Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging.
In aged mice, the redox-regulated transcription factor nuclear factor-kappaB (NF-kappaB) 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 alpha isoform of the peroxisome proliferator-activated receptor (PPARalpha) was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-kappaB, and a loss in spontaneous inflammatory cytokine production. Aged animals bearing a null mutation in PPARalpha failed to elicit these changes following treatment with PPARalpha activators, but remained responsive to vitamin E supplementation. Aged C57BL/6 mice were found to express reduced transcript levels of PPARalpha and the peroxisome-associated genes acyl-CoA oxidase and catalase. Supplementation of these aged mice with PPARalpha activators or with vitamin E caused elevations in these transcripts to levels seen in young animals. Our results suggest that PPARalpha and the genes under its control play a role in the evolution of oxidative stress excesses observed in aging.
Poynter
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Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA.
Daynes
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D042962:Acyl-CoA Oxidase; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D017931:DNA Primers; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000235:genetics; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010641:Phenotype; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D008054:Lipid Peroxides; D016328:NF-kappa B; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019314:Dehydroepiandrosterone Sulfate; C006253:pirinixic acid; D010088:Oxidoreductases; D002374:Catalase; D042962:Acyl-CoA Oxidase