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

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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.