Interaction of caloric restriction with longevity genes

描述（由申请人提供）：我们的长期目标是阐明激素（胰岛素/IGF-1）信号传导在哺乳动物衰老和长寿控制中的作用，并确定营养摄入如何与长寿基因相互作用。我们已经证明，热量限制（CR）增加寿命的艾姆斯侏儒小鼠，一个长寿的低血压突变，但令人惊讶的是，未能延长寿命的另一个长寿的突变，生长激素（GH）抗性，GH受体敲除（GHRKO）小鼠。在正常和艾姆斯侏儒小鼠中，CR改善了对注射胰岛素的敏感性，但在GHRKO动物中没有。我们假设CR未能延长GHRKO小鼠的生命是由于极低的胰岛素水平和CR无法进一步增加这些动物的胰岛素敏感性。我们进一步假设应激抵抗与胰岛素敏感性有关，CR将无法改善GHRKO小鼠的应激抵抗。这些假设将通过确定显示改善葡萄糖耐量和胰岛素分泌的IGF-1的胰岛特异性表达或IGF-1或胰岛素的替代疗法是否将使GHRKO小鼠中对短期CR的应答正常化来检验。这些治疗的效果将通过测量胰岛素和葡萄糖耐量、肝脏、骨骼肌和心脏中胰岛素相关基因的表达（对CR的反应的“分子特征”）、培养的皮肤成纤维细胞和完整小鼠对各种应激源的抗性、测量身体核心温度（Tco）以及研究与胰岛素作用和应激抗性相关的其他参数来评估。随后，我们将使用使GHRKO小鼠对短期CR的反应最接近“正常化”的疗法，以确定其是否也将导致GHRKO小鼠通过延长寿命而恢复对慢性CR的反应能力。我们还将研究CR在最近开发的Ghrh-KO小鼠孤立GH缺乏症和表达GH拮抗剂的转基因小鼠中的作用。总的来说，这些研究将确定CR对胰岛素信号传导和应激抵抗的影响，这些影响与各种基因型的长寿一致。结果将提供新的见解CR的抗衰老作用的机制和胰岛素水平和行动的关系，以抗应激，衰老和长寿，一个具有重大意义的问题，在公共卫生的背景下，目前的“流行病”的胰岛素抵抗和代谢综合征。

DESCRIPTION (provided by applicant): 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 various stressors, 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.