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

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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.