Sex Hormones, Aging, Alzheimer's Disease and Other Neurodegenerative Diseases in Women

摘要 随着一般人口的老龄化，了解有助于长寿、健康老龄化和 残疾是最重要的。性激素（SH）已被假设为可能的原因之一， 在寿命和神经退行性疾病（ND）方面的性别差异。13 SH，特别是雌激素， 孕酮和睾酮）在动物和细胞系研究中显示出神经保护作用，14-16， 阿尔茨海默病、17-24帕金森病、25-29和亨廷顿病的疾病相关动物模型 疾病30 -35以前的研究分析了性激素（生殖史或激素）的影响 代谢基因）对ND和人类寿命的观察性研究尚未得出结论。36-104也 分析绝经后激素治疗是否具有 105 -113因此，SH对长寿和ND的作用仍然是难以捉摸的。 该项目的目标是分析性激素与表观遗传衰老和年龄之间的关联- 相关的神经退行性疾病。该项目分为三个目标。在第一个目标中， 预测SH水平的方法将使用全基因组遗传学，大规模甲基化数据， 基于数据库的信息。在第二个目标中，测量的SH和SH预测分数将被 与表观遗传年龄有关已知表观遗传年龄与死亡率密切相关，因此， 是估计寿命的可靠指标。114，115在第三个目标中， 和帕金森病）以及发病年龄（阿尔茨海默病、帕金森病和亨廷顿舞蹈病 疾病），将与基于第一目标的SH预测评分相关联。最后，假设 在目标2和3中确定了关联，调解分析将作为潜在的子目标进行， 分析表观遗传老化是否可以部分解释性激素和ND之间的关联。到 确保统计能力以及验证和复制结果的能力，几个大型观测数据集 将用于这些研究和方法将从不同角度解决性激素的作用， 将有助于三角证据，并为未来的研究提供潜在的治疗靶点。 通过遗传学、表观遗传学和流行病学方面的几位专家的培训和合作， 分析，申请人将获得专业知识，以解开其中一些问题，并有助于老化， 神经退行性疾病相关的发现。最大限度地利用跨学科方法， 遗传学，表观遗传学，流行病学，生物统计学和神经学的考虑，将产生广泛的 独立研究。

Abstract As the general population ages, understanding the factors that contribute to longevity, healthy aging, and disability is paramount. Sex hormones (SH) have been hypothesized to be one of the possible reasons for the gender difference in both longevity and neurodegenerative disorders (ND).13 SH, specifically estrogen, progesterone and testosterone) have shown neuroprotective effects in animal and cell-line studies,14–16 and in disease-related animal models for Alzheimer’s Disease,17–24 Parkinson’s Disease,25–29 and Huntington’s Disease.30–35 Previous studies analyzing the effect of sex hormones (reproductive history or hormone metabolizing genes) on ND and longevity in human observational studies have been inconclusive. 36–104 Also inconsistent have been the clinical trials that analyzed whether postmenopausal hormone therapy had a positive effect on ND.105–113 Hence, the role of SH on longevity and ND remain elusive. The goal of this project is to analyze the association between sex hormones and epigenetic aging and age- related neurodegenerative diseases. The project is divided into three aims. In the first aim, three different methods to predict SH levels will be created using whole genome genetics, large-scale methylation data, and questionnaire-based information. In the second aim, both measured SH and SH predictive scores will be associated with epigenetic age. Epigenetic age is known to be strongly associated with mortality and therefore, is a robust measure to estimate longevity.114,115 In the third aim, the development of ND (Alzheimer’s disease and Parkinson’s disease), as well as age of onset (Alzheimer’s disease, Parkinson’s disease and Huntington’s disease), will be associated with the SH predictive scores based on the first aim. Finally, assuming an association was identified in aims 2 and 3, mediation analysis will be performed as a potential sub-aim to analyze whether epigenetic aging can partially explain the association between sex hormones and ND. To ensure statistical power and the ability to verify and replicate the findings, several large observational datasets will be used. These studies and approaches will address the role of sex hormones from various angles, and will help to triangulate evidence and inform future research into potential therapeutic targets. With training from, and collaborations with several experts in genetic, epigenetic, and epidemiological analyses, the applicant will gain expertise to unlock some of these questions and contribute to aging and neurodegenerative disease-related discoveries. Maximizing an interdisciplinary approach, incorporating genetics, epigenetics, epidemiology, biostatistics and neurology considerations, will generate a broad range of independent research.