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

哺乳动物衰老的调节：热量限制和抑制 GH-IGF-1 轴的影响之间的差异

• 批准号: 15390128
• 负责人: SHIMOAKAWA Isao
• 金额: $ 4.93万
• 依托单位: Nagasaki University Graduate School of Biomedical Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390128/
• 关键词: Aging; Longevity; Calorie-restriction; Insulin; Growth hormone; Insulin-like growth factor; Stress response; Energy metabolism

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.

1.胰岛素信号传导：在CR和GH-IGF-1抑制转基因（Tg）大鼠的肝脏和骨骼肌中分析胰岛素信号传导。结果表明，CR不仅敏化了胰岛素对糖代谢的作用，而且激活了胰岛素非依赖性途径。由CR诱导的这些机制可能是由抑制的GH-IGF-1轴引起的（Yamaza H等人，Exp Gerontol 2004 ; Hayashi H等人Biomedical Gerontol 2005）。我们研究了脂联素-AMP-活化蛋白激酶（AMPK）通路在胰岛素非依赖性机制中的潜在作用。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通路。2.应激反应：我们用DNA阵列方法分析了CR大鼠的炎症应激反应。结果证实了CR大鼠的抗应激能力。肝脏中的DNA阵列分析表明，CR的保护作用来自组成性表达的基因产物，而不是NF-κ B诱导性表达的基因产物（Tsuchiya T等人，机械老化发展2005）。GH-IGF-1抑制大鼠表现出极大增强的应激反应。这种作用可能部分是由于NF-κ B诱导的促炎反应的衰减。目前，我们正在研究NF-κ B B通路以外的氧化还原敏感性转录因子和信号通路。3.线粒体中的氧化应激：包括谷胱甘肽和谷胱甘肽二硫化物的分析表明，严重抑制GH-IGF-1轴诱导氧化应激，增加肿瘤疾病，缩短大鼠的寿命，尽管中度抑制GH-IGF-1轴增加寿命。

项目成果

Handbook for Models of Human Aging (Chapter 31 A transgenic mini rat strain as a tool for studying aging and calorie restriction)

人类衰老模型手册（第31章转基因迷你大鼠品系作为研究衰老和热量限制的工具）

• 发表时间: 2006
• 作者: Shimokawa I.;Higami Y 他;林 洋子 他;Yamaza H;Tanaka K;樋上 賀一;嘉陽 毅;Shimokawa I.;Shimokawa I.;下川 功;Shimokawa I;Shimokawa I;Shimokawa I (Conn M編集)
• 通讯作者: Shimokawa I (Conn M編集)

Role of leptin signaling in the hypothalamus in the effect of calorie restriction

下丘脑瘦素信号在热量限制中的作用

• 发表时间: 2006
• 期刊: J Gerontology (in press)
• 作者: Cao;X.;Tsukamoto;T.;Nozaki;K.;Mizoshita;T.;Ogasawara;N.;Tanaka;H.;Takenaka;Y.;Kaminishi;M.;Tatematsu;M.;Higami Y;Komatsu T
• 通讯作者: Komatsu T

Calorie restriction/Healthy aging (in Japanese)

热量限制/健康老龄化（日语）

• 发表时间: 2006
• 期刊: Gerontology New Horizon 18
• 作者: Komatsu T;Chiba T;Yamaza H;To K;Toyama H;Higami Y;Shimokawa I.;Shimokawa I.
• 通讯作者: Shimokawa I.

Laboratory findings of caloric restriction in rodents and primates

啮齿动物和灵长类动物热量限制的实验室结果

• 发表时间: 2005
• 期刊: Adv Clin Chem 39
• 作者: Mizoshita;T.;Tsukamoto;T.;Nakanishi;H.;Inada;K.;Ogasawara;N.;Joh.;T.;Itoh;M.;Yamamura;Y.;Tatematsu;M.;Higami Y
• 通讯作者: Higami Y

Acute stress response in calorie-restricted rats to lipopolysaccharide-induced inflammation

• DOI: 10.1016/j.mad.2004.11.007
• 发表时间: 2005-05-01
• 期刊: MECHANISMS OF AGEING AND DEVELOPMENT
• 影响因子: 5.3
• 作者: Tsuchiya, T;Higami, Y;Shimokawa, I
• 通讯作者: Shimokawa, I