Molecular Mechanisms Of Dietary Restriction-induced Delay Of Aging Via Regulation Of Lipid Metabolism

THESIS: Fatty Acid Transport Protein1 Tunes Longevity and Lipid Metabolism through MAPK pathway in Response to Dietary Restriction SPECIALIZATION: BiologyPh.D.CANDIDATE: Di WuSUPERVISOR: Di Chen,ProfessorAbstractDietary restriction(DR),reduced food intake without malnutrition,is the most robust environmental manipulation that significantly delays aging in a wide variety of metazoans.Previous studies on DR have mainly focused on identifying transcriptional regulators that mediate the beneficial effects of DR.However,the molecular mechanisms of DR to delay aging from the perspective of energy metabolism have not been well characterized.To investigate the interaction between DR,lipid metabolism and aging,RNAi based screen of acyl-Co A synthetases(ACS)family were performed to find the mediator of aging under DR.The ACS family were involved in catalyzing free fatty acids to form acyl-Co A derivates,which were necessary in almost processes of lipid metabolism containing catabolism,anabolism,fatty acid transport or lipid modification.In this study,we have identified ACS-22,homolog of fatty acid transport protein 1(FATP1),as a positive regulator of lifespan and lipid levels in response to DR.Functional decline in ACS-22 totally suppressed longevity and lipid levels in the intestine under DR through disturbing the MAPK pathway,while overexpression was sufficient to promote longevity.Specifically,reduction of fatty acid transport protein activity of ACS-22 / FATP1 in neurons and pharynx activated the phosphorylation of PMK-1 / MAPK in the intestine.The higher tyrosine phosphorylation of PMK-1 were required for the lifespan and TAGs defects caused by the acs-22 mutant under DR.Transcriptional analysis indicated that PMK-1 also functioned as a key factor to regulate the transcriptional network of the acs-22 mutant under DR.Further studied helped to underlie the molecular mechanism of PMK-1 in cooperating nutrients,lipid metabolism and aging through transcriptionally regulating genes involved in the peroxisome β-oxidation.Together,these results revealed a novel mechanism by which DR influenced aging and lipid metabolism.