Research Project
10294797
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 17?-estradiol (17?-E2). 17?-E2 is a diastereomer of 17?-estradiol (17?-E2) with considerably less binding affinity for classical estrogen receptors than 17?-E2. The NIA Interventions Testing Program has shown that 17?-E2 extends lifespan in male, but not female, mice at two doses. The mechanisms that promote sexually divergent responses to 17?-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 17?-E2 modulates aging and metabolism in a sex-specific manner. Successful completion of this project will determine: 1) if estrogen receptor ? (ER?) is required for 17?-E2 to elicit benefits on healthspan, disease pathology, and lifespan, 2) if 17?-E2 modulates metabolic parameters predominantly through hypothalamic ER?-mediated signaling, 3) if the beneficial effects of 17?-E2 on metabolic parameters can be mimicked by activating hypothalamic ER? through chemogenetic approaches, and 4) if the elimination of endogenous estrogen production render female mice responsive to 17?-E2-mediated effects on metabolism, and if this is ER? dependent. We hypothesize that 17?- E2 signals through ER? 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 17?-E2 in an ER?-dependent manner. Aim 1: Determine if 17?-E2 improves healthspan and lifespan in an ER?-dependent manner. We will evaluate the effects of chronic 17?-E2 treatment on indices of healthspan and lifespan in wild-type and global ER?KO mice. Aim 2: Determine if 17?- E2 elicits metabolic benefits through ER? in the hypothalamus. We will evaluate the effects of 17?-E2 treatment on metabolic and healthspan parameters in mice with a hypothalamus-specific deletion of ER? using stereotaxic delivery of adeno-associated virus (AAV) that drives expression of Cre in ER?-flox mice. Aim 3: Determine if chemogenetic activation of hypothalamic ER?-expressing cells can mimic the health benefits observed with 17?- E2 treatment. We will evaluate the effects of stimulating hypothalamic ER?-expressing cells on metabolic and healthspan outcomes via site-specific expression of AAV Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in ER?-flox mice. Aim 4: Determine if the elimination of endogenous estrogen production renders female mice responsive to 17?-E2 treatment. We will evaluate the effects of 17?-E2 treatment on metabolic and healthspan parameters in wild-type and global ER?KO 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.
