Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging

Abstract

In aged mice, the redox-regulated transcription factor nuclear factor- κB (NF-κB) becomes constitutively active in many tissues, as well as in cells of the hematopoietic system. This oxidative stress-induced activity promotes the production of a number of pro-inflammatory cytokines, which can contribute to the pathology of many disease states associated with aging. The administration to aged mice of agents capable of activating the a isoform of the peroxisome proliferator-activated receptor (PPARα) was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-κB, and a loss in spontaneous inflammatory cytokine production. Aged animals bearing a null mutation in PPARα failed to elicit these changes following treatment with PPARα activators, but remained responsive to vitamin E supplementation. Aged C57BL/6 mice were found to express reduced transcript levels of PPARα and the peroxisome-associated genes acyl-CoA oxidase and catalase. Supplementation of these aged mice with PPARα activators or with vitamin E caused elevations in these transcripts to levels seen in young animals. Our results suggest that PPARα and the genes under its control play a role in the evolution of oxidative stress excesses observed in aging.