Ding and Shen Telomere -dependent aging DNA damage-initiated aging Telomere shortening Exogenous/endogenous DNA damage DNA damage response DNA repair deficiencies Genomic instability p53 activation Cellular senescence/apoptosis Human aging Figure 1 A hypothetical model: Genomic instability plays a central role during the aging process, triggered by two main stimuli, telomere shortening and DNA damage. (1) Telomere-dependent aging:Telomeres are essential for chromosomal stability.Telomere shortening and dysfunction can trigger DNA damage responses and are sufﬁcient to induce cellular senescence. (2) DNA damage-initiated aging: DNA damage accumulates, along with DNA repair deﬁciencies, resulting in genomic instability and accelerated cellular senescence. Both mechanisms depend strongly on p53. These two mechanisms can act cooperatively to increase the overall level of genomic instability and trigger the onset of human aging phenotypes. Conﬂict of interest The authors report no conﬂicts of interest in this work. References Agrelo R, Cheng WH, Setien F, et al. 2006. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci U S A, 103:8822–7. Alberts B, Johnson A, Lewis J, et al. 2002. Development of multicellular organisms. In: Alberts B (ed): Molecular Biology of the Cell, 4th edi- tion. New York: Garland Science. Alcorta DA, Xiong Y, Phelps D, et al. 1996. Involvement of the cyclin- dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human ﬁbroblasts, Proc Natl Acad Sci U S A, 93:13742–7. Andressoo JO, Hoeijmakers JH. 2005. Transcription-coupled repair and premature ageing. Mutat Res, 577:179–94. Bachrati CZ, Hickson ID. 2003. RecQ helicases: Suppressors of tumorigen- esis and premature aging. Biochem J, 374:577–606. Balajee AS, Machwe A, May A, et al. 1999. The Werner syndrome protein is involved in RNA polymerase II transcription. Mol Biol Cell, 10:2655–68. 440 Bambara RA, Murante RS, Hendrickson LA. 1997. Enzymes and reactions at the eukaryotic DNA replication fork. J Biol Chem, 272:4647–50. Baynton K, Otterlei M, Bjøras M. et al. 2003. WRN interacts physically and functionally with the recombination mediator protein RAD52. J Biol Chem, 278:36476–86. Beck LA, Hosick TJ, Sinensky M. 1990. Isoprenylation is required for the processing of the lamin A precursor. J Cell Biol, 110:1489–99. Beckman KB, Ames BN. 1998. The free radical theory of aging matures. Physiol Rev, 78:547–81. Bergo MO, Gavino B, Ross J, et al. 2002. Zmpste24 deﬁciency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc Natl Acad Sci U S A, 99:13049–54. Bischof O, Kim SH, Irving J, et al. 2001. Regulation and localization of the Bloom syndrome protein in response to DNA damage. J Cell Biol, 153:367–80. Blander G, Zalle N, Daniely Y, et al. 2002. DNA damage-induced translo- cation of the Werner helicase is regulated by acetylation. J Biol Chem, 277:50934–40. Blank A, Bobola MS, Gold B, et al. 2004. The Werner syndrome protein con- fers resistance to the DNA lesions N3-methyladenine and O(6)-methyl- guanine: implications for WRN function. DNA Repair, 3:629–38. Clinical Interventions in Aging 2008:3(3)