Ding and Shen (Martin and Oshima 2000; Spann et al 2002; Hickson 2003; Andressoo and Hoeijmakers 2005). In addition, skin ﬁbroblast biopsies from patients with HGPS fail to show evidence of normal DNA strand rejoining in vitro after exposure to irradiation, suggesting that DNA repair may be absent or greatly reduced in the cells (Epstein et al 1973). Thus, these two PSs directly mimic the clinical and molecular features of natural aging, providing unique insights into the molecular mechanisms underlying human aging (Martin 1978, 1985). In this review, we will focus on these two best characterized PSs, with particular emphasis on the functions of the mutated syndrome-causing genes, and their potential implications for resemble aging. Based on the current information on these two syndromes, we also propose a model to explain human aging. Werner’s syndrome Werner’s syndrome is a rare autosomal recessive disorder characterized by premature aging (Epstein et al 1966; Martin et al 1970; Goto et al 1996; Yu et al 1996). The WRN gene responsible for WS encodes the 1432 amino acid WRN protein, which is a member of the RecQ DNA helicase family (Yu et al 1996). The C-terminal region of WRN contains the conserved RQC domain, which includes a nucleolar targeting sequence (NTS) (Marciniak et al 1998; von Kobbe and Bohr 2002), and the helicase and RNaseD C-terminal (HRDC) domain (Liu et al 1999). WRN has DNA-dependent ATPase, DNA strand annealing, DNA helicase, and exonuclease activities (Gray et al 1997; Suzuki et al 1997, 1999; Huang et al 1998). WRN, as a “caretaker of the genome”, is needed to prevent telomere dysfunction and consequent genomic instability (Opresko et al 2003; Crabbe et al 2004; Du et al 2004). Since most of the mutations identiﬁed in WRN cause premature termina- tion of translation (Goto 1997; Yu et al 1997), resulting in impaired nuclear import of the protein (Matsumoto et al 1997), the clinical features and cellular phenotypes of WS patients are major due to an absolute lack of normal WRN in the nucleus. WS cells have defects in DNA replication, resulting in dysfunction in multiple cellular DNA metabolic processes, such as DNA replication initiation, replication foci establishment, and the resolution of stalled replication forks during replication and DNA repair (Martin et al 1970; Hasty et al 2003). In addition, a large number of reports have shown that many cellular events, including transcrip- tion and apoptosis, are affected in WS cells (Ogburn et al 1997; Balajee et al 1999; Spillare et al 1999, 2006; Som- mers et al 2005). The loss of WRN function in WS appears 432 as chromosome instability, a shorter life span in culture (Martin 1977), and accelerated telomere shortening (Schulz et al 1996), suggesting that breakdown of WRN function is important in promoting aging (Martin et al 1970; Hasty et al 2003). Multiple functions of the WRN protein Biochemistry and catalytic activities WRN, a multifunctional nuclear protein, interacts with a number of proteins to catalyze four major DNA-dependent enzymatic activities, acting (1) as a DNA-dependent ATPase, (2) as an intrinsic 3′→5′ helicase (Gray et al 1997), (3) as a 3′→5′ exonuclease (Huang et al 1998, 2000), and (4) in DNA strand annealing (Machwe et al 2005), and interacts with factors with established roles in DNA metabolic path- ways (Brosh and Bohr 2002). WRN contains three distinct structure-speciﬁc DNA-binding domains, one N-terminal domain and two different C-terminal fragments (the RecQ and HRDC domains), each of which plays roles in distinct DNA metabolic pathways (von Kobbe et al 2003a). ATP-stimulated activities are required for the suc- cessive steps in the hydrolytic reaction, such as structure recognition, DNA binding, and 3′-terminal hydrolysis. In this context, WRN plays a DNA-dependent ATPase, using the energy from ATP hydrolysis to unwind double-stranded DNA, and its exonuclease and helicase activities act in con- cert to catalyze structure-dependent DNA degradation in resolving aberrant DNA structures (Shen and Loeb 2000). As a helicase, WRN is active on the forked end of a DNA duplex, while, as an exonuclease, it acts on the blunt end of the same duplex (Gray et al 1997; Huang et al 1998; Opresko et al 2001). WRN exonuclease can efﬁciently remove a mismatched nucleotide at a 3′ recessed terminus and can initiate DNA degradation from a 12-nucleotide gap or a nick (Huang et al 2000). Furthermore, WRN forms a trimer, which interacts with the proliferating cell nuclear antigen (PCNA) to participate in the replication restart process (Huang et al 2000; Rodríguez-López et al 2003; Jeziorny et al 2006). WRN exonuclease activity is suppressed by interaction with p53 (Brosh et al 2001a) or BLM (von Kobbe et al 2002) and stimulated by interaction with Ku70/80 (Li and Comai 2001) or phosphorylation (Karmakar et al 2002). WRN helicase activity is stimulated by interaction with replication protein A (RPA) (Shen et al 1998) or telomere repeat binding factor 2 (TRF2) (Opresko et al 2002) and phosphorylation (Karmakar et al 2002). Clinical Interventions in Aging 2008:3(3)