Proteomic aging in adults before and after cancer diagnosis

项目摘要 癌症幸存者在比无癌症者更早的年龄经历与年龄有关的疾病，这表明， 癌症幸存者加速衰老癌症幸存者的加速衰老可能是由以下原因引起的： 癌症治疗，但它也可能与免疫反应和慢性炎症有关。慢性 炎症也见于随后发展为癌症的个体中， 这是一种加速衰老的过程，甚至在癌症诊断之前就已经开始了。评估 在癌症诊断之前和之后的生物衰老，我们将使用现有的蛋白质组学数据， 在社区基于人群的动脉粥样硬化风险前瞻性研究中验证蛋白质组衰老时钟 （ARIC）群组。在过去的20年里，这些蛋白质已经用高灵敏度的 SomaScan测定。蛋白质组衰老时钟将在多种族研究中进行外部验证， 动脉粥样硬化（梅萨）。蛋白质组衰老时钟的优势在于这些时钟很容易测量， 准确预测生物衰老，并与年龄相关的疾病和死亡率有关。但据 目前尚不清楚蛋白质组衰老时钟是否能预测癌症幸存者的癌症风险或结果， 关于癌症背景下的最佳时钟的协议。为了克服这一知识差距，我们将 构建并验证ARIC参与者中的蛋白质组衰老时钟，这些参与者没有癌症，但可能有其他 这些时钟将是癌症特异性蛋白质组老化时钟（所谓的CaPAC）。此外，本发明还提供了一种方法， 我们将检查先前发表和验证的蛋白质组老化时钟。我们的核心假设是， 加速衰老与（1）基线时无癌症的人患癌症的风险增加有关， (2)中晚期癌症幸存者的过早死亡率和发病率。在第一个目标中，我们将 检查所有CaPAC的年龄加速与整体癌症风险之间的关联， ARIC和梅萨中的癌症类型。这些关联也将按性别和种族分层。第二个目标， 我们将研究所有CaPAC的年龄加速与全因死亡率之间的关系， 除了他们的指数癌症，癌症幸存者在ARIC中的脆弱性。此外，我们将比较 与癌症幸存者和无癌症史者死亡率的关系。使用现有数据 从ARIC和梅萨研究将允许快速和具有成本效益的测试我们的假设。的 癌症中蛋白质组老化的定量在临床上是重要的，因为生物学年龄的知识将 不仅为风险分层癌症筛查和诊断后癌症监测提供信息， 开发抗衰老药物。 1

PROJECT SUMMARY Cancer survivors experience age-related diseases at earlier age than cancer-free persons, suggesting that cancer survivors have accelerated aging. Accelerated aging among cancer survivors could be caused by cancer treatment, but it could also be related to immune response and chronic inflammation. Chronic inflammation is also found in individuals who subsequently develop cancer with subsequent risk of cancer development, and it is possible that accelerated aging starts even before cancer diagnosis. To assess biological aging before and after cancer diagnosis, we will use existing proteomic data and construct and validate proteomic aging clocks in the prospective population-based Atherosclerosis Risk in the Community (ARIC) cohort. The proteins have been already measured three times over 20 years using highly sensitive SomaScan assay. The proteomic aging clocks will be externally validated in the Multi-Ethnic Study of Atherosclerosis (MESA). The strengths of proteomic aging clocks are that these clocks are easily measured, accurately predict biological aging, and are associated with age-related diseases and mortality. However, it is unknown whether proteomic aging clocks predict cancer risk or outcomes in cancer survivors, and there is no agreement about the optimal clock in the context of cancer. To overcome this gap in knowledge, we will construct and validate proteomic aging clocks in ARIC participants who are cancer free but may have other conditions, i.e. these clocks will be cancer-specific proteomic aging clocks (so called, CaPACs). In addition, we will examine the previously published and validated proteomic aging clocks. Our central hypothesis is that accelerated aging is associated with (1) increased cancer risk in persons who are cancer-free at baseline and (2) premature mortality and morbidity among cancer survivors at middle and later age. In the first aim, we will examine the associations between age acceleration for all CaPACs and the risk of overall cancer and specific cancer types in ARIC and MESA. The associations will be also stratified by sex and race. In the second aim, we will examine associations between age acceleration for all CaPACs and all-cause mortality, mortality from causes other than their index cancer, and frailty among cancer survivors in ARIC. In addition, we will compare associations with mortality among cancer survivors and those without cancer history. The use of existing data from the ARIC and MESA studies will allow for quick and cost-efficient testing of our hypothesis. The quantification of proteomic aging in cancer is clinically important because the knowledge of biological age will not only inform risk-stratified cancer screening and post-diagnosis cancer surveillance, but also facilitate the development of anti-aging drugs. 1