Sex-Specific Effects of Endocrine Disruption on Aging and Alzheimer's Disease

总体：总结/摘要Michelle M. Mielke博士 与年龄相关的身体和认知能力下降以及阿尔茨海默病（AD）是影响男性的疾病 和女性在生命周期中的不同。这些都有重要的性别差异 疾病，包括风险因素、表现、治疗反应、发病率和死亡率。的 马约诊所性研究卓越专业中心（SCORE）的首要主题 差异是探讨卵巢激素突然丢失，造成双侧输卵管卵巢切除术 (BSO)在自然绝经前，影响整体衰老、身体和认知功能以及AD风险 病理生理学考虑到大量有绝经前BSO病史的老年妇女， 迫切需要了解长期的身体和认知结果。另外，我们需要新的证据 赋予考虑预防性BSO的妇女权力，使其在未来做出更明智的决定。中央 我们SCORE更新的假设是，绝经前BSO引起的突然内分泌干扰将 加速病理性衰老过程，表现为身体和认知功能的下降， AD病理生理学。这一假设将通过三个相互关联的翻译项目进行检验， 由三个相互依赖的核心支持。我们的跨学科翻译方法， （项目1和2）和小鼠（项目3）提供了基础：1）建立突然内分泌的影响， 2）对所涉及的生物机制有更全面的了解，3） 设计有针对性的方法来识别和减轻不良后果，4）设计未来的研究， 机械地测试靶向衰老细胞是否减轻了这些细胞中加速老化的影响， 5）赋予考虑预防性BSO的妇女权力，使其做出更明智的决定。我们严格的 通过领导行政核心，由经验丰富的领导团队， 资源支持核心-临床，将为参与者提供财务和运营效率 招聘，并通过职业提升核心，将提供职业充实，领导力培训， 资助主要项目的辅助研究。这些资源会激发人们对性的新兴趣 差异和妇女健康。马约诊所SCORE将作为教育和 传播基于性别的创新转化研究方法、成果和最佳做法。我们 研究、培训和教育的综合方法与性行为评分的目标一致 RFA的差异，并通过培训确保在妇女健康和性别差异领域继续进行研究 未来的劳动力。

OVERALL: SUMMARY/ABSTRACT Michelle M. Mielke, Ph.D. Aging-associated physical and cognitive decline and Alzheimer's disease (AD) are conditions that affect men and women differently across their lifespan. There are important sex and gender differences for these conditions, including risk factors, manifestations, response to treatments, morbidity, and mortality. The overarching theme of the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences is to investigate how abrupt loss of ovarian hormones, caused by bilateral salpingo-oophorectomy (BSO) prior to natural menopause, affects overall aging, physical and cognitive function, and risk for AD pathophysiology. Given the large number of aging women with a history of premenopausal BSO, there is an urgent need to understand the long-term physical and cognitive outcomes. In addition, we need new evidence to empower women considering prophylactic BSO to make more informed decisions in the future. The central hypothesis of our SCORE renewal is that the abrupt endocrine disruption caused by premenopausal BSO will accelerate pathological aging processes that manifest as reductions in physical and cognitive function and in AD pathophysiology. This hypothesis will be tested through three inter-related translational projects, which are supported by three inter-dependent Cores. Our interdisciplinary translational approach using both humans (Projects 1 and 2) and mice (Project 3) provides the foundation to: 1) establish the effects of abrupt endocrine disruption in women, 2) develop a more complete understanding of the biological mechanisms involved, 3) devise a targeted approach to identify and mitigate the adverse outcomes, 4) design future studies to mechanistically test whether targeting senescent cells mitigates the effects of accelerated aging in these women, and 5) empower women considering prophylactic BSO to make more informed decisions. Our rigorous approach is supported by an experienced leadership team through the Leadership Administrative Core, by a Resource Support Core - Clinical that will provide financial and operational efficiency for participant recruitment, and by a Career Enhancement Core that will provide career enrichment, leadership training, and funds to support ancillary studies of the main projects. These resources will stimulate new interest in sex differences and women's health. The Mayo Clinic SCORE will serve as a vital hub for education and dissemination of innovative sex-based translational research methods, results, and best practices. Our integrated approach for research, training, and education is consistent with the goals of the SCORE on Sex Differences RFA, and assures continuing research in areas of women's health and sex differences by training the work force of the future.