degradation (Ly et al 2000; Goldman et al 2002; Scafﬁdi and Misteli 2005). Immunoﬂuorescence of HGPS ﬁbro- blasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane (Eriksson et al 2003). In addition, HGPS cells have also altered histone modiﬁcation patterns, including reduced heterochromatin-speciﬁc trimethylation of Lys9 on histone H3 (Tri-Me-K9H3) (Scafﬁdi and Misteli 2005, 2006). A recent study implicated lamin A in physiological aging, showing that the molecular mechanism responsible for the premature aging (Hasty and Vijg 2004; Scafﬁdi and Misteli 2006). Thus, accelerated aging in HGPS might thus reﬂect an exaggerated lamin A-dependent mechanism, which contributes to physiological aging. Defects in prelamin A processing Lamin A has a conserved C-terminal CAAX motif, which is a potential target for subsequent processing steps. To generate mature lamin A, prelamin A undergoes substantial post-translational modiﬁcation of its CAAX motif via four processing steps (Zhang and Casey 1996; Young et al 2006). First, a 15-carbon farnesyl lipid is added to the thiol group of the cysteine by a cytosolic enzyme, protein farnesyltrans- ferase. Second, the last three amino acids of the protein (ie, the -AAX) are clipped off by the metalloprotease ZMP- STE24 and/or RCE1 (Bergo et al 2002; Corrigan et al 2005). Third, the newly exposed farnesylcysteine is carboxylmethyl- ated by ICMT, a prenylprotein-speciﬁc methyltransferase in the endoplasmic reticulum (Clarke et al 1988; Dai et al 1998). Fourth, the last 15 amino acids of the protein, including the farnesylcysteine methyl ester, are clipped off by ZMPSTE24 and degraded, releasing mature lamin A (Weber et al 1989; Beck et al 1990; Corrigan et al 2005; Young et al 2006). In HGPS, a 50-amino acid deletion in the C-terminus of the pro- tein (amino acids 607–656) lacks an important endoprotease cleavage site recognized by ZMPSTE24 during prelamin A post-translational processing, so no mature lamin A is formed and a farnesylated mutant prelamin A (progerin) accumulates in cells (De Sandre-Giovannoli et al 2003; Eriksson et al 2003; Navarro et al 2006; Sun and Schatten 2006; Tsai et al 2006; Young et al 2006). Progerin accumulation and nuclear morphology abnormalities The mutant prelamin A is targeted to the nuclear rim, where it disrupts the integrity of the nuclear lamina, leading to premature cell death (Eriksson et al 2003; Goldman et al 2004; Varela et al 2005; Yang et al 2005; Fong et al 2006). Clinical Interventions in Aging 2008:3(3) Werner’s and Hutchinson-Gilford progeria syndromes The GGC GGT (G608G) mutation of LMNA causes accumulation of farnesyl-prelamin A in the nucleus in a cel- lular age-dependent manner, and the cells display irregular nuclear shapes, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral hetero- chromatin, and clustering of nuclear pores (Eriksson et al 2003; Goldman et al 2004). Aberrant nuclear morphology is also reported with other LMNA mutations, which have been linked to other ‘‘laminopathies’’, such as Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy-1A, Dun- nigan-type familial partial lipodystrophy, mandibuloacral dysplasia, and atypical WS (Goldman et al 2002; Chen et al 2003). In HGPS cells, the nuclei and lamina appeared normal at early passages, but, at later passages, the nuclei are severely misshapen and contain an abnormally thick lamina (de Sandre-Giovannoli et al 2003; Eriksson et al 2003). These structural defects worsen as HGPS cells age in culture, and their severity correlates with an obvious increase in mutant lamin A (Goldman et al 2004). An abnormal distribution of nuclear pore complexes is seen in late pas- sage HGPS cells. The changes in nuclear pore complexes gradually affect various aspects of the normal trafﬁcking of protein and RNA across the nuclear envelope, having severe effects on the physiological state of HGPS cells (Yoshida and Blobel 2001). In addition, mutant lamin A induces decreased cellular proliferation, premature senescence, and altered motility (Goldman et al 2004). The highly lobulated late passage HGPS cells primarily exhibit PCNA patterns resembling early S phase, suggesting that there is a block in the transition from the early chain-elongation phase of DNA replication to the mid- and later phases of replication. Mutant lamin A (progerin) progressively accumulates in the nucleus with cellular age, resulting in premature cessation of growth in the later passages of HGPS cells (Goldman et al 2004). Universal transcriptional alterations Lamin A is a major constituent of the nuclear membrane, and an immunoﬂuorescence study of HGPS ﬁbroblast nuclei demonstrated abnormalities (Goldman et al 2004). Given the prominent structural role of lamin A in the nuclear membrane, it is suggested that this protein has diverse roles in DNA metabolism, including DNA replication and transcription. Gene expression in HGPS was investigated by measuring mRNA levels in ﬁbroblasts isolated from young, middle aged, and old humans with or without progeria (Ly et al 2000). Of the 152 genes studied, 47 (31%) were differentially transcribed in both old and HGPS compared 437