3-hydroxybutyrate: an unexpected longevity factor in yeast

Abstract Saccharomyces cerevisiae (budding yeast) has played a key role in identifying and characterizing multiple longevity factors and healthspan/lifespan interventions such as caloric restriction (CR), methionine restriction (MetR) and rapamycin (TOR inhibition) but has been absent from the elucidation of ketone bodies in lifespan regulation. This is likely because the traditional enzymes for ketogenesis, ketone body catabolism, and the major ketone body metabolites acetoacetate and b-hydroxybutyrate (BHB), had not been characterized or significantly detected in this organism. Furthermore, previous metabolomics experiments with yeast were primarily performed on exponentially growing cells with abundant nutrients (the “fed state”), a condition that shouldn’t favor ketogenesis if it were to occur. We have unexpectedly detected BHB as a metabolite in yeast cells as the enter stationary phase, and especially when grown under CR conditions. This effect is consistent with the ketogenesis that occurs in mammals during extended fasting or starvation. We also observed strong chronological lifespan (CLS) extension by BHB supplementation that was equivalent in magnitude to the effect of CR. Additionally, CR or BHB supplementation correlated with induction of a recently discovered post-translational protein modification from mammals linked with ketosis, lysine b- hydroxybutyrylation. Therefore, the goal of this exploratory R21 project is to now characterize the ketogenesis pathway and develop S. cerevisiae into a novel genetic system for studying the potential longevity benefits of BHB.