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.