lastname: Domínguez-Gerpe
authors.forename: David
authors.initials: D
authors.lastname: Araújo-Vilar
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D011371:Progeria / Q000235:genetics* / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics* / Q000378:metabolism; D000071657:Werner Syndrome Helicase
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase