Grant: Discovery Grants Program - Individual

Aging of organisms is caused by age-related changes in cellular processes. These changes can be slowed down by some dietary and pharmacological interventions that delay cellular aging in evolutionarily distant organisms. Recent studies have suggested that the metabolism and interorganellar transport of lipids are among the key processes involved in regulating cellular aging, influencing age-related pathologies and defining organismal longevity in many organisms. However, mechanisms linking lipid metabolism to cellular aging and organismal longevity remain unknown. The baker's yeast Saccharomyces cerevisiae is a unicellular organism used for defining mechanisms of cellular and organismal aging in multicellular organisms. The long-term goal of our research program is to uncover mechanisms and biological principles underlying the essential role of lipid metabolism in regulating cellular aging and defining organismal longevity using the yeast S. cerevisiae as a model organism. In a quest for small molecules that can increase yeast lifespan by remodeling lipid metabolism and transport within various cellular organelles, we identified many previously unknown longevity-extending compounds. Our recent findings suggest a mechanism underlying the ability of one of them, a bile acid called lithocholic acid, to delay cellular aging by remodeling coordinated lipid dynamics in mitochondria, the endoplasmic reticulum, lipid droplets and peroxisomes. In the proposed mechanism, exogenously added lithocholic acid enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane and also associates with the outer mitochondrial membrane. Lithocholic acid elicits a remodeling of lipid synthesis and movement within both mitochondrial membranes, thereby altering their lipid composition and triggering changes in mitochondrial size, number and morphology. In synergy, all these changes extend yeast longevity by (i) altering the age-related chronology of longevity-defining processes in mitochondria; (ii) reducing the extent of mitochondrial fragmentation, thereby slowing down the release of pro-apoptotic proteins from mitochondria and decelerating an age-related form of apoptotic cell death; (iii) causing an age-related remodeling of lipid metabolism and transport in the endoplasmic reticulum, lipid droplets and peroxisomes, thereby postponing a previously unknown age-related mode of programmed cell death called ""liponecrosis""; and (iv) remodeling central metabolism in the cytosol, thereby increasing cellular ATP levels and delaying an age-related decline of mitochondrial functionality. The objective of the proposed research program is to uncover mechanisms linking lipid metabolism to cellular aging in yeast. To achieve this objective, we will use lithocholic acid and various genetic interventions for targeting these mechanisms by manipulating coordinated lipid metabolism and transport within mitochondria, the endoplasmic reticulum, lipid droplets and peroxisomes of yeast cells. We will employ various experimental approaches to monitor how these different manipulations affect yeast lifespan and many longevity-defining cellular processes. The proposed research program (i) has the potential to be highly innovative; (ii) will have a major impact on developing the new paradigm of an intricate network of intercompartmental communications underlying cellular aging in evolutionarily distant organisms; (iii) will uncover new mechanisms that link aging of eukaryotic cells to coordinated lipid dynamics within various cellular organelles; and (iv) will conceptually advance the current understanding of fundamental mechanisms and biological principles underlying the inherent complexity of cellular aging.