Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Apoptosis in response to DNA damage, a major tumor suppressor mechanism, is antagonistically pleiotropic, promoting the development of specific ageing phenotypes as well as suppressing the development of cancer. This is illustrated by reduced spontaneous tumor formation and premature appearance of other aging-related phenotypes in several mouse mutants harboring genetic defects in genome maintenance. Here we studied one of these mutants, the XpdTTD mutant mouse model, harboring a defect in both nucleotide excision repair (NER) and general transcription. We observed a dramatic age-related increase in apoptosis in the liver as compared to control mice. The increase in apoptosis may contribute to the accelerated aging phenotypes and the reduced incidence of cancer observed in these mutants. To gain further insight into the molecular basis for the up-regulation of apoptosis and its relation to the mutant-specific manifestation of age-related phenotypes, gene expression profiles of mutant and control mouse liver were compared with normal aging. The results indicate that genes involved in lipid metabolism and immune response are significantly down-regulated in mutant liver compared to wild type liver. Comparison of expression profiles with normal liver aging indicated similar changes in lipid metabolism, but increased expression levels of genes involved in immune response and other responses to stresses. We conclude that the premature aging phenotype associated with the XpdTTD defect in repair and transcription causes an imbalance of normal patterns of growth and metabolism that is both similar and distinct from alterations during normal liver aging.