title: Accelerated ageing: from mechanism to therapy through animal models.
abstract: Ageing research benefits from the study of accelerated ageing syndromes such as Hutchinson-Gilford progeria syndrome (HGPS), characterized by the early appearance of symptoms normally associated with advanced age. Most HGPS cases are caused by a mutation in the gene LMNA, which leads to the synthesis of a truncated precursor of lamin A known as progerin that lacks the target sequence for the metallopotease FACE-1/ZMPSTE24 and remains constitutively farnesylated. The use of Face-1/Zmpste24-deficient mice allowed us to demonstrate that accumulation of farnesylated prelamin A causes severe abnormalities of the nuclear envelope, hyper-activation of p53 signalling, cellular senescence, stem cell dysfunction and the development of a progeroid phenotype. The reduction of prenylated prelamin A levels in genetically modified mice leads to a complete reversal of the progeroid phenotype, suggesting that inhibition of protein farnesylation could represent a therapeutic option for the treatment of progeria. However, we found that both prelamin A and its truncated form progerin can undergo either farnesylation or geranylgeranylation, revealing the need of targeting both activities for an efficient treatment of HGPS. Using Face-1/Zmpste24-deficient mice as model, we found that a combination of statins and aminobisphosphonates inhibits both types of modifications of prelamin A and progerin, improves the ageing-like symptoms of these mice and extends substantially their longevity, opening a new therapeutic possibility for human progeroid syndromes associated with nuclear-envelope defects. We discuss here the use of this and other animal models to investigate the molecular mechanisms underlying accelerated ageing and to test strategies for its treatment.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006, Oviedo, Spain.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Obaya
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008666:Metalloendopeptidases / Q000502:physiology*; D011371:Progeria / Q000378:metabolism / Q000628:therapy*
chemical_list: D008565:Membrane Proteins; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse