During oxidative metabolism harmful reactive oxygen species (ROS) are generated. These species are neutralized by antioxidant enzymes. Firstly, superoxide dismutase (Sod) converts superoxide radicals (.O2-) to hydrogen peroxide (H2O2). Thereafter catalase (Cat) and glutathione peroxidase (Gpx) independently convert this to water. An imbalance in the ratio of Sod to Gpx and Cat results in the accumulation of H2O2 which may participate in the Fenton reaction, resulting in the formation of noxious hydroxyl radicals. These ROS are highly reactive and cause damage to macromolecules such as DNA, protein and lipids. We propose that it is the balance in the activity of the Sod to Gpx plus Cat ratio (Sod/(Gpx plus Cat)) that is an important determinant of cellular aging. This is based on our observation that an altered Cu/Zn-superoxide dismutase (Sod1)/(Gpx1 plus Cat) ratio exists in the brain of aging mice and that this correlates with increased lipid damage. Conversely, aging liver and kidney have an unaffected Sod1/(Gpx1 plus Cat) ratio and lipid damage is not increased with aging. We also examine the Sod1 to Gpx1 ratio in Down syndrome tissue and show that all organs have an altered ratio. This may contribute to the premature aging seen in these individuals. We show that binding of a p50/p65 complex to an NF-kappa B consensus sequence is enhanced by H2O2 treatment in NIH3T3 cells. Thus an altered Sod1/(Gpx1 plus Cat) ratio may also affect gene expression by altering the binding and/or availability of transcription factors to DNA.