Reduced Genome Maintenance

There are now numerous mouse models in which DNA repair or genome maintenance systems have been compromised by genetic manipulation. These models include disruptions to virtually all the major DNA repair systems, as well as disruptions to genes that regulate the DNA damage response. Given the importance of mutations for cancer development, it is not surprising that many of these mice are cancer prone. However, a number of these mice also show segmental premature aging, and cells from such mice also show an increased propensity to undergo cellular senescence or apop-tosis (154,155). Collectively, these mouse models suggest that genome maintenance systems are important longevity-assurance mechanisms, and that the cellular responses to damage (senescence and cell death) can contribute to aging phenotypes. But have these mouse models taught us anything beyond the general importance of genome maintenance for longevity assurance? A recent mouse model has provided an important insight.

The XPF-ERCC1 complex is a structure-specific endonu-clease that is essential for repairing helix-distorting DNA lesions and interstrand cross-links. Mice carrying a severe mutation in XPF, similar to that found in a human patient, are extremely short lived. They die with several symptoms of accelerated aging and a high level of apoptosis in many tissues (156,157).

Gene expression profiles from the liver of these mice showed that the severe genotoxic stress caused by XPF deficiency increased the expression of genes that provide antioxidant defenses and decreased the expression of genes important for insulin/insulin-like growth factor-1 (IGF-1) signaling (156). The insulin/IGF-1 signaling pathway is now known to be an evolutionarily conserved pathway that regulates aging; modest decreases in the output of this pathway have been shown to increase the life span of nematodes, fruit flies, and mice (11,158). Notably, this pattern of gene expression was also seen in control mice subjected to chronic low-level genotoxic stress, calorie restriction, and normal aging (156). These findings suggest that damage and aging elicit a similar set of conserved metabolic responses: an increase in antioxidant protection and a decrease in insulin/IGF-1 signaling. These responses are similar to the effects of caloric restriction and presumably act to preserve, or attempt to preserve, somatic tissues (Chapter 23). This study also illustrates an important consideration in evaluating gene expression changes that occur during aging; although in some cases, changes in gene expression might reflect decrements in function or pathology, in other cases, as in the case of XPF mutant mice, they may indicate beneficial compensatory changes.

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