Ding and Shen to young. The direction of the change was the same in old and HGPS for all coregulated genes. Genes involved in mitosis were downregulated and the observed changes might result in increased rates of somatic mutation, leading to chromosome aberrations and mutations manifesting as an aging phenotype. Csoka and colleagues (2004b) found that the genes differentially expressed in HGPS ﬁbroblasts compared to age-matched control cell lines are involved in a variety of biological processes. Of the approximately 33,000 genes analyzed, 361 (1.1%) showed at least a 2 fold change in HGPS compared to the aged controls. The most prominent categories encoded transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene was MEOX/GAX, a homeobox gene that func- tions as a negative regulator of proliferation. Several genes involved in DNA replication and chromatin remodeling were downregulated. These changes were interpreted as contrib- uting to depression of cellular proliferation. Some of the transcription changes suggested excess extracellular matrix deposition through the increased expression of extracellular matrix components and decreased expression of extracellular matrix remodeling enzymes. Of the 58 genes examined by both of these groups, the expression of 17 (29%) changed in the same direction, demonstrating a reasonable agreement between the two studies considering their different designs. The studies by Kyng and Bohr (2005) and Csoka and col- leagues (2004b) point to a shared mechanism of aging accel- eration in PSs ie, misregulated transcription. The idea that aging is due to the loss of the proper transcriptional state of the cell followed by “dysdifferentiation” had been previously proposed by other investigators (Kator et al 1985; Zs-Nagy et al 1988; Fossel 2003; Prolla 2005). These ﬁndings that HGPS patients show inappropriate transcriptional patterns provides new evidence that transcriptional deregulation can contribute to the aging process in humans. Genomic instability DNA damage accumulation and the effects of repair defects can lead to genomic instability associated with premature aging and have causal roles in normal aging (Lombard et al 2005; von Zglinicki et al 2005). Indeed, defective recruitment of 53BP1 and RAD51 to sites of DNA lesion is seen in HGPS ﬁbroblasts, resulting in a delayed checkpoint response and defective DNA repair (Liu et al 2005). Wild-type mouse embryonic ﬁbroblasts ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair (Liu et al 2005). 438 These results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb the DNA damage response and repair, resulting in genomic instability, which might contribute to laminopathy-based premature aging (Liu et al 2005). In HGPS cells, DNA dam- age checkpoints are persistently activated, and inactivation of checkpoint kinases ATM and ATR can partially restore cell cycle progression into S-phase (Cortez et al 2001; Liu et al 2006), suggesting that senescence can be suppressed by inactivating DNA damage response pathways in HGPS cells. Organismal aging has been linked to activation of p53-dependent signaling pathways and initiation of the senescence program in a premature aging mouse model (Varela et al 2005). Inhibition of aberrant splicing of lamin A results in signiﬁcant downregulation of p21, IGFBP3, and GADD45B compared with mock-treated cells (Scafﬁdi and Misteli 2006). Consistent with the reduction in p53 activa- tion, upon elimination of Δ50 lamin A from old cells, the fraction of 5-bromo-2’-deoxyuridine-positive proliferating cells increased by 30% and was similar to that in mock- treated young cells. Over the past few years, there have been reports that progerin leads to defective DNA repair and genome instability (Liu et al 2005), overexpression of p53 target genes (Varela et al 2005), and changes in his- tone methylation that affect heterochromatin organization (Shumaker et al 2006). Farnesyltransferase inhibitor Farnesyl-prelamin A is targeted to the nuclear envelope, where it interferes with the integrity of the nuclear enve- lope and causes misshapen cell nuclei. It has also been shown to affect the mechanical stability of the nucleus (Dahl et al 2006). Farnesyltransferase inhibitors (FTIs) can block prelamin A processing and reduce the percent- age of cells with misshapen nuclei (Capell et al 2005; Glynn and Glover 2005; Mallampalli et al 2005; Toth et al 2005). Thus, the favorable effects of FTIs raise the ques- tion whether an FTI might improve disease phenotypes in HGPS (Young et al 2006). It is also important to deﬁne the extent to which these abnormalities are affected by an FTI and to determine whether FTIs will be a useful therapy in children with HGPS. A recent study found that treatment of patient’s cells with an FTI did not result in a reduction in DNA DSBs and damage checkpoint signaling, although it signiﬁcantly reversed the aberrant shape of their nuclei (Liu et al 2006), suggesting that DNA damage accumula- tion and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these Clinical Interventions in Aging 2008:3(3)