Inflammatory Mediators, Cardiovascular Health, and Longevity in Women

项目总结/摘要 慢性炎症，定义为局部和全身促炎因子的持续升高，是一种 生物老化的标志我们和其他人已经表明，循环下游标志物的慢性水平 全身性炎症与年龄相关的疾病状态有关，特别是心血管疾病， 以及长寿。然而，越来越多的证据表明，炎症的上游介质是 更有可能在疾病发病机制中发挥因果作用，并反过来作为有效的治疗靶点。 人类炎症的上游起始主要由花生四烯酸的小分子效应物控制。 酸代谢，称为类二十烷酸。这些具有促炎和抗炎活性的生物活性脂质效应物 包括血栓烷、前列腺素、脂氧素和白细胞三烯。到目前为止，类花生酸与 途径和年龄相关疾病表型仍然知之甚少，从而限制了我们利用 它们的治疗潜力。本提案旨在更详细地了解上游如何 类二十烷酸途径可能是不活跃的、不平衡的，并且与个体的倾向相关地受到干扰， 发展或逃避与年龄有关的疾病。新出现的数据表明，选择类花生酸和遗传 促进其生物合成的酶的多态性特别与心血管疾病相关。 风险以及寿命，但缺乏大规模队列的综合研究。先进的方法使用 质谱法现在可以快速和准确地定量>150种上游类花生酸介质 代表多种酶源。我们将用这些方法综合分析不同的亲- 和抗炎类二十烷酸，并检查它们与健康心血管衰老的测量的关系， 一个大型女性队列的长寿结果，其中包含代表风险谱的个体 因素负担以及一系列实现的寿命。这项研究的目的是促进我们的理解 上游炎症通路如何与女性的健康衰老和长寿相关， 寿命比男性长，但由于仍然存在的原因，在晚年比男性承担更大的慢性疾病负担 不清楚因此，我们的具体目标是：（1）评估循环中的类花生酸介质是否与系统性 炎症与女性长寿有关;（2）评估不同炎症与女性长寿之间的关系。 类花生酸介导的全身性炎症和妇女的发病率概况。我们的系统方法， 全面调查上游炎症活动的组成部分，在一个大的，良好的表型 队列研究有望对健康老龄化和长寿的决定因素产生重要的见解。重要的是， 鉴于其重点是上游炎症活动，这项工作将为后续研究铺平道路， 抗炎疗法（现有的和新的药剂）用于调节不同炎症因子的变化的功效， 类花生酸以及结果。

PROJECT SUMMARY/ABSTRACT Chronic inflammation, defined by a persistent elevation of local and systemic pro-inflammatory factors, is a hallmark of biological aging. We and others have shown that chronic levels of circulating downstream markers of systemic inflammation are associated with age-related disease states, particularly cardiovascular disease, as well as longevity. However, accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis and, in turn, serve as effective therapeutic targets. Upstream initiation of inflammation in humans is governed primarily by small molecule effectors of arachidonic acid metabolism, termed eicosanoids. These bioactive lipid effectors of both pro- and anti-inflammatory activity include thromboxanes, prostaglandins, lipoxins, and leukotrienes. To date, the interaction between eicosanoid pathways and age-related disease phenotypes remain poorly understood, thus limiting our ability to harness their therapeutic potential. This proposal aims to provide a more detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and perturbed in relation to an individual’s propensity for developing or escaping age-related disease. Emerging data suggest that select eicosanoids and genetic polymorphisms in enzymes contributing to their biosynthesis are associated particularly with cardiovascular risk as well as longevity, but comprehensive studies in large cohorts are lacking. Advanced methods using mass spectrometry now allow for the rapid and accurate quantification of >150 upstream eicosanoid mediators representing the multiple enzymatic origins. We will use these methods to comprehensively assay distinct pro- and anti-inflammatory eicosanoids and examine their relation to measures of healthy cardiovascular aging and longevity outcomes in a large cohort of women, enriched with individuals representing the spectrum of risk factor burden as well as a range of achieved lifespans. The goal of this study is to advance our understanding of how upstream inflammatory pathways are related to healthy aging and longevity in women, who continue to outlive men and yet carry a greater burden of chronic disease in later life than men for reasons that remain unclear. Thus, our specific aims are (1) to assess whether circulating eicosanoid mediators of systemic inflammation are associated with longevity in women; and, (2) to evaluate the association between distinct eicosanoid mediators of systemic inflammation and morbidity profiles in women. Our systematic approach to comprehensively investigating the components of upstream inflammatory activity in a large, well-phenotyped cohort promises to yield important insights into the determinants of healthy aging and longevity. Importantly, given its focus on upstream inflammatory activity, this work will pave the way for follow-up studies investigating the efficacy of anti-inflammatory therapies (both existing and novel agents) for modulating variation in distinct eicosanoids as well as outcomes.