Nearly 40 years ago it was proposed that accumulation of mutations or increased levels of DNA damage might contribute to aging processes. Despite several correlative studies in this area, the answer as to whether genomic integrity contributes to aging has remained illusive. More recently it has been hypothesized that decreased mitochondrial DNA integrity plays a role in aging. To begin to test these hypotheses more directly, we are developing transgenic mouse and cell culture model systems. For example, transgenic mice overexpressing the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) have been made and have a reduced spontaneous frequency of hepatocellular carcinoma. A lifespan study using the MGMT transgenic mice is in progress in an effort to determine whether cancer impacts on the median or maximal lifespan of a species. Second, a quantitative PCR technique is being used to measure mitochondrial DNA damage in mitotic and post-mitotic cells to determine if the level of damage and/or repair is different based on mitotic status. Finally, mice deficient in metallothionein-I and -II are being used in an effort to determine if the subcellular distribution of metals impact on oxidative damage with increased age.