Triacylglycerol and lifespan control in a model organism Saccharomyces cerevisiae

Michigan State University, East Lansing MI

Investigators

Abstract

The overarching goal of this project is to delineate how triacylglycerol (TAG), a ubiquitous storage fat in eukaryotic systems, preserves the longevity of the underlying cells. This lifespan preservation function of TAG is independent of its canonical role of energy provision, thereby potentially transforming the understanding of the interplay between a well-known but long-overlooked biomolecule and cellular pathways pivotal to long-term survival. Interestingly, while analyzing microalgal lipases, the PI's group made the unexpected discovery that yeast cells deficient in TAG lipases have a prolonged chronological lifespan. These observations formed the basis for the hypothesis that fat storage droplets may serve as sinks for reactive oxygen radicals (ROS) that are known to be toxic to cells and hence reduces lifespan. The proposal is founded on a set of strong preliminary studies that correlate increased chronological aging in yeast with accumulation of TAG and decreased chronological aging with reduced TAG levels in stationary phase cells. Three yeast strains already available to the PI (wild type, 'lean' and 'fat') will be used to test the hypothesis and make a positive outcome highly likely. The project will train doctoral and undergraduate students to become critical, independent, and ethical researchers. In addition, this project further broadens its impact by integrating the core concept of lifespan preservation by TAG into an advanced biochemistry laboratory course offered to senior students (~90 each year) that major in biochemistry and biotechnology. Studies of lifespan control in model organisms have revealed key pathways shared by species from yeast to humans. However, despite decades of research, the molecular causes underlying cellular senescence remain elusive. The Kuo group discovered that the intracellular TAG of budding yeast S. cerevisiae is a key determinant for chronological lifespan (CLS), a quantitative measurement of viability of post-mitotic cells kept in the stationary phase. Genetically engineered strains with higher TAG content survive much longer, whereas those deprived of TAG die shortly after entering the stationary phase but exhibit normal vegetative growth. Blocking TAG hydrolysis for energy extraction leads to TAG accumulation and lifespan extension, arguing strongly for a novel function outside energy utilization. Because TAG is a ubiquitous lipid species in eukaryotes, these findings may provide a clue explaining "obesity paradox," that is, adult humans deemed overweight have the lowest all-cause mortality. In this project, the Kuo group proposes to use yeast as the model to uncover the mechanistic details and functional relationship between TAG metabolism and lifespan regulation. Specifically, the following hypotheses will be tested: (1) TAG protects aging cells by acting as a sink that traps free radicals that are detrimental to lifespan preservation (= Radicals Sink Hypothesis). (2) Enzymes key to TAG metabolism are regulators of chronological lifespan and genetically interact with other lifespan regulatory pathways. Genetic experiments will help construct an integrative lifespan regulation network in yeast. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.