Mechanism through which an anti-aging natural compound extends longevity of yeast by remodeling cellular lipid dynamics
The fundamental mechanisms of aging are conserved from yeast to humans. We use the yeast Saccharomyces cerevisiae as a model system with which to study the molecular mechanisms of aging. Our high-throughput chemical genetic screen of extensive compound libraries has identified lithocholic acid (LCA), a bile acid, as a potent anti-aging and anti-cancer compound (Aging (2010) 2:361-370). We found that LCA extends longevity of chronologically aging yeast. Our findings imply that: 1) exogenously added LCA enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane and also associates with the outer mitochondrial membrane; and 2) delivered to mitochondria LCA elicits a remodeling of lipid synthesis and movement within both membranes, thereby altering the mitochondrial membrane lipidome and triggering changes in mitochondrial size, number and morphology (Aging (2013) 5: 551-574). Our recent data suggest a mechanism underlying the ability of LCA to delay cellular aging by remodeling coordinated lipid dynamics not only in mitochondria but also in the endoplasmic reticulum (ER), lipid droplets (LD) and peroxisomes. In this mechanism, the stimulated by LCA changes in mitochondrial lipids and morphology extend yeast longevity by 1) altering the age-related chronology of longevity-defining processes in mitochondria; 2) 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; 3) causing a remodeling of lipid metabolism and transport in the ER, LD and peroxisomes, thereby postponing a previously unknown age-related mode of programmed cell death that we call lipoptosis; and 4) remodeling central metabolism in the cytosol, thereby increasing cellular ATP and NADH levels and delaying an age-related decline of mitochondrial functionality. The objective of the proposed research project is to validate our hypothesis on the above mechanism for a delay of cellular aging by LCA. To attain this objective, the intern will use LCA and various genetic interventions to manipulate lipid synthesis, transport and degradation within mitochondria, the ER, LD and peroxisomes of yeast cells. He or she will monitor how these different manipulations affect yeast lifespan and longevity-defining cellular processes. The intern will first examine how LCA affects the lifespans of the following mutant strains: 1) ups1?, tam41?, gep4?, crd1?, cld1?, taz1? and psd1?, each lacking a non-essential enzyme involved in the synthesis of various lipids within the inner mitochondrial membrane or in their bidirectional movement via mitochondria-ER contact sites; 2) fat1?, faa1?, gpt2?, sct1?, ayr1?, ale1?, slc1?, lro1?, dga1? and are1?, each lacking a non-essential enzyme involved in lipid synthesis within the ER membrane; 3) tgl1?, tgl3?, tgl4? and tgl5?, each lacking a non-essential lipase involved in the hydrolysis of triacylglycerols, neutral lipid species that are stored in LD; and 4) fox1?, fox2? and fox3?, each lacking a non-essential enzyme involved in peroxisomal fatty acid oxidation. He or she will then investigate how exogenously added to yeast cells LCA influences the age-related dynamics of longevity-defining processes that integrate lipid metabolism and interorganellar transport into a biomolecular network of cellular aging.
