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Accelerated ageing: from mechanism to therapy through animal models

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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.

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Acknowledgments

We thank I. Varela, X.S. Puente, J. Cadiñanos and G. Velasco for helpful comments and advice. This work was supported by grants from Ministerio de Educación y Ciencia-Spain, Fundación “La Caixa”, Fundación “M. Botín”, and the European Union (FP6 CancerDegradome and FP7 Microenvimet). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias.

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  1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006, Oviedo, Spain

    Fernando G. Osorio, Carlos López-Otín & José M. P. Freije

  2. Departamento de Biología Funcional (Fisiología), Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006, Oviedo, Spain

    Álvaro J. Obaya

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  1. Fernando G. Osorio
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Correspondence to José M. P. Freije.

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Osorio, F.G., Obaya, Á.J., López-Otín, C. et al. Accelerated ageing: from mechanism to therapy through animal models. Transgenic Res 18, 7–15 (2009). https://doi.org/10.1007/s11248-008-9226-z

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