Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
Departments of Medicine & Pharmacology, University of California San Diego, San Diego, California.
Aging Cell. 2018 Aug;17(4):e12786. doi: 10.1111/acel.12786. Epub 2018 May 27.
Longevity in mammals is influenced by sex, and lifespan extension in response to anti-aging interventions is often sex-specific, although the mechanisms underlying these sexual dimorphisms are largely unknown. Treatment of mice with 17-α estradiol (17aE2) results in sex-specific lifespan extension, with an increase in median survival in males of 19% and no survival effect in females. Given the links between lifespan extension and metabolism, we performed untargeted metabolomics analysis of liver, skeletal muscle and plasma from male and female mice treated with 17aE2 for eight months. We find that 17aE2 generates distinct sex-specific changes in the metabolomic profile of liver and plasma. In males, 17aE2 treatment raised the abundance of several amino acids in the liver, and this was further associated with elevations in metabolites involved in urea cycling, suggesting altered amino acid metabolism. In females, amino acids and urea cycling metabolites were unaffected by 17aE2. 17aE2 also results in male-specific elevations in a second estrogenic steroid-estriol-3-sulfate-suggesting different metabolism of this drug in males and females. To understand the underlying endocrine causes for these sexual dimorphisms, we castrated males and ovariectomized females prior to 17aE2 treatment, and found that virtually all the male-specific metabolite responses to 17aE2 are inhibited or reduced by male castration. These results suggest novel metabolic pathways linked to male-specific lifespan extension and show that the male-specific metabolomic response to 17aE2 depends on the production of testicular hormones in adult life.
哺乳动物的寿命受性别影响，而抗衰老干预措施所延长的寿命通常具有性别特异性，尽管这些性别二态性的机制在很大程度上尚不清楚。用 17-α 雌二醇（17aE2）治疗小鼠会导致性别特异性的寿命延长，雄性的中位生存期延长 19%，而雌性则没有生存效果。鉴于寿命延长与代谢之间的联系，我们对接受 17aE2 治疗 8 个月的雄性和雌性小鼠的肝脏、骨骼肌和血浆进行了非靶向代谢组学分析。我们发现，17aE2 在肝脏和血浆的代谢组学图谱中产生了独特的性别特异性变化。在雄性中，17aE2 治疗使肝脏中几种氨基酸的丰度升高，这与参与尿素循环的代谢物升高进一步相关，表明氨基酸代谢发生了改变。在雌性中，17aE2 处理对氨基酸和尿素循环代谢物没有影响。17aE2 还导致雄性特有的雌激素类固醇-雌三醇-3-硫酸盐水平升高，这表明这种药物在雄性和雌性中的代谢方式不同。为了了解这些性别二态性的潜在内分泌原因，我们在 17aE2 治疗前对雄性进行了去势，对雌性进行了卵巢切除术，发现 17aE2 对雄性特有的几乎所有代谢物反应都被雄性去势抑制或减少。这些结果表明与雄性特有的寿命延长相关的新的代谢途径，并表明 17aE2 对雄性特有的代谢组学反应取决于成年期睾丸激素的产生。
