J.H.J. Hoeijmakers

12 DNA Repair and Aging

One major theory of aging is based on the notion that DNA damage accumulates with age. This damage causes genomic instability and cellular dysfunction via its effect on chromosome replication, transcription, and other DNA metabolic transactions. Overall, DNA damage has the potential for several deleterious effects: It may cause cell death, impaired function, or permanent proliferative arrest (senescence), or it may cause mutations. Whereas the latter is associated primarily with cancer, all of these appear to contribute to the aging process. This notion is supported by studies using cells from human segmental progerias or mouse models with defined DNA-repair defects. Besides stochastic accumulation of DNA damage, there is also a genetic component to aging involving cellular defenses against DNA damage and the insulin-like growth factor-1 (IGF-1)-somatotrophic axis that controls metabolism, which is influenced by DNA damage and stress. DNA DAMAGE DNA is constantly subjected to a barrage of undesirable chemical modifications introduced by internal sources including metabolic reactive oxygen species (ROS) and by external sources such as ubiquitous environmental physical radiation and numerous chemical agents (Lindahl 1993; Wogan et al. 2004). The most abundant damages generated are DNA base lesions, although sugar and DNA backbone modifications arise as well. In particular, normal cellular oxidative processes and ROS attack can generate a large number of oxidative DNA base damages (see examples in Fig. 1): Currently, more than 70 different oxidative base lesions have been identified (Dizdaroglu et al. 2002; Sander et al. 2005). Exposure to external environmental agents can induce bulky...