Aging as a Risk Factor and Target for Prevention of Liver Cancer

项目总结--总体 肝癌(主要是肝细胞癌)的发病率正在增加，疾病转归 很穷。因此，迫切需要新的治疗方法和更好的预防战略。年龄是最重要的 肝癌的危险因素。与老年科学假说一致，我们假设衰老会导致功能失调。 线粒体、表观遗传和代谢网络促进和加剧与年龄相关的失调 肝脏的免疫功能和炎症。跨多个系统的动态平衡的丧失是允许的 肿瘤性肝病我们进一步假设，失调的慢性干扰素信号是这一过程的中心 致病网络。我们将解剖这个网络并测试慢性干扰素信号的后果，以 了解为什么肝癌的发病率会随着年龄的增长而增加。我们还将调查针对 这一网络对他们预防和抗击肝癌的能力表示赞赏。我们的总体具体目标是： 目标1.研究与年龄相关的线粒体、染色质、代谢(特别是胆汁酸)的变化 以及先天免疫和获得性免疫，它们在肝细胞癌中的因果作用和潜在机制。 目标2.研究这些不同系统之间的相互作用和年龄相关性的调节失调 这些相互作用促成了肝细胞癌的发生。 目标3.测试这样一种假设：至少其中一些与年龄相关的改变和由此产生的 肝细胞癌的易感性依赖于老年组织中的慢性干扰素信号。 目标4.研究针对年龄失调的方法，例如慢性干扰素的抑制物 激活、有丝分裂激素干预、雷帕霉素、感觉剂、胆汁酸调节剂和免疫调节剂，用于 他们有能力抑制肝癌的发生，更好地对抗已确定的癌症。 由于年龄是肝细胞癌最大的单一危险因素，因此对年龄的分子理解- 对肝癌的依赖可以通过风险评估、早期发现、 预测和治疗。此外，对肝细胞癌在衰老过程中如何发展的了解也可以导致 预防性干预。这一PPG将定义支持年龄相关性的关键分子机制 肝细胞癌。我们还将通过应用、测试和改进来促进改进风险评估的方法 以转录组为基础的“致瘤指数”来量化患肝癌的风险。最后，根据我们的发现， 我们将测试一组候选干预措施，以确定那些可以预防和抗击肝癌的干预措施。

PROJECT SUMMARY – OVERALL The incidences of liver cancer (primarily hepatocellular carcinoma (HCC)) are increasing and disease outcome is poor. Consequently, there is an urgent need for new therapies and better preventive strategies. Age is a major risk factor for HCC. In line with the geroscience hypothesis, we hypothesize that aging drives a dysfunctional mitochondrial, epigenetic and metabolic network that promotes and exacerbates age-associated dysregulation of immune function and inflammation in liver. Loss of homeostasis across multiple systems is permissive for neoplastic liver disease. We further hypothesize that dysregulated chronic interferon signaling is central to this pathogenic network. We will dissect this network and test the consequence of chronic interferon signaling, to understand why the incidence of liver cancer increases with age. We will also investigate approaches that target this network for their ability to prevent and combat liver cancer. Our overall specific objectives are: Objective 1. Investigate age-associated changes to mitochondria, chromatin, metabolism (specifically, bile acids) and innate and adaptive immunity, their causal role in HCC and underlying mechanisms. Objective 2. Investigate how interactions between these different systems and age-dependent dysregulation of these interactions contributes to HCC. Objective 3. Test the hypothesis that at least some of these age-associated alterations and consequent predisposition to HCC are dependent on chronic interferon signaling in aged tissue. Objective 4. Investigate approaches that target age dysregulation, for example suppressors of chronic interferon activation, mitohormetic interventions, rapamycin, senolytics, bile acid modulators and immune-modulators, for their ability to suppress the onset of liver cancer and better counter established cancer. Since age is the biggest single risk factor for HCC, it follows that a molecular understanding of the age- dependence of HCC can lead to improved disease management through risk assessment, early detection, prognostication and therapy. Moreover, an understanding of how HCC develops during aging can also lead to preventative interventions. This PPG will define critical molecular mechanisms underpinning age-dependence of HCC. We will also promote approaches for improved risk assessment through application, testing and refinement of a transcriptome-based “tumorigenic index” to quantitate the risk of HCC. Finally, based on our discoveries, we will test a panel of candidate interventions for those that can prevent and combat HCC.