Prolonging the Longevity of Budding Yeast: New Aging-Delaying Plant Extracts and the Identification of their Cellular Signaling Pathways

In studies presented in this thesis, we used a robust cell viability assay to conduct two screens of commercially available plant extract libraries in search of plant extracts that can delay chronological aging and prolong the longevity of the budding yeast S. cerevisiae. Many of the plant extracts in the library have been used for centuries in traditional Chinese and other herbal medicines or the Mediterranean and other customary diets. None of these plant extracts, however, were previously tested for their ability to slow aging and extend the longevity of any organism. Our screens have allowed us to discover twenty-one plant extracts that significantly prolong the longevity of chronologically aging yeast cells that are not limited in calorie supply. We provided evidence that each of these longevity-extending plant extracts is a geroprotector that lowers the rate of yeast chronological aging and elicits a hormetic stress response. Our findings demonstrated that the efficiencies of aging delay and longevity extension by many of these geroprotective plant extracts significantly exceed those for any of the chemical compounds previously known for their abilities to slow aging and prolong lifespan in yeasts, filamentous fungi, nematodes, fruit flies, daphnias, mosquitoes, honey bees, fish, mammals and cultured human cells. Our findings also revealed that each of the twenty-one geroprotective plant extracts mimics in limited in calorie supply yeast cells v that are not the aging-delaying, longevity-extending, stress-protecting, metabolic and physiological effects of a caloric restriction diet. We also demonstrated that the discovered geroprotective plant extracts elicit partially overlapping effects on a distinct set of longevity-defining cellular processes. Such processes include the coupled mitochondrial respiration, maintenance of the electrochemical potential across the inner mitochondrial membrane, preservation of the cellular homeostasis of reactive oxygen species, protection of cellular macromolecules from reactive oxygen species- inflicted oxidative damage, maintenance of cell resistance to oxidative and thermal stresses, the efficiency of the lipolytic cleavage of neutral lipids deposited and stored in lipid droplets. We provided evidence that some of the discovered geroprotective plant extracts slow yeast chronological aging because they target different hubs, nodes and/or links of the longevity-defining network integrating specific evolutionarily conserved signaling pathways and protein kinases.