Growth Signaling in Aging and Disease

Thesis (Ph.D.)--University of Washington, 2013Nutrient sensing and growth signaling pathways are key regulators of healthspan and longevity. Caloric restriction, the most widely studied and well documented intervention in aging, functions largely through effects on nutrient sensing and growth signaling pathways. Genetic approaches to studying aging have further emphasized the central role that growth signaling plays in regulating longevity by identifying key components of growth signaling pathways as critical modifiers of the aging process. Among these genetic factors are the insulin/insulin-like growth factor signaling, AMP kinase, and the mechanistic target of rapamycin (mTOR) complexes. mTOR forms two distinct complexes, mTORC1 and mTORC2, which together act as central coordinators of a variety of intra- and extra-cellular nutrient and growth signals. mTOR integrates extracellular signaling through insulin, IGF, and Akt, intracellular energy status sensing by AMP kinase, intracellular amino acid levels through sensing at the lysosome, and cellular translational capacity through association with the ribosome, As a central regulator of a variety of critical energy sensing pathways mTOR has been demonstrated to significantly contribute to aging and disease. Pathways downstream of mTOR include translation, autophagy, metabolism, and inflammation. The studies presented here examine the relationship between genotype and response to caloric restriction, examining the therapeutic role of mTOR inhibition in a mouse model of a human mitochondrial disease, and investigating the role of a major molecular process regulated by mTOR, autophagy, in the development of cardiac hypertrophy. These studies are diverse but linked by a central focus on the role of growth signaling pathways in aging and human disease and the work presented here provides important and novel insights into disease and aging