title: Females live longer than males: role of oxidative stress.
abstract: One of the most significant achievements of the twentieth century is the increase in human lifespan. In any period studied, females live longer than males. We showed that mitochondrial oxidative stress is higher in males than females and that the higher levels of estrogens in females protect them against ageing, by up-regulating the expression of antioxidant, longevity-related genes. The chemical structure of estradiol confers antioxidant properties to the molecule. However, the low concentration of estrogens in females makes it unlikely that they exhibit significant antioxidant capacity in the organism. Therefore we studied the mechanisms enabling estradiol to be antioxidant at physiological levels. Our results show that physiological concentrations of estrogens activate estrogen receptors and the MAPK and NFKB pathway. Activation of NFkB by estrogens subsequently activates the expression of Mn-SOD and GPx. Moreover, we have demonstrated that genistein, the most abundant phytoestrogen in soya, reproduces the antioxidant effect of estradiol at nutritionally relevant concentrations by the same mechanism, both in healthy ageing and in Alzheimer's disease. We conclude that estrogens and phytoestrogens up-regulate expression of antioxidant enzymes via the estrogen receptor and MAPK activation, which in turn activate the NFkB signalling pathway, resulting in the up-regulation of the expression of longevity-related genes.
authors.affiliation: Department of Physiology, Valencia, Spain. jose.vina@uv.es
authors.forename: Jose
authors.initials: J
authors.lastname: Vina
authors.forename: Juan
authors.initials: J
authors.lastname: Gambini
authors.forename: Raul
authors.initials: R
authors.lastname: Lopez-Grueso
authors.forename: Khira M
authors.initials: KM
authors.lastname: Abdelaziz
authors.forename: Mariona
authors.initials: M
authors.lastname: Jove
authors.forename: Consuelo
authors.initials: C
authors.lastname: Borras
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D005260:Female; D006801:Humans; D008017:Life Expectancy; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D048789:Phytoestrogens / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: D000975:Antioxidants; D004967:Estrogens; D048789:Phytoestrogens; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen