Regulation of aging in mammals : Difference between the effects of calorie restriction and suppression of the GH-IGF-1 axis

1.胰岛素信号传导：分析CR和gh - igf -1抑制转基因（Tg）大鼠肝脏和骨骼肌中的胰岛素信号传导。结果表明，CR不仅使胰岛素对葡萄糖代谢的作用增敏，而且激活了胰岛素非依赖性通路。CR诱导的这些机制可能源于GH-IGF-1轴受到抑制（Yamaza H et al., Exp Gerontol 2004; Hayashi H et al.）。生物医学（Gerontol, 2005）。我们研究了脂联素- amp活化蛋白激酶（AMPK）途径在胰岛素不依赖机制中的潜在作用。然而，出乎意料的是，CR抑制了AMPK的活性，并且抑制的GH-IGF-1轴不影响AMPK途径2。应激反应：采用DNA阵列法分析CR大鼠的炎症应激反应。结果证实了CR大鼠的应激抵抗。肝脏DNA阵列分析表明，CR的保护作用来自于组成性表达的基因产物，而不是nf - κ b诱导表达的基因产物（Tsuchiya et al., Mech Ageing Develop 2005）。gh - igf -1抑制大鼠表现出明显增强的应激反应。这种影响可能部分是由于nf - κ b诱导的促炎反应的衰减。目前，我们正在研究除NF-kappa B途径外的氧化还原敏感转录因子和信号通路。线粒体氧化应激：包括谷胱甘肽和谷胱甘肽二硫化物在内的分析表明，严重抑制GH-IGF-1轴诱导氧化应激，增加肿瘤疾病，缩短大鼠寿命，尽管适度抑制GH-IGF-1轴可延长寿命。

1.Insulin signaling : The insulin signaling was analyzed in liver and skeletal muscle in CR and GH-IGF-1-suppressed transgenic (Tg) rats. The results suggested that CR not only sensitized the insulin action for glucose metabolism but also activated insulin-independent pathways. These mechanisms induced by CR could result from the suppressed GH-IGF-1 axis (Yamaza H et al., Exp Gerontol 2004 ; Hayashi H et al. Biomedical Gerontol 2005). We investigated a potential role for the adiponectin-AMP-activated protein kinase (AMPK) pathway in insulin-independent mechanisms. However, unexpectedly, CR suppressed the activity of AMPK and also the suppressed GH-IGF-1 axis did not affect the AMPK pathway.2.Stress response : We analyzed the inflammatory stress response in CR rats using the DNA array method. The results confirmed the stress-resistance in CR rats. The DNA array analysis in liver suggested that the protective effect by CR emerges from constitutively, rather than NF-kappa B-inductively, expressed gene products (Tsuchiya T et al., Mech Ageing Develop 2005). GH-IGF-1-suppressed rats exhibited greatly enhanced stress response. This effect could be partly due to attenuation of the NF-kappa B-induced proinflammatory response. At present, we are investigating redox-sensitive transcription factors and signaling pathways other than the NF-kappa B pathway.3.Oxidative stress in mitochondria : Analyses including glutathione and glutathione disulfide indicated that severe suppression of GH-IGF-1 axis induced oxidative stresses, increased neoplastic diseases, and shorten lifespan in rats, although moderate suppression of GH-IGF-1 axis increased lifespan.