ABSTRACT
According to ‘disposable soma theory’, the strongest candidates for longevity genes are those regulating somatic maintenance and repair, including the cellular responses to stress (Kirkwood, 1977). Recently, the lamin A gene (LMNA) has been linked to longevity and was proposed to be a guardian of somatic cells during their lifetime (Hutchison and Worman, 2004). Mutations in the LMNA gene cause a spectrum of 20 human age-related diseases and progeroid syndromes, termed laminopathies, which affect the maintenance of one or more tissues of mesenchymal origin including skeletal muscle, tendons, adipose, skin, bone, peripheral neurones, myocardium and vasculature (Pekovic and Hutchison, 2008; see Figure 3 in the colour plate section). Tissues affected by LMNA mutations often show degenerative changes accompanied with an increased fibrosis and/or adipose-like tissue replacements (Hutchison and Worman, 2004). The compromised tissue functions in laminopathies are proposed to be a consequence of decreased cellular proliferation (Pekovic et al., 2007), a failure to maintain a differentiated state (Markiewicz et al., 2005) and a loss of tissue repair during regeneration (Bakay et al., 2006). Mouse models of lmna knock-out (KO), mutated lmna knock-in (KI) or transgenic mice have been produced that manifest muscular dystrophy (Arimura et al., 2005; Sullivan et al., 1999), premature ageing (Mounkes et al., 2003; Varga et al., 2006) and dilated cardiomyopathy (Mounkes et al., 2005), respectively. These mouse models have a shortened lifespan and die prematurely between 2 and 13 months of age. Moreover, mouse models null in the lamin A processing enzyme Zmpste24 also have shortened lifespan and show progeria-like pathologies of bone and muscle (Bergo et al., 2002; Pendas et al., 2002), whilst down-regulation of Celamin in Caenorhabditis elegans leads to a 16% decrease in lifespan (Haithcock et al., 2005).
