Aging and Estrogenic Control of the Bioenergetic System in Brain

我们早期对雌激素在大脑中作用的机制分析导致发现雌激素是主宰。 大脑中生物能量系统的调节器，促进葡萄糖的运输，葡萄糖代谢， 线粒体呼吸和三磷酸腺苷的生成。总的来说，这些数据为雌激素提供了令人信服的证据。 作为系统生物学在脑中的代谢调节器，阐明了与 一个正在挨饿的老化女性大脑。雌激素作为生物能量系统的主要调节器发挥作用 在女性大脑中，雌激素必须整合核和线粒体基因组反应。更远的距离 从系统水平的角度来看，雌激素也有必要调节细胞质信号 实时反馈核和线粒体基因转录功能结果的机制。 要研究的基本问题是雌激素结合生物能量的机制。 跨两个基因组隔间的响应，同时监控能量需求和 实时性能。拟议的研究计划旨在检验两个假设。第一, 雌激素控制女性大脑中的生物能量系统需要：1)核和线粒体 基因组；2)跨基因组区段的基因表达的整合；3)快速激活 信号级联以提供对生物能量性能的实时反馈。第二，我们假设 衰老女性大脑中雌激素的丢失导致核内雌激素调控的系统性解体 线粒体基因组随之而来的是生物能量感知机制的下降。雌激素的调控作用 脑的生物能量系统及其拆解具有基础性、转化性和临床意义。 从发现的角度来看，提出的研究方案在探索机制方面是独一无二的 核和线粒体基因表达的雌激素整合及其实时反馈 控制大脑生物能量系统的机制。此外，这种控制的过程 系统解体在老年女性大脑中是未知的领域，对理解具有很高的意义 大脑中的生物能量老化。翻译过来，就是确定系统性拆解背后的机制 脑内生物能量室雌激素整合的研究具有检测治疗靶点的潜力 在老化的女性大脑中维持生物能量功能。临床上，更年期的衰老过渡，是独一无二的 女性，是一个同时破坏大脑的生殖能力和潜在的生物能量能力的过程。 这尤其与年龄相关的神经系统疾病与葡萄糖缺乏有关。 低代谢症，如阿尔茨海默氏症、抑郁症和多发性硬化症，在 绝经后的女性。本文建议的研究符合NIA战略研究目标A和C以及 “需要更好地区分大脑老化的模式”https://www.nia.nih.gov/about/living-long-well-21st- 世纪-战略方向-研究-老龄化和妇女健康研究办公室的目标。

Our earlier mechanistic analyses of estrogen action in brain led to the discovery that estrogen is a master regulator of the bioenergetic system in brain that promotes glucose transport, glucose metabolism, mitochondrial respiration and ATP generation. Collectively, the data provided compelling evidence for estrogen as a systems biology metabolic regulator in brain and illuminated compensatory mechanisms consistent with an aging female brain that is starving. For estrogen to function as master regulator of the bioenergetic system in the female brain, estrogen must be integrating nuclear and mitochondrial genomic responses. Further from a systems level perspective, it would be necessary for estrogen to also regulate cytoplasmic signaling mechanisms for real time feedback on the functional outcomes of nuclear and mitochondrial gene transcription. The fundamental issues to be investigated are the mechanisms whereby estrogen integrates bioenergetic responses across two genomic compartments while simultaneously monitoring energetic demand and performance in real time. The proposed program of research is designed to test two hypotheses. First, estrogenic control of the bioenergetic system in the female brain requires: 1) both nuclear and mitochondrial genomes; 2) integration of gene expression across both genomic compartments and 3) activation of rapid signaling cascades to provide real time feedback on bioenergetic performance. Second, we hypothesize that loss of estrogen in the aging female brain leads to a systematic dis-integration of estrogenic control of nuclear and mitochondrial genomes followed by decline in bioenergetic sensing mechanisms. Estrogenic control of the bioenergetic system of the brain and the dismantling thereof has basic, translational and clinical significance. From a discovery perspective the proposed program of research is unique in exploring the mechanisms underlying estrogenic integration of nuclear and mitochondrial gene expression and the real time feedback mechanisms that control the bioenergetic system of the brain. Further, the process by which this control system is dismantled in the aging female brain is uncharted territory of high significance for understanding bioenergetic aging in brain. Translationally, determining the mechanisms underlying the systematic dismantling of estrogenic integration of bioenergetic compartments in brain has the potential to detect therapeutic targets to sustain bioenergetic function in the aging female brain. Clinically, the aging transition of menopause, unique to the female, is a process that dismantles both reproductive ability and potentially bioenergetic capacity in brain. This is particularly relevant to age-related neurological conditions associated with deficits in glucose hypometabolism such as Alzheimer's, depression and multiple sclerosis which have greater prevalence in postmenopausal women. Research proposed herein aligns with NIA Strategic Research Goals A and C and the “need to better distinguish patterns of brain aging” https://www.nia.nih.gov/about/living-long-well-21st- century-strategic-directions-research-aging and to objectives of Office of Research on Women's Health.