Bioinformatics Approaches to Biomarker and Drug Discovery in Aging and Disease

Over the past two decades, high-throughput (HTP) technologies such as microarrays and mass spectrometry have fundamentally changed the landscape of aging and disease biology. They have revealed novel molecular markers of aging, disease state, and drug response. Some have been translated into the clinic as tools for early disease diagnosis, prognosis, and individualized treatment and response monitoring. Despite these successes, many challenges remain: HTP platforms are often noisy and suffer from false positives and false negatives; optimal analysis and successful validation require complex workflows; and the underlying biology of aging and disease is heterogeneous and complex. Methods from integrative computational biology can help diminish these challenges by creating new analytical methods and software tools that leverage the large and diverse quantity of publicly available HTP data. In this thesis I report on four projects that develop and apply strategies from integrative computational biology to identify improved biomarkers and therapeutics for aging and disease. In Chapter 2, I proposed a new network analysis method to identify gene expression biomarkers of aging, and applied it to study the pathway-level effects of aging and infer the functions of poorly-characterized longevity genes. In Chapter 4, I adapted gene-level HTP chemogenomic data to study drug response at the systems level; I connected drugs to pathways, phenotypes and networks, and built the NetwoRx web portal to make these data publicly available. And in Chapters 3 and 5, I developed a novel meta-analysis pipeline to identify new drugs that mimic the beneficial gene expression changes seen with calorie restriction (Chapter 3), or that reverse the pathological gene changes associated with lung cancer (Chapter 5). The projects described in this thesis will help provide a systems-level understanding of the causes and consequences of aging and disease, as well as new tools for diagnosis (biomarkers) and treatment (therapeutics).Ph