Fenofibrate: Panacea for Aging-Related Conditions?

Fenofibrate, a selective peroxisome proliferator-activated receptors alpha (PPAR-┙) activator, has been primarily developed to treat human dyslipidemia. PPAR modulate the expression of genes involved in lipid metabolism through peroxisome proliferator response elements (Willson et al., 2000). Although fenofibrate became commercially available in 1974 (Fournier, Inc., France), its lipid-lowering action mechanism has not been clarified until the late 1990’s, contributing to open new research doors. With respect to the mechanisms of action, the drug with pleiotropic activity may be regarded as a “21st-century agent” (Staels et al., 1995). Fenofibrate as a ligand of PPAR-┙ exhibits lipid-lowering effects by activating PPAR-┙. PPAR-┙ activators stimulate the ┚-oxidation of fatty acids in the liver resulting in a decreased availability of fatty acids for triglyceride (TG) synthesis (Schoonjans et al., 1995, 1996a, 1996b). In addition, fenofibrate enhances the production of apo-AI and apo-AII: the major component of HDL by activating PPAR-αand increases plasma level of HDL-C directly (Vu-Dac, 1994, 1995). Thus, the lipid-lowering action mechanism of fenofibrate involves potent TG-reducing and HDL-C-increasing actions. Statins, another type of lipidlowering agent do not show such actions, though statins can inhibit hydroxymethylglutaryl (HMG)-CoA reductase (Endo A, 1992). Furthermore, fenofibrate decreased the level of low-density lipoprotein cholesterol (LDL-C), especially “small dense LDL”, which may be a powerful metabolic contributor to arteriosclerosis (Superko, 2000). PPAR-┙ regulates the transcription of lipid-associated genes and various genes involved in homeostasis, suggesting the PPAR-┙-mediated pleiotropic activities of fenofibrate. The reports on the pleiotropic activities of fenofibrate has been accumulated in a variety of largescale, randomized, controlled trials (RCTs). The studies presumably associated with the anti-aging actions of fenofibrate are reviewed in this article.