Somatic mutations have been implicated as a major cause of both cancer and aging. Using a transgenic mouse model with a chromosomally integrated lacZ mutational target gene, mutations were found to accumulate with age in an organ-specific manner. Depending on the organ, many of the accumulated mutations were genome rearrangements rather than point mutations, some of them involving millions of basepairs (Dolle and Vijg, Genome Research 2002;12:1732-1738). Such large rearrangements could find their origin in misannealing of DNA double-strand breaks during error-prone repair. Hence, one would expect symptoms of premature aging in mouse models with defects in the repair of double strand lesions in the DNA. Indeed, both mice defective in non-homologous endjoining (Ku80) and inter-strand cross-links (Ercc1) show symptoms of accelerated aging (for review, see Hasty et al., Science 2003;299:1355-1359). We demonstrate that progeroid mice with defects in the repair of double-strand lesions show accelerated accumulation of large genome rearrangements, while cancer-prone mice with a defect in nucleotide excision repair or mismatch repair accumulate only point mutations and show increased susceptibility to cancer without symptoms of accelerated aging. We are presently attempting to directly detect genome rearrangements - and their possible consequences in terms of alterations in patterns of gene expression - at the single cell level in old versus young liver and heart cells, using both interphase chromosome painting and whole genome or global mRNA amplification followed by real-time PCR. Some preliminary results of these studies will be presented at the conference.