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

项目摘要/摘要 几种药理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是17α-雌二醇(17α-E2)，可以延长健康寿命和寿命。17α-E2 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较低 高于17β-E_2。NIA干预测试计划显示，17α-E2延长了男性的寿命，但不是 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 理解并赞同日益认识到的老龄化和特定疾病的发病率 通常不同性别之间的差异。该项目将探索17α-E2调节衰老的潜在机制 并以性别特有的方式进行新陈代谢。这个项目的成功完成将决定：1)雌激素是否 受体α(ERα)是17α-E2所必需的，才能在健康、疾病病理和寿命方面产生益处，2)如果 17α-E2主要通过下丘脑ERα介导的信号调节代谢参数，3)如果 17α-E_2对代谢参数的有益影响可通过激活下丘脑ER-α来模拟 化学遗传学方法，以及4)如果内源性雌激素产生的消除使雌性小鼠 反应17α-E_2对代谢的影响，如果这是ERα依赖的。我们假设17α- 雌二醇通过ERα在雄性小鼠体内发出信号，以延长健康寿命和寿命，这些影响至少是 部分通过下丘脑进行调节。我们还假设雌性小鼠缺乏内源性 雌激素将以ER-α依赖的方式对17α-E2作出有益的反应。目标1：确定17α-E2是否 以ERα依赖的方式提高健康寿命和寿命。我们将评估慢性17α-E2的疗效 野生型和整合型ERαKO小鼠健康寿命和寿命指标的治疗。目标2：确定17α- 雌二醇通过下丘脑中的ERα产生代谢益处。我们将评估17α-E_2治疗的效果 立体定向法研究下丘脑特异性ERα缺失小鼠的代谢和健康跨度参数 递送腺相关病毒在ERα-FLOX小鼠中驱动Cre表达。目标3：确定是否 下丘脑ERα表达细胞的化学激活可以模拟17α的健康益处 雌二醇组。我们将评估刺激下丘脑ERα表达细胞对代谢和 AAV GQ偶联设计者受体专属激活部位特异性表达对健康的影响 由设计药物(DREADD)在ERα-FLOX小鼠中使用。目的4：确定内源性雌激素的消除 生产使雌性小鼠对17α-E2处理有反应。我们将评估17α-E_2治疗的效果 卵巢摘除后野生型和整体型ERαKO雌性小鼠代谢和健康跨度参数的研究 或4-乙烯基环己烯二环氧化物引起的卵巢功能不全。这项研究的最终目标是发展 针对性别的延缓衰老和慢性病的药物干预。

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.