17-α-estradiol (17aE2) treatment extends lifespan in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of lifespan regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are mediated by sex hormones and whether hypothalamic changes extend to other brain regions in old age. Manipulating sex hormone levels through gonadectomy, we show that sex-specific effects of 17aE2 on age-associated gliosis are brain region-specific and are partially dependent on gonadal hormone production. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration prior to 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis. By contrast, sex-specific changes in microgliosis with 17aE2 were not significantly affected by castration in males. While 17aE2 treatment had no effect of hypothalamic astrocytes or microglia in intact females, ovariectomy significantly increased the occurrence of hypothalamic gliosis evaluated in 25-month-old females, which was partially reduced by 17aE2. In the hippocampus, both male and female gonadally-derived hormones influenced the severity of gliosis and the responsiveness to 17aE2 in a region-dependent manner. The male-specific effects of 17aE2 correlate with changes in hypothalamic ERα expression, highlighting a receptor through which 17aE2 could act. The results of this study demonstrate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex‐specific gonads. Interactions between sex-steroids and neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in aging.

中文翻译：

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潜在的17a-雌二醇性激素对神经炎症的影响。

17-α-雌二醇（17aE2）治疗可延长雄性小鼠的寿命，并可减少12个月大雄性小鼠下丘脑的神经炎症反应。尽管17aE2可以提高雄性的寿命，但雌性小鼠却不受影响，这表明其寿命调控具有性二态性。我们测试了17aE2对神经炎症反应的性别特异性作用是否由性激素介导，以及下丘脑变化是否在老年时扩展到其他大脑区域。通过性腺切除术控制性激素水平，我们显示17aE2对与年龄相关的神经胶质变性的性别特异性作用是脑区域特异性的，部分取决于性腺激素的产生。17aE2治疗始于4个月大，可保护25个月大的男性免于下丘脑发炎。在暴露于17aE2之前去势可降低17aE2对下丘脑星形胶质增生的影响。相比之下，男性去势不明显影响17aE2引起的小胶质细胞变性。尽管17aE2治疗对完整女性没有下丘脑星形胶质细胞或小胶质细胞的作用，但卵巢切除术显着增加了25个月大女性的下丘脑神经胶质增生的发生率，但17aE2部分降低了这种效果。在海马中，雄性和雌性性腺源性激素均以区域依赖的方式影响神经胶质的严重程度和对17aE2的反应性。17aE2的男性特异性作用与下丘脑ERα表达的变化相关，突出了17aE2可以通过其起作用的受体。这项研究的结果表明，对17aE2的神经炎症反应部分受到性别特异性性腺的控制。因此，性类固醇与神经炎症之间的相互作用可能影响晚年的健康状况和疾病发作，从而导致衰老中的性二态性。