Department of Physiology, Valencia, Spain.
Curr Pharm Des. 2011 Dec 1;17(36):3959-65. doi: 10.2174/138161211798764942.
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.
二十世纪最显著的成就之一是人类寿命的延长。在任何研究的时期，女性的寿命都比男性长。我们表明，线粒体氧化应激在男性中比女性更高，而女性中更高水平的雌激素通过上调抗氧化、与长寿相关的基因的表达来保护她们免受衰老的影响。雌二醇的化学结构赋予了该分子抗氧化特性。然而，女性体内雌激素的浓度较低，使得它们不太可能在体内表现出显著的抗氧化能力。因此，我们研究了使雌二醇在生理水平具有抗氧化作用的机制。我们的研究结果表明，生理浓度的雌激素激活雌激素受体和 MAPK 和 NFKB 途径。雌激素激活 NFkB 随后激活 Mn-SOD 和 GPx 的表达。此外，我们已经证明，大豆中最丰富的植物雌激素染料木黄酮通过相同的机制，在健康衰老和阿尔茨海默病中，以营养相关的浓度复制了雌二醇的抗氧化作用。我们的结论是，雌激素和植物雌激素通过雌激素受体和 MAPK 激活来上调抗氧化酶的表达，这反过来又激活了 NFkB 信号通路，导致与长寿相关的基因表达上调。
