Role of estrogen receptor-a in aging and sex-specific responses to 17a-estradiol

项目总结/摘要 几种药理学化合物已显示出作为延长寿命的干预策略的前景。 最近研究的一种化合物显示，改善健康和长寿是17α-雌二醇（17α-E2）。17α-雌二醇 是17β-雌二醇（17β-E2）的非对映异构体，与经典雌激素受体的结合亲和力显著降低 17β-E2 NIA干预测试计划表明，17α-E2可以延长男性的寿命， 雌性，两种剂量的小鼠。促进对17α-E2的性分化反应的机制很差 人们越来越认识到，衰老和特定疾病的发病率 在性别之间往往不同。本项目将探索17α-E2调节衰老的潜在机制 和新陈代谢的能力。这个项目的成功完成将决定：1）如果雌激素 受体α（ERα）是17α-E2所必需的，以引起对健康寿命、疾病病理学和寿命的益处，2）如果 17α-E2主要通过下丘脑ERα介导的信号传导调节代谢参数，3）如果 17α-E2对代谢参数的有益作用可以通过激活下丘脑ERα来模拟， 化学遗传学方法，以及4）如果消除内源性雌激素产生使雌性小鼠 对17α-E2介导的代谢效应有反应，如果这是ERα依赖性的。我们假设17α- 在雄性小鼠中，E2通过ERα传递信号，以增强健康和长寿，这些作用至少是 部分通过下丘脑介导。我们还假设缺乏内源性激素的雌性小鼠 雌激素将以ERα依赖性方式对17α-E2产生有益的反应。目的1：确定17α-E2是否 以ERα依赖的方式改善健康和寿命。我们将评估慢性17α-E2 治疗对野生型和整体ERαKO小鼠的健康寿命和寿命指数的影响。目的2：确定17α- E2通过下丘脑中的ERα促进代谢益处。我们将评估17α-E2治疗的效果 对使用立体定位仪检测下丘脑特异性ERα缺失小鼠的代谢和健康寿命参数的影响 在ERα-flox小鼠中递送驱动Cre表达的腺相关病毒（AAV）。目标3：确定是否 下丘脑ERα表达细胞的化学发生激活可以模拟17α- E2治疗。我们将评估刺激下丘脑ERα表达细胞对代谢和 通过AAV Gq偶联的设计者受体的位点特异性表达的健康跨度结果 在ERα-flox小鼠中通过Designer Drugs（DREADDs）。目的4：确定是否消除内源性雌激素 生产使雌性小鼠对17α-E2治疗有反应。我们将评估17α-E2治疗的效果 对接受卵巢切除术的野生型和全局ERαKO雌性小鼠的代谢和健康寿命参数的影响 或4-乙烯基环己烯二环氧诱导的卵巢功能不全。这项研究的最终目标是开发 针对性别的药物干预，以减轻衰老和慢性疾病。

PROJECT SUMMARY/ABSTRACT Several pharmacological compounds have shown promise as interventional strategies for extending longevity. One recently studied compound shown to improve healthspan and longevity is 17α-estradiol (17α-E2). 17α-E2 is a diastereomer of 17β-estradiol (17β-E2) with considerably less binding affinity for classical estrogen receptors than 17β-E2. The NIA Interventions Testing Program has shown that 17α-E2 extends lifespan in male, but not female, mice at two doses. The mechanisms that promote sexually divergent responses to 17α-E2 are poorly understood and are aligned with the increasing recognition that aging and the incidence of specific diseases often differ between the sexes. This project will explore potential mechanisms by which 17α-E2 modulates aging and metabolism in a sex-specific manner. Successful completion of this project will determine: 1) if estrogen receptor α (ERα) is required for 17α-E2 to elicit benefits on healthspan, disease pathology, and lifespan, 2) if 17α-E2 modulates metabolic parameters predominantly through hypothalamic ERα-mediated signaling, 3) if the beneficial effects of 17α-E2 on metabolic parameters can be mimicked by activating hypothalamic ERα through chemogenetic approaches, and 4) if the elimination of endogenous estrogen production render female mice responsive to 17α-E2-mediated effects on metabolism, and if this is ERα dependent. We hypothesize that 17α- E2 signals through ERα in male mice to enhance healthspan and longevity and that these effects are at least partially mediated through the hypothalamus. We also hypothesize that female mice lacking endogenous estrogens will beneficially respond to 17α-E2 in an ERα-dependent manner. Aim 1: Determine if 17α-E2 improves healthspan and lifespan in an ERα-dependent manner. We will evaluate the effects of chronic 17α-E2 treatment on indices of healthspan and lifespan in wild-type and global ERαKO mice. Aim 2: Determine if 17α- E2 elicits metabolic benefits through ERα in the hypothalamus. We will evaluate the effects of 17α-E2 treatment on metabolic and healthspan parameters in mice with a hypothalamus-specific deletion of ERα using stereotaxic delivery of adeno-associated virus (AAV) that drives expression of Cre in ERα-flox mice. Aim 3: Determine if chemogenetic activation of hypothalamic ERα-expressing cells can mimic the health benefits observed with 17α- E2 treatment. We will evaluate the effects of stimulating hypothalamic ERα-expressing cells on metabolic and healthspan outcomes via site-specific expression of AAV Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in ERα-flox mice. Aim 4: Determine if the elimination of endogenous estrogen production renders female mice responsive to 17α-E2 treatment. We will evaluate the effects of 17α-E2 treatment on metabolic and healthspan parameters in wild-type and global ERαKO female mice undergoing ovariectomy or 4-vinylcyclohexene diepoxide-induced ovarian insufficiency. The ultimate goal of this research is to develop sex-specific pharmacological interventions for attenuating aging and chronic diseases.