ReviewDNA double-strand breaks: A potential causative factor for mammalian aging?
Introduction
For mammals, aging is the time-dependent deterioration of an individual that decreases fitness and ultimately causes death and is caused by many factors that are influenced by both genetics and environment. Aging is not greatly influenced by natural selection since evolutionary pressure subsides once the individual has lived long enough for procreation (Kirkwood, 2002). Thus, aging is subject to little regulation making the aging process appear highly variable, stochastic and pleiotropic. As a result age-related decline is subject to a large number of potential influences and identifying these influences can be difficult and controversial. One potential aging target is nuclear DNA since it is a permanent blueprint that controls cellular processes. Thus, DNA replication and genome maintenance mechanisms are highly regulated to ensure faithful reproduction and maintenance of the blueprint and these pathways assure sufficient longevity for procreation and survival of the species. There are many of these longevity assurance mechanisms that are necessary to maintain this blueprint and imperfections in any of them can cause lasting changes called mutations. Therefore, aging may be a consequence of imperfect longevity assurance mechanisms designed to protect the genome from damage and to prevent the accumulation of mutations. The most deleterious damage to DNA is a double-strand break (DSB); thus, presenting the intriguing possibility that imperfections or defects in DSB repair pathways contribute to the aging process.
Section snippets
Factors that generate DNA DSBs
There are two general types of DNA damage: single-strand DNA (ssDNA) and double-strand DNA (dsDNA) lesions. ssDNA lesions include base lesions, intrastrand crosslinks and single-strand breaks (SSBs) while dsDNA lesions include DSBs and interstrand crosslinks (ICLs). Therefore, a wide range of DNA lesions exist and any of them may contribute to the aging process, but DSBs and ICLs are much more toxic than ssDNA lesions because they are incompatible with DNA replication (Bessho, 2003). A
Pathways that repair or suppress DNA DSBs
DNA repair pathways correct DNA lesions to prevent mutations and preserve genomic integrity (Hoeijmakers, 2001). These pathways are regarded as longevity assurance mechanisms important for suppressing tumor-causing mutations. Specific pathways are specialized for repairing specific damage, even though there is some functional overlap. For example, a variety of excision repair pathways correct ssDNA lesions including BER (Almeida and Sobol, 2007, Barnes and Lindahl, 2004), nucleotide excision
Accumulation of damage/mutations
Increasing evidence demonstrates that DNA damage and mutations accumulate with age in mice and humans including the type of damage/mutations that result from imperfect DSB repair. For example unrepaired DNA DSBs (Sedelnikova et al., 2004) and GCRs (Dolle et al., 1997) accumulate in a variety of tissues as mice age. In addition, GCRs (both spontaneous and H2O2-induced) appear in replicating and quiescent cells while point mutations (both spontaneous and UV-induced) are highly
DNA damage defective mammalian models of aging
A number of premature aging syndromes have been described in humans called segmental progeroid syndromes. These syndromes are called segmental since they display only a subset of age-related pathologies and were described based on clinical observations. Therefore, it is striking that most of them result from defective chromosomal metabolism. A complete description of these syndromes and their phenotypes has been provided (Bohr, 2002).
The best-known segmental progeroid syndrome is Werner's
DNA damage responses and cytotoxicity
DNA damage checkpoints respond to many forms of DNA damage, including DSBs, to facilitate repair or removal of these lesions (Campisi and d’Adda di Fagagna, 2007). These checkpoint machineries monitor the genome for problems that adversely affect DNA replication or mitosis and halt cell cycle progression when such problems are encountered to allow time for the damage to be repaired. If damage is severe or irreparable, these machineries engage either cell death (apoptosis) or cellular senescence
Comparison of GCRs to small mutations
Are dsDNA lesions and GCRs more likely to impact aging than ssDNA lesions and point mutations? Both GCRs and point mutations increase with age in a tissue-specific manner, so either could be important for at least some tissues. However, current data suggests that GCRs are more important. For example, aging does not always correlate to point mutation levels since mice defective for antioxidant defense clearly show elevated point mutations but do not show signs of early aging with the exception
Summary
Aging is a pleiotropic and stochastic process heavily influenced by genetic and environmental factors making aging-related processes difficult to understand and controversial. Here we argue that DNA repair pathways are essential for longevity and imperfections or defects in these pathways have the potential to cause early aging. As a result DNA damage and mutations may heavily influence the aging process either directly or perhaps indirectly by inducing either apoptosis or cellular senescence.
Acknowledgements
This work was supported by P01 AG17242, R01 CA76317-05A1, UO1 ES11044 to PH.
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Current address: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.