What is the target of anti-aging action of calorie restriction?

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Growth hormone(GH)/insulin/IGF-1 axis and their subsequent targets, forkhead transcriptional factors, are likely to be an important regulator of lifespan from C. elegans to mammals. Calorie restriction(CR) is a robust, reproducible and simple experimental manipulation known to extend lifespan and retard aging process in several species, but the underlying mechanism is still debatable. However, CR reduces serum level of GH, insulin and IGF-1. Therefore, GH/insulin/IGF-1 and their signal cascade might be involved in the anti-aging action of CR. To understand the mechanism of CR, particularly on a role of GH/IGF-1 axis, we examined lifespan, hepatic gane expression profile and serum and plasma biochemical analysis from wild(-/-), transgenic homozygous mini rats bearing anti-sense GH transgene(severe suppression of GH/IGF-1, tg/tg), and their F1 heterozygous rats(moderate suppression, tg/-) fed ad libitum and 70 % CR.Regardless severity of GH/IGF-1 suppression, CR extended survival markedl … More y on three rat lines, suggesting that the anti-aging action of CR dose not merely depend on GH/IGF-1 axis. The gene expressions modulated by CR were likely to be regulated with GH/IGF-1-dependent and -independent manners. The former up-regulated stress response and xenobiotics metabolism-related gene expressions and the latter modulated lipid metabolism-related gene expressions predominantly. Our data on lipid metabolism of CR rats showed effective lipid utilization including the enhanced lipid anabolism after feeding and lipid catabolism with mitochondrial beta-oxidation more predominantly than peroxisomal beta-oxidation under food shortage possibly through ADD1/SREBP1 and PPARalpha activation. The accelerated efficiency of energy utilization prevents excess energy supplied by feeding from wasting and subsequent cellular damage, suggesting that CR stimulates the intrinsic adaptive system against food shortage through the modulation of lipid metabolism and probably maximizes survival and retards aging process. Less