muscles of Drosophila is associated with reduced lifespan. The accumulation of neuronal and muscular ROS appears to contribute to age-associated impairments. When overexpression of mitochondrial SOD2 is induced, the lifespan of adult Drosophila is extended. Among black garden ants (Lasius niger), the lifespan of queens is an order of magnitude greater than of workers despite no systematic nucleotide sequence difference between them. The SOD3 gene was found to be the most differentially over-expressed in the brains of queen vs worker ants. This finding raises the possibility of an important role of antioxidant function in modulating lifespan. SOD knockdowns in the worm C. elegans do not cause major physiological disruptions. However, the lifespan of C. elegans can be extended by superoxide/catalase mimetics suggesting that oxidative stress is a major determinant of the rate of aging. Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the budding yeast Saccharomyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. In wild-type S. cerevisiae, DNA damage rates increased 3-fold with age, but more than 5-fold in mutants deleted for either the SOD1 or SOD2 genes. Reactive oxygen species levels increase with age in these mutant strains and show a similar pattern to the pattern of DNA damage increase with age. Thus it appears that superoxide dismutase plays a substantial role in preserving genome integrity during aging in S. cerevisiae. SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan. In the fission yeast Schizosaccharomyces pombe, deficiency of mitochondrial superoxide dismutase SOD2 accelerates chronological aging. Several prokaryotic SOD null mutants have been generated, including E. coli. The loss of periplasmic CuZnSOD causes loss of virulence and might be an attractive target for new antibiotics. Role in disease Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease). The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. The other two isoforms of SOD have not been linked to many human diseases, however, in mice inactivation of SOD2 causes perinatal lethality and inactivation of SOD1 causes hepatocellular carcinoma. Mutations in SOD1 can cause familial ALS (several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients.), by a