PSs. Yang and colleagues (2006) created gene-targeted mice with an HGPS mutation (LmnaHG/+) and examined the effect of an FTI on the disease phenotypes. The LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. In addition, osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI ame- liorated the disease phenotypes, resulting in an increased adipose tissue mass, improved body weight curves, a reduc- tion in the number of rib fractures, and improved bone mineralization and bone cortical thickness, suggesting that FTIs could be useful for treating HGPS patients (Yang et al 2006). Though FTIs fall short of curing the disease (Yang et al 2006), these ﬁndings have established a paradigm for ameliorating the most obvious cellular pathology in HGPS and suggest a potential strategy for treating this disease. A hypothetical model of aging The molecular mechanisms involved in human senescence are complicated. Two canonical PSs, WS and HGPS, characterized by clinical features mimicking physiologi- cal aging at an early age, have provided insights into the mechanisms of natural aging. In these PSs, several cel- lular pathways are affected, resulting in the formation of endogenous and exogenous sources of oxidative stress, telomere attrition, and a decline in DNA repair, which can jointly contribute to genomic instability, and subsequently result in growth arrest and apoptosis, leading to the human aging phenotypes (Karanjawala and Lieber 2004; Prolla 2005; Collado 2007). The gene defective in WS, WRN, encodes a helicase of the RecQ family and possesses an exonuclease domain. WRN is involves in multiple DNA repair pathways and plays a signiﬁcant role in the maintenance of overall genomic stability (Bachrati and Hickson 2003) (as seen in WS). The clinical features of HGPS show similarities to WS, but progress more rapidly (Hennekam 2006). LMNA, the gene defective in HGPS, affects the structure or post-translational maturation of lamin A, a major nuclear component (Eriksson et al 2003). Recently, several studies have established a functional link between DNA repair and A-type lamin-associated syndromes, which are associated with transcriptional alterations, abnormal DNA replication, changed organi- zation of higher order chromatin structure, and genomic instability (Serrano and Blasco 2007), suggesting a link between these syndromes and physiological aging (as seen in HGPS). DNA damage is generated throughout Clinical Interventions in Aging 2008:3(3) Werner’s and Hutchinson-Gilford progeria syndromes life and causes continuous damage to the macromolecular components of cells. Importantly, the rate of DNA damage production increases with ageing (Hasty and Vijg 2004; Serrano and Blasco 2007). Thus, the causal relationship between the DNA dam- age response and cellular senescence suggests that DNA damage-initiated genomic instability can induce human aging phenotypes (Harman 1956). p53-mediated senescence and apoptosis in response to DNA damage also probably contribute to aging. Indeed, p53, as a master integrator of cellular stress, is able to respond to a wide range of DNA damage (Horn and Vousden 2007), then, if the stress per- sists, prevent propagation of the damaged cells (by apop- tosis or senescence) (Vousden and Lane 2007). Following DNA damage, activation of p53 leads to transcription and upregulation of p53 target genes, among which P21 acts as the major effector of p53-induced cellular senescence. P21 levels increase gradually as cells pass into senescence (Alcorta et al 1996). Collectively, these results suggest that p53 activation is at least partially responsible for the induction of cellular senescence in response to DNA dam- age. On the other hand, various lines of evidence have shown that telomere shortening and dysfunction can also trigger DNA damage responses and are sufﬁcient to induce cellular senescence (d’Adda di Fagagna et al 2003; Takai et al 2003; Chang et al 2004; Du et al 2004). Some HGP ﬁbroblasts also appear refractory to telomerase-mediated immortalization (Wallis et al 2004), and most cultures show elevated apoptosis and senescence (Bridger and Kill 2004). Numerous studies indicate that, in the setting of WRN deﬁciency, dysfunctional telomeres trigger the onset of premature aging phenotypes, suggesting a link between increased telomere dysfunction and the genomic instability associated with the aging process (d’Adda di Fagagna et al 2003; Takai et al 2003; Smogorzewska and de Lange 2004; Chang et al 2004; Du et al 2004). On the basis of the infor- mation available for WS and HGPS, we suggest a model of human aging (Figure 1). Human aging can be triggered by two main mechanisms, telomere shortening and DNA dam- age. In telomere-dependent aging, telomere shortening and dysfunction can lead to DNA damage responses, inducing cellular senescence. In DNA damage-initiated aging, DNA damage accumulates, along with DNA repair deﬁciencies, resulting in genomic instability and accelerated cellular senescence. Both aging mechanisms depend strongly on p53 status. These two mechanisms can act cooperatively to increase the overall level of genomic instability and trigger the onset of human aging phenotypes. 439