Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk

卵巢衰老和心血管风险的纵向评估

• 批准号: 9310311
• 负责人: MARCELLE Ivonne CEDARS
• 金额: $ 137.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310311
• 关键词: Address; Affect; Age; Aging; Appearance; Area; Awareness; Behavioral; Biological Markers; C-reactive protein; Cardiac; Cardiovascular Diseases; Cell Aging; Chronology; Communities; Diagnosis; Disease; Early identification; Emotional; Estrogens; Ethnic Origin; Evaluation; F2-Isoprostanes; Functional disorder; Genetic Risk; Health; Infertility; Inflammation; Intercellular adhesion molecule 1; Interleukin-6; Isoprostanes; Lead; Length; Leukocytes; Measures; Mediating; Mediation; Menopause; Menstrual cycle; Methods; Microvascular Dysfunction; Mitochondria; Mitochondrial DNA; Modeling; Oocytes; Ovarian; Ovary; Oxidative Stress; Pattern; Peripheral; Plasma; Population; Population Heterogeneity; Predisposition; Pregnancy; Premature Menopause; Prevention; Process; Public Health; Race; Reproductive History; Risk; Risk Factors; Risk Marker; Risk Reduction; Socioeconomic Status; Somatic Cell; System; Telomere Shortening; Testing; Time; Woman; Women' s Health; aged; aging population; base; cardiovascular disorder risk; cardiovascular risk factor; cohort; ethnic disparity; ethnic diversity; high risk population; improved; indexing; mitochondrial dysfunction; novel; novel strategies; psychosocial; reproductive; reproductive function; telomere

ABSTRACT Despite significant improvements in prevention and treatment of cardiovascular disease (CVD), the growing aging population suggests CVD will continue to pose a significant public health burden. Women are a special group where microvascular disease is more common and traditional risk factors may not fully identify risk. Women's reproductive history (e.g. menarcheal age, menstrual cycles, infertility, pregnancy, menopause) may pose unique risk and suggests an opportunity for new approaches. We propose a women-centered approach for early identification of women at risk that investigates the unique loss of reproductive function at an age long before other vital systems fail. Despite the importance of this process, little is known about the determinants or correlates of ovarian aging, or the health implications, especially in diverse populations. With reliable bio-markers of the remaining oocyte pool available, we have a unique opportunity to characterize the association between “ovarian age” and the health implications of accelerated oocyte loss. We hypothesize a risk independent of the well-known impact of early menopause and estrogen deficiency. Rather, we propose that common underlying cellular aging mechanisms, first evident in the ovary due to its sensitivity and earlier demise, make the ovary a window on underlying somatic health. Confirming an association between a decline in markers of ovarian age and CVD risk would allow a potentially high-risk population to be identified decades before traditional risk factors develop. The Ovarian Aging (OVA) cohort is the largest and most ethnically diverse, community-based cohort available that can be used to determine the race/ethnic and behavioral determinants of ovarian aging and its association with CVD risk in a young cycling population. To assess the relationship between markers of ovarian age (reflecting past exposures and genetic risk), the rate of ovarian aging (representing current exposures) and CVD risk, we propose to: 1. Determine whether markers of ovarian age/aging are associated with increased CVD risk by testing if ovarian age/aging is independently associated with increased CVD risk, as measured by peripheral endothelial function testing; 2. Determine whether ovarian aging may moderate or mediate established associations between race/ethnicity and/or socio/emotional health and CVD risk by examining whether observed race/ethnic disparities, or effects of socio/emotional health, on CVD risk, may vary by (moderation model) or be partially attributable to (mediation model) ovarian aging; and 3. Determine whether ovarian aging, CVD risk, and the temporal pattern of appearance correlate with markers of cellular aging: telomere length and mtDNA in peripheral leukocytes, oxidative stress (plasma F2α-isoprostanes), and indices of inflammation (C-reactive protein, interleukin- 6, and soluble intercellular adhesion molecule-1). Overall Impact: Our novel longitudinal approach to evaluating markers of ovarian and cellular aging as predictors of CVD could lead to a new way to identify women at earlier and/or increased CVD risk and be used to develop new risk-reduction strategies.

抽象的 尽管心血管疾病（CVD）的预防和治疗显着改善，但增长 人口老龄化表明，CVD将继续造成巨大的公共卫生伯恩。女人很特别 微血管疾病更常见的组，传统的风险因素可能无法完全识别风险。 妇女的生殖历史（例如初始化年龄，月经周期，不育，怀孕，蒙诺普斯） 带来独特的风险，并为新方法提供了机会。我们建议以女性为中心的方法 为了早日确定有风险的妇女，该妇女在年龄段研究了独特的生殖功能丧失 在其他重要系统失败之前很久。尽管这一过程很重要，但对 卵巢衰老或健康影响的决定因素或相关性，尤其是在潜水员人群中。和 可靠的剩余卵母细胞池的可靠生物标志物，我们有一个独特的机会来表征 “卵巢时代”与加速卵母细胞损失的健康影响之间的关联。我们假设一个 风险与早期更年期和雌激素缺乏的众所周知的影响无关。相反，我们 提出的普通潜在细胞衰老机制，由于其敏感性而在卵巢中的第一个证据 更早的灭亡，使卵巢成为潜在的躯体健康的窗口。确认协会 卵巢年龄标记和CVD风险的下降将使潜在的高风险人口得以实现 在传统风险因素发展之前，几十年来都可以识别。卵巢老化（OVA）队列是最大的 以及可用的大多数种族潜水员，以社区为基础的队列，可用于确定 卵巢衰老的种族/种族和行为决定者及其与年轻骑行中CVD风险的关联 人口。评估卵巢时代标记之间的关系（反映过去的暴露和遗传 风险），卵巢衰老率（代表当前暴露）和​​CVD风险，我们建议：1。 卵巢年龄/衰老的标记是否与卵巢测试是否与CVD风险增加有关 年龄/衰老与CVD风险增加有关，如周围内皮测量 功能测试； 2。确定卵巢衰老是否可以适度或介导的已建立关联 在种族/种族和/或社会/情绪健康和CVD风险之间检查是否观察到种族/种族 社会/情感健康对CVD风险的差异或影响可能因（适度模型）而有所不同或部分是 归因于（调解模型）卵巢老化；和3。确定卵巢衰老，CVD风险和是否是否 外观的临时模式与细胞衰老的标记相关：端粒长度和mtDNA 外周白细胞，氧化应激（等离子体F2α-异丙烷）和炎症指标（C反应性 蛋白质，白细胞介素6和固体间细胞间粘合分子-1）。总体影响：我们的小说纵向 评估卵巢和细胞衰老标志物作为CVD的预测因子的方法可能导致一种新的方法 确定较早和/或增加CVD风险的妇女，并用于制定新的降低风险策略。