Department of Biological Sciences, Integrative Biosciences Center (IBio), Wayne State University, Detroit, Michigan, USA.
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, USA.
J Gerontol A Biol Sci Med Sci. 2022 Jan 7;77(1):66-74. doi: 10.1093/gerona/glab216.
17-α-Estradiol (17aE2) treatment from 4 months of age extends life span 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 life-span regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are affected by gonadal removal and whether hypothalamic changes extend to other brain regions in old age. We show that sex-specific effects of 17aE2 on age-associated gliosis are brain region specific and are partially dependent on gonadectomy. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration before 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis in males. In contrast, sex-specific inhibition of microgliosis generated by 17aE2 was not significantly affected by castration. In the hippocampus, gonadectomy influenced the severity of gliosis and the responsiveness to 17aE2 in a region-dependent manner. The male-specific effects of 17aE2 correlate with increases in hypothalamic estrogen receptor alpha expression, specifically in gonadally intact males, consistent with the idea that 17aE2 might act through this receptor. Our results indicate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Loss of gonadal function and age-associated neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in both aging and in response to drugs that modify the pace of aging.
17-α-雌二醇（17aE2）从 4 个月大开始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 可延长雄性寿命，但雌性小鼠不受影响，这表明寿命调节存在性别二态模式。我们测试了 17aE2 对神经炎症反应的性别特异性影响是否受性腺切除的影响，以及下丘脑的变化是否会在老年时扩展到大脑的其他区域。我们发现，17aE2 对与年龄相关的神经胶质增生的性别特异性影响具有大脑区域特异性，并且部分依赖于性腺切除术。从 4 个月大开始的 17aE2 治疗可保护 25 个月大的雄性免受下丘脑炎症的影响。在暴露于 17aE2 之前进行去势会降低 17aE2 对雄性下丘脑星形胶质增生的作用。相比之下，17aE2 产生的性别特异性小胶质细胞增生抑制作用不受去势的显著影响。在海马体中，性腺切除术以依赖于区域的方式影响神经胶质增生的严重程度和对 17aE2 的反应。17aE2 的雄性特异性作用与下丘脑雌激素受体 α 表达的增加相关，特别是在性腺完整的雄性中，这与 17aE2 可能通过该受体起作用的观点一致。我们的结果表明，17aE2 对神经炎症反应的影响部分受性别特异性性腺的控制。性腺功能丧失和与年龄相关的神经炎症可能会影响晚年的健康和疾病发作，从而导致衰老和对改变衰老速度的药物的反应中出现性别二态性。
