Molecular exploration of age-related NF-kappaB/IKK downregulation by calorie restriction in rat kidney.
Accumulating evidence strongly suggests that oxidative stress underlies aging processes, and that in a variety of organisms, calorie restriction (CR) retards these processes, thereby extending their lifespan. Recent studies revealed that the anti-aging action of CR depends on its anti-oxidative mechanism. In previous papers, we reported that aging activates the redox-sensitive transcription factor, NF-kappaB, and further reported that age-related NF-kappaB activation correlates with age-related oxidative stress. In the present paper, we present evidence that increased NF-kappaB binding activity during aging is elicited through the phosphorylation of IkappaB kinase (IKK), causing a degradation of IkappaBalpha and IkappaBbeta. We further show that CR inhibits IKK activation, down-regulating NF-kappaB activation as evidenced by increased bound IkappaBalpha and IkappaBbeta proteins in cytoplasm. These findings led to the conclusions that age-related oxidative stress may be a primary cause of up-regulated and altered NF-kappaB activity in aged kidney, and that the anti-oxidative action of CR is a major force responsible for the maintenance of a properly functioning NF-kappaB/IkappaB-IKK signaling pathway, which might be involved in CR's life-prolonging action.
Kim
Hyon Jeen
HJ
College of Pharmacy, Pusan National University, San 30, Jang-jun-jong, Gumjung-gu, Pusan 609-735, Korea.
Yu
Byung Pal
BP
Chung
Hae Young
HY
D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D002149:Energy Intake; D005978:Glutathione / Q000378:metabolism; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007668:Kidney / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D005978:Glutathione