title: Lipid-lowering fibrates extend C. elegans lifespan in a NHR-49/PPARalpha-dependent manner.
abstract: Compounds that delay aging in model organisms may be of significant interest to anti-aging medicine, since these substances potentially provide pharmaceutical approaches to promote healthy lifespan in humans. We here aimed to test whether pharmaceutical concentrations of three fibrates, pharmacologically established serum lipid-lowering drugs and ligands of the nuclear receptor PPARalpha in mammals, are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. Adult C. elegans (wild-type N2 as well as two nhr-49-deficient strains, RB1716 and VC870) were maintained on agar plates and were fed E. coli strain OP50 bacteria. Bezafibrate, clofibrate, and fenofibrate were applied to the agar, respectively, to test whether they may promote longevity by quantifying survival in the presence and absence of the respective compounds. All three fibrates extended C. elegans N2 lifespan when applied at a concentration of 10 micromolar. Bezafibrate additionally extended C. elegans N2 lifespan at concentrations of 1 micromolar and 0.1 micromolar. In strains deficient for nhr-49, a functional orthologue of the mammalian peroxisome proliferator-activated receptor alpha (PPARalpha), all three compounds were incapable of extending lifespan. Taken together, fibrates promote C. elegans longevity in an NHR-49-dependent manner possibly by promoting mitohormesis and suggesting that these compounds may promote lifespan also in mammals.
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena D-07743, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Brandstädt
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schmeisser
authors.forename: Kim
authors.initials: K
authors.lastname: Zarse
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D058607:Fibric Acids / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008055:Lipids / Q000037:antagonists & inhibitors*; D008136:Longevity / Q000187:drug effects*; D009154:Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D058607:Fibric Acids; D000960:Hypolipidemic Agents; D008055:Lipids; C505159:NHR-49 protein, C elegans; D018160:Receptors, Cytoplasmic and Nuclear