Interaction of caloric restriction with longevity genes

我们的长期目标是阐明激素(胰岛素/IGF-1)信号在控制衰老和 目的是研究哺乳动物的长寿情况，并确定营养摄入如何与长寿基因相互作用。我们有 研究表明，限制卡路里(CR)可以延长Ames侏儒小鼠的寿命，Ames侏儒小鼠是一种长寿的甲状腺功能低下症小鼠 突变体，但令人惊讶的是，未能延长另一种长寿突变体生长激素(GH)的寿命 抗性生长激素受体基因敲除(GHRKO)小鼠。CR改善了患者对注射胰岛素的敏感性 正常，在Ames侏儒小鼠中，但在GHRKO动物中不是。我们假设CR的失败不能延长寿命 在GHRKO小鼠中是由于极低的胰岛素水平和CR无法进一步增加胰岛素 这些动物的敏感度。我们进一步假设应激抵抗与胰岛素敏感性和 该CR不能提高GHRKO小鼠的抗应激能力。这些假设将通过以下方式进行验证 确定胰岛特异性表达的IGF-1是否有改善血糖的作用 耐受性和胰岛素分泌或用IGF-1或胰岛素替代治疗将使对 GHRKO小鼠短期CR试验。这些治疗的效果将通过测量胰岛素和 葡萄糖耐量，胰岛素相关基因在肝脏、骨骼肌和心脏中的表达(“分子 对CR的反应的特征)，培养的皮肤成纤维细胞和正常小鼠对各种应激源的抵抗力， 测量体温(TCO)和研究其他与胰岛素作用有关的参数 抗逆性。随后，我们将使用治疗方法，最接近地使对短小的- 在GHRKO小鼠中使用CR来确定它是否也会导致GHRKO小鼠恢复能力 通过延长寿命来应对慢性CR。我们还将检查CR在最近开发的 GHRH-KO单纯性GH缺陷小鼠和表达GH拮抗剂的转基因小鼠。总而言之， 这些研究将确定CR对胰岛素信号转导和应激抵抗的影响 与各种不同的基因型别的长寿有关。研究结果将提供新的见解 探讨黄连的抗衰老作用机制及胰岛素水平与应激作用的关系 抵抗、衰老和长寿，这是当前环境下公共卫生中的一个重大问题 胰岛素抵抗和代谢综合征的“流行病”。

Our long-term goals are to elucidate the role of hormonal (insulin/IGF-1) signaling in the control of aging and longevity in mammals and to determine how nutritional intake interacts with longevity genes. We have shown that caloric restriction (CR) increases longevity in the Ames dwarf mouse, a long-lived hypopituitary mutant, but surprisingly fails to extend longevity in another long-lived mutant, the growth hormone (GH) resistant, GH receptor knockout (GHRKO) mouse. Sensitivity to injected insulin was improved by CR in normal and in Ames dwarf mice but not in GHRKO animals. We hypothesize that failure of CR to prolong life in GHRKO mice is due to extremely low insulin levels and the inability of CR to further increase insulin sensitivity in these animals. We further hypothesize that stress resistance is related to insulin sensitivity and that CR will fail to improve stress resistance in GHRKO mice. These hypotheses will be tested by determining whether pancreatic islet-specific expression of IGF-1 that was shown to improve glucose tolerance and insulin secretion or replacement therapy with IGF-1 or insulin will normalize responses to short-term CR in GHRKO mice. Effects of these treatments will be assessed by measuring insulin and glucose tolerance, expression of insulin-related genes in the liver, skeletal muscle and heart (the "molecular signature" of responses to CR), resistance of cultured skin fibroblasts and intact mice to variousstressors, measurements of body core temperature (Tco) and study of other parameters related to insulin action and stress resistance. Subsequently, we will use therapy that most closely "normalizes" the responses to short- term CR in GHRKO mice to determine whether it will also result in GHRKO mice regaining the ability to respond to chronic CR by increasing longevity. We will also examine effects of CR in the recently developed Ghrh-KO mice with isolated GH deficiency and in transgenic mice expressing GH antagonist. Collectively, these studies will identify the effects of CR on insulin signaling and stress resistance that are consistently associated with prolonged longevity across a variety of genotypes. The results will provide novel insights into the mechanisms of anti-aging actions of CR and into the relationship of insulin level and actions to stress resistance, aging and longevity, an issue of major significance in public health in the context of the current "epidemic" of insulin resistance and metabolic syndrome.