Lipid-lowering fibrates extend C. elegans lifespan in a NHR-49/PPARalpha-dependent manner

Sven Brandstädt,Kim Zarse,Kathrin Schmeisser,Michael Ristow

doi:10.18632/aging.100548

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.

Highlights

Promotion of longevity and in particular extension of healthy lifespan is of eminent interest to most humans
By continuously exposing nematodes starting at young adult age for their entire lifespan to defined concentrations of three different fibrates, which in mammals serve as ligands for the nuclear receptor PPARalpha, we tested whether and to which extent these compounds affect C. elegans lifespan
To potentially support the ongoing search for compounds that may promote human health especially at higher age, we here show that the fibrates clofibrate, bezafibrate, and fenofibrate induce longevity in a nematodal model organism, the roundworm C. elegans

Summary

INTRODUCTION

Promotion of longevity and in particular extension of healthy lifespan ( named ‘healthspan’) is of eminent interest to most humans. Fibrates are amphipatic carboxylic acids that are used to treat metabolic disorders, primarily hypercholesterolemia and/or hypertriglyceridemia [26]. As lipidmodifying substances they are capable of increasing HDL cholesterol levels and decreasing triglycerides and www.impactaging.com. PPARs are nuclear receptors that act as transcription factors They typically heterodimerize with the retinoic X receptor (RXR) and regulate expression of genes involved in development, metabolism, and cellular differentiation after binding to their respective response elements (PPREs) [27]. The nematodal nuclear hormone receptor 49 (NHR-49) has sequence homology to the human hepatocyte nuclear factor 4 (HNF4), but is assumed to act as the functional orthologue of mammalian PPARalpha since it shares most of the biological activities of the latter [31]. In this study we have tested whether various fibrates, namely bezafibrate, clofibrate, and fenofibrate, at pharmaceutical doses may be capable of extending the life span of the nematodal model organism C. elegans

RESULTS

DISCUSSION

METHODS