Early gender differences in the redox status of the brain mitochondria with age: effects of melatonin therapy

Abstract Mitochondrial dysfunction(definition) and oxidative/nitrosative stress are common features of senescence(definition), and they explain some of the pathophysiological events during aging. In different animal models of aging, the existence of oxidative stress, inflammation, and mitochondrial dysfunction has been reported. There is no information, however, regarding the age when these symptoms begin and if they account for gender differences in aging. Here we analyzed oxidative/nitrosative stress markers and bioenergetics in the brain mitochondria of normal mice during the first 10 months of life, looking for early signs of senescence. Male and female mice were treated with vehicle or melatonin during the first 9 months of life, starting at weaning. Mice were sacrificed at 5 and 10 months of life, and pure brain mitochondria were prepared and assayed for respiratory chain activity, ATP production, and oxidative/nitrosative stress status. The results showed that the brain mitochondria from male mice have a better glutathione cycle than female mice, whereas female mice have higher electron transport chain activity and ATP production at 5 months old. Five months later, however, oxidative/nitrosative stress markers increased in both male and female mice, thus eliminating the differences between the genders. More importantly, these changes were prevented by chronic melatonin administration, which also restored the gender differences found in 5-month-old mice. Thus, melatonin administration as a single therapy can maintain the full function of the brain mitochondria during the early events of aging, a finding that has important consequences in the pathophysiology of brain senescence.