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RESEARCH PRODUCT

Estrogenic Modulation of Longevity by Induction of Antioxidant Enzymes

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In many species including humans, females live longer than males. We and others have observed that mitochondria from females of Wistar rats and of OF1 mice produce half the amount of peroxide produced by males. We attributed this to a change in the expression of antioxidant, longevity-related genes. We have found that in those species in which females live longer than males, estrogens activate longevity-related genes, particularly antioxidant ones. It should be emphasized that estrogens do not act as antioxidants because of their phenolic ring but rather they act indirectly; that is, they behave as hormones and bind to estrogen receptors, which eventually leads to the upregulation of the expression of antioxidant genes. The pathway by which estrogens activate the expression of these genes has been elucidated, and we have traced it to the activation of the mitogen activated proteins (MAP) kinase pathway. It is remarkable that estrogens activate proliferation genes (related to their feminizing function and also to their cancer-promoting effects) by binding to estrogen receptor alpha whereas the longevity-related genes, in particular the antioxidant ones, are mediated by binding to estrogen receptor beta. Phytoestrogens, which in their vast majority bind to estrogen receptor beta, promote longevity-related genes without increasing the rate of cell division or promoting feminization. Thus, a practical approach discussed here is that administration of phytoestrogens may be very beneficial for longevity because they bind very preferentially to estrogen receptor beta and promote the upregulation of longevity-related genes.