Abstract

This thesis describes studies in which the budding yeast Saccharomyces cerevisiae was used as a model organism for uncovering mechanisms underlying aging of eukaryotic cells. We identified lithocholic acid (LCA), a bile acid, as a natural compound that increases the chronological lifespan of yeast cultured under longevity-extending caloric restriction (CR) conditions by targeting lipid metabolism. Our findings revealed mechanisms by which LCA extends yeast chronological lifespan, drives the evolution of longevity regulation within ecosystems, and suppresses mitochondrial deficiency known to cause a neurological disorder in humans. We demonstrated that the age-dependent dynamics of the mitochondrial tubular network regulates longevity of chronologically aging yeast by modulating age-related apoptosis. This mitochondria-controlled form of programmed apoptotic death is elicited by the efflux of the pro-apoptotic proteins cytochrome c, Aif1p and Nuc1p from mitochondria in reproductively mature yeast cells that enter stationary growth phase; furthermore, this form of age-related apoptotic death depends on the metacaspase Yca1p. We provided evidence that the CR diet delays the fragmentation of the mitochondrial tubular network during early stationary phase. This, in turn, slows down the age-related exit of pro-apoptotic proteins from mitochondria, attenuates apoptotic cell death, and ultimately prolongs lifespan. Our findings also revealed that LCA further increases the chronological lifespan of CR yeast by preventing mitochondrial fragmentation during late stationary phase, thus averting the age-related exit of pro-apoptotic proteins from mitochondria and inhibiting programmed apoptotic cell death. Moreover, findings reported in this thesis imply that LCA extends longevity of chronologically aging yeast only if added at certain critical periods of their lifespan. Based on these findings, we propose a hypothesis of a biomolecular longevity network undergoing a stepwise progression through a series of checkpoints in chronologically aging yeast. In this thesis we also propose a hypothesis in which LCA - as well as other interspecies chemical signals released into the environment - create xenohormetic, hormetic and cytostatic selective forces driving the ecosystemic evolution of longevity regulation mechanisms. Moreover, findings described in this thesis suggest a previously unknown mechanism by which LCA suppresses mitochondrial deficiency causing the late-onset Leigh syndrome, a severe neurological disorder in humans.