Investigating Metabolism-Based Pharmacologic and Dietary Strategies of Nutrient Restriction to Impact Health and Disease

Abstract

Metabolism is essential for life and is involved in disease. By studying metabolism, we can understand basic cellular and organismal physiology, and try to modulate metabolism to treat diseases where it is implicated. Nutrient restriction, through both pharmacologic and dietary methods, is one way metabolism can be modulated because nutrients feed metabolism. In this dissertation, I examine both pharmacologic and dietary strategies of limiting different nutrients, and the impact on metabolism, physiology, and on models of disease. I use different model systems including mammalian cell culture, flies, and mice and examine their overall health and/or growth under different types of nutrient restriction. I examine metabolism using a liquid chromatography-mass spectrometry-based metabolomics method, which allows the simultaneous measurement of the relative levels of hundreds of polar and semi-polar metabolites. By using pharmacologic inhibitors that target glycolysis and connected pathways, my colleagues and I found that cancer cell viability and growth are reduced and showed how these metabolic pathways are used to benefit cancer growth. I also used pharmacologic and dietary strategies to target cysteine metabolism and found an unexpected connection with altered nucleotide metabolism when cysteine was limited in cancer cells and flies. Finally, I examined the impact of restrictive diets in mice, and my preliminary findings show that glucose metabolism is altered in these mice. This work collectively shows how metabolism can be altered by different methods of nutrient restriction, and how these strategies could be useful for treating diseases like cancer and promoting health and longevity.