Gene expression in liver tissue from Ghrh-KO and normal (wild-type) mice

The hypothalamus has recently emerged as a key regulator of metabolism and aging in mammals. We have examined the impact of targeted disruption of hypothalamic hypophysiotropic peptide: Growth Hormone-releasing Hormone (GHRH) in mice on longevity, and the putative mechanisms of delayed aging. GHRH knockout (KO) mice are remarkably long-lived and in comparison to genetically normal (wild type) animals exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of GH. While these effects overlap with those of caloric restriction (CR), we show that effects of CR and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity. Hepatic tissue was obtained from 3 Ghrh-KO mice and 3 control (wild-type) mice (males). Expression in each sample was profiled using Affymetrix Mouse Genome 430 2.0 arrays.下丘脑（hypothalamus）近年来被证实为调控哺乳动物代谢与衰老的关键中枢。本研究针对小鼠下丘脑促垂体肽——生长激素释放激素（GHRH）的靶向敲除对寿命的影响，以及延缓衰老的潜在机制展开了系统探究。GHRH基因敲除（GHRH-KO）小鼠寿命显著延长；相较于遗传背景正常的野生型对照小鼠，该类小鼠在异生物质解毒、应激抵抗及胰岛素信号通路相关基因的表达上呈现显著改变。此类突变小鼠的脂联素水平升高，且葡萄糖稳态出现与生长激素抗胰岛素作用消除相符的异常。尽管上述效应与热量限制（CR）的效应存在重叠，但本研究证实热量限制与GHRH突变的效应具有叠加性：GHRH-KO小鼠的寿命可通过热量限制进一步延长。综上，GHRH-KO小鼠存在与应激抵抗、代谢调控及炎症相关的信号通路网络紊乱，因此可作为新型模型，用于探究GHRH抑制、生长轴（somatotropic axis）下调与寿命延长之间的内在关联。本研究从3只Ghrh-KO雄性小鼠与3只野生型雄性对照小鼠中获取肝组织，采用Affymetrix小鼠基因组430 2.0芯片对每个样本的基因表达谱进行了检测。