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

生长激素(GH)/胰岛素/IGF-1轴及其后续靶点叉头转录因子可能是秀丽隐杆线虫到哺乳动物寿命的重要调节因子。热量限制（CR）是一种强大的、可重复的、简单的实验操作，已知在一些物种中延长寿命和延缓衰老过程，但其潜在机制仍有争议。然而，CR降低了GH、胰岛素和IGF-1的血清水平。因此，GH/胰岛素/IGF-1及其信号级联可能参与了CR的抗衰老作用。为了了解CR的机制，特别是GH/IGF-1轴的作用，我们检测了野生（-/-）、携带反义GH转基因的纯合子小鼠（严重抑制GH/IGF-1， tg/tg）和它们的F1杂合子大鼠（中度抑制GH/IGF-1， tg/tg）的寿命、肝脏基因表达谱和血清和血浆生化分析。无论GH/IGF-1抑制的严重程度如何，CR在三个大鼠品系上都延长了生存期，这表明CR的抗衰老作用不仅仅依赖于GH/IGF-1轴。CR调控的基因表达可能通过依赖或不依赖GH/ igf -1的方式进行调控。前者上调应激反应和外源代谢相关基因表达，后者主要调节脂质代谢相关基因表达。我们的脂质代谢数据显示，CR大鼠的脂质利用是有效的，包括喂养后脂质合成代谢的增强，以及在食物短缺的情况下，线粒体β -氧化比过氧化物酶体β -氧化更主要的脂质分解代谢，可能是通过ADD1/SREBP1和ppar α激活。能量利用效率的提高防止了因进食而产生的能量过剩和随后的细胞损伤，这表明CR通过调节脂质代谢刺激了内在的适应系统，以应对食物短缺，可能最大限度地提高了存活率并延缓了衰老过程。少

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