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Long-lived growth hormone receptor knockout mice: Interaction of reduced IGF-1/insulin signaling and caloric restriction.

机译：长寿命生长激素受体敲除小鼠：降低的IGF-1 /胰岛素信号传导和热量限制的相互作用。

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摘要

Reduced IGF-1/insulin signaling and caloric restriction (CR) are known to extend life span and delay age-related diseases. To address the interaction of these two interventions, we subjected normal (N) and the long-lived growth hormone receptor knockout (GHRKO) mice to CR starting at weaning for 20 months. We also used bovine growth hormone transgenic (bGH Tg) mice which overexpress GH and are short-lived and insulin resistant for comparison. Circulating insulin and IGF-1 levels were reduced by CR in N animals while GHRKO animals exhibited very low insulin and undetectable IGF-1. Consistently, hepatic Akt phosphorylation was reduced by CR and very low in GHRKO mice. bGH Tg mice exhibited increased active Akt. The transcription factor Foxo1 was additively increased by CR and GHRKO at the mRNA level. However, Foxo1 protein levels were only elevated in GHRKO mice. The coactivator PGC-1alpha was increased at both gene and protein levels in GHRKO mice. N-CR and GHRKO mice also exhibited increased phosphorylated CREB and active p38 as compared to the N-AL mice and the levels of these proteins were greatly diminished in bGH Tg mice. The protein levels of the deacetylase SIRT1 were elevated in the two CR groups and unexpectedly, also in bGH Tg mice. These results suggest a major role for Akt/Foxo1 pathway in the regulation of longevity in rodents. Activated gluconeogenic pathway and increased fat metabolism may be involved in mediating the effects of reduced somatotropic and insulin signaling on longevity. These results also add to the evidence that targeted disruption of the GHR/GHBP gene and CR act via overlapping but distinct mechanisms.; In the skeletal muscle, CR resulted in increased active AMPK and PGC-1alpha and reduced active JNK2 in normal and GHRKO mice. GHRKO animals exhibited decreased protein levels of phosphorylated PKClambda/zeta and Foxo transcription factors (Foxo1 and Foxo3). JNK1 was reduced in N-CR as well as in GHRKO mice. Reduced Foxo proteins and unaltered active Akt levels suggest that skeletal muscle is not likely to be directly involved in the life extending actions of CR and GHR mutation. However, alterations in other proteins examined in the present study suggest increased insulin sensitivity and glucose uptake which would in turn reduce insulin demand, and thus contribute to extending longevity.; Molecular alterations that favor increased stress resistance and extended longevity were more pronounced in liver than in skeletal muscle. The role of skeletal muscle appeared to be secondary to its effect in reducing circulating insulin which in turn will favor extended longevity.
机译：降低的IGF-1 /胰岛素信号传导和热量限制（CR）可以延长寿命并延缓与年龄有关的疾病。为了解决这两种干预措施之间的相互作用，我们对正常（N）和长寿的生长激素受体敲除（GHRKO）小鼠进行了20个月的断奶CR。我们还使用了牛生长激素转基因（bGH Tg）小鼠，该小鼠过表达GH，且寿命短且具有胰岛素抵抗性，以进行比较。 CR降低了N只动物的循环胰岛素和IGF-1水平，而GHRKO动物表现出非常低的胰岛素和不可检测的IGF-1。一致地，CR降低了肝Akt磷酸化，而GHRKO小鼠的肝脏Akt磷酸化非常低。 bGH Tg小鼠表现出增加的活性Akt。转录因子Foxo1在mRNA水平上被CR和GHRKO加性增加。但是，Foxo1蛋白水平仅在GHRKO小鼠中升高。在GHRKO小鼠中，辅助激活剂PGC-1alpha在基因和蛋白质水平上均增加。与N-AL小鼠相比，N-CR和GHRKO小鼠还表现出增加的磷酸化CREB和活性p38，并且这些蛋白的水平在bGH Tg小鼠中大大降低。脱乙酰基酶SIRT1的蛋白质水平在两个CR组中升高，并且出乎意料地在bGH Tg小鼠中也升高。这些结果表明Akt / Foxo1途径在啮齿动物寿命调节中的主要作用。激活的糖异生途径和增加的脂肪代谢可能参与介导生长激素和胰岛素信号降低对寿命的影响。这些结果也增加了证据，表明GHR / GHBP基因和CR的靶向破坏是通过重叠但截然不同的机制起作用的。在骨骼肌中，CR导致正常小鼠和GHRKO小鼠的活性AMPK和PGC-1alpha升高，活性JNK2降低。 GHRKO动物的磷酸化PKClambda / zeta和Foxo转录因子（Foxo1和Foxo3）的蛋白质水平降低。在N-CR和GHRKO小鼠中，JNK1均降低。 Foxo蛋白的降低和活性Akt的水平未改变表明，骨骼肌不太可能直接参与CR和GHR突变的寿命延长活动。然而，本研究中其他蛋白质的改变表明胰岛素敏感性和葡萄糖摄取增加，这反过来又会减少胰岛素需求，从而有助于延长寿命。有利于增加抗逆性和延长寿命的分子变化在肝脏中比在骨骼肌中更为明显。骨骼肌的作用似乎次于其在减少循环胰岛素中的作用，继而有利于延长寿命。

著录项

  • 作者

    Al-Regaiey, Khalid Abdullah.;

  • 作者单位

    Southern Illinois University at Carbondale.;

  • 授予单位 Southern Illinois University at Carbondale.;
  • 学科 Biology Animal Physiology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 91 p.
  • 总页数 91
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生理学;
  • 关键词

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