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.

Figure 1. Bezafibrate extends lifespan of adult C. elegans

Life span analyses with several hundred N2 wild type nematodes each at three different concentrations of bezafibrate (0.1, 1, and 10 micromolar) versus control (0.1% DMSO).

Figure 2. Clofibrate extends lifespan of adult C. elegans

Life span analyses with several hundred N2 wild type nematodes each at three different concentrations of clofibrate (0.1, 1, and 10 micromolar) versus control (0.1% DMSO).

Figure 3. Fenofibrate extends lifespan of adult C. elegans

Life span analyses with several hundred N2 wild type nematodes each at three different concentrations of fenofibrate (0.1, 1, and 10 micromolar) versus control (0.1% DMSO).

Figure 4. Life span extension through fibrates is NHR-49/PPARalpha-dependent

A Life span analyses with several hundred nhr-49 knockout nematodes (variation ok2165, strain RB1716) at 10 micromolar bezafibrate, clofibrate, and fenofibrate versus control (0.1% DMSO). B Life span analyses with several hundred nhr-49 knockout nematodes (variation gk405, strain VC870) at 10 micromolar bezafribrate, clofibrate, and fenofibrate versus control (0.1% DMSO).