Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals

Oxidation of proteins by reactive oxygen species is associated with aging, oxidative stress, and many diseases. Although free and protein-bound methio nine residues are particularly sensitive to oxidation to methionine sulfoxi de derivatives, these oxidations are readily repaired by the action of meth ionine sulfoxide reductase (MsrA). To gain a better understanding of the bi ological roles of MsrA in metabolism, we have created a strain of mouse tha t lacks the MsrA gene. Compared with the wild type, this mutant: (i) exhibi ts enhanced sensitivity to oxidative stress (exposure to 100% oxygen); (ii) has a shorter lifespan under both normal and hyperoxic conditions; (iii) d evelops an atypical (tip-toe) walking pattern after 6 months of age; (iv) a ccumulates higher tissue levels of oxidized protein (carbonyl derivatives) under oxidative stress; and (v) is less able to up-regulate expression of t hioredoxin reductase under oxidative stress. It thus seems that MsrA may pl ay an important role in aging and neurological disorders.