Metabolism in Cancer and Aging

Abstract

Metabolism is one of the most fundamental processes in living systems: the conversion of nutrients to energy and cellular building blocks and the disposal of wastes and toxins enables organisms to live and grow. The essential nature of metabolism renders animals sensitive to conditions and factors that disrupt ordinary metabolism, such as cancer and aging. Understanding the features of metabolism that dysfunction in such states is thus instrumental in developing strategies to counteract these pathologies. In this thesis, I discuss the use of untargeted metabolomic profiling by liquid chromatography coupled to mass spectrometry (LC- MS) in addition to more targeted analyses using stable isotope tracers in studies of cancer and aging. First, I discuss metabolic profiling to interrogate the pro-oxidant activity of pharmacologic ascorbate as an anti-cancer treatment, leading to the discovery that dietary selenium restriction can sensitize cancer to ascorbate in vivo. I then discuss the application of metabolomics and stable isotope tracing for flux studies in aging mice in two distinct analyses. The first of these analyses entails a highly detailed analysis of whole-body NAD+ metabolism in aging mice, and the second encompasses a much broader, yet highly comprehensive, analysis of metabolic changes associated with aging and how they differ from those that present in obesity. Collectively, my work demonstrates the power of metabolic analyses in establishing biochemical mechanisms and to differentiate confounding factors that present in pathological states and establish an exhaustive resource for future studies on metabolism in the context of mammalian aging.