Unexpected Longevity Factors

Caloric restriction (CR), without malnutrition, is the most robust intervention used to increase the “healthspan” and extend the lifespan in model organisms ranging from yeast to mammals. It has been proposed that CR attenuates growth and improves cellular resistance to stress, thus leading to longevity. Longevity via CR hinges on extrinsic factors and intrinsic pathways at an organism’s disposal. Saccharomyces cerevisiae (budding yeast) represents a well-studied model organism to enrich our understanding of how extrinsic factors and intrinsic pathways can activate longevity pathways. Over the years, scientists have learned a lot about aging pathways from altering genes and the environmental conditions in this single cell eukaryote. It has been shown that temperature, carbon source, metabolite availability, and pH all matter in regulating the longevity of yeast. At the molecular level, new canonical aging pathways and metabolites have emerged with clear links to growth and nutrient signaling including the sirtuins, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), polyamines, and nicotinamide adenine dinucleotide (NAD+). Our overarching goal is to add to the understanding of these mechanisms by which CR extends lifespan. One of those mechanisms appears to be through the unexpected underutilization of amino acids, such as methionine, suggesting a link between CR (glucose restriction), amino acid restriction, and methionine restriction (MetR), either at the level of transport or reduced catabolism relative to Non-Restriction (NR) conditions. In Chapter II, I focus on the unexpected similarities and common pathways between CR and MetR. In Chapter IV, I show that this low consumption of amino acids in CR, contrasts with the high demand of amino acids in the Non-Restriction (NR) condition suggesting that they are limiting for longevity in the context of NR. In Chapter III, I demonstrate how yeast chronological lifespan (CLS) assays can be used to study quiescence, and I conduct experiments to show that yeast is an organism with negligible senescence.