Interaction of caloric restriction with longevity genes

我们的长期目标是阐明激素（胰岛素/IGF-1）信号在控制衰老中的作用， 研究哺乳动物的寿命，并确定营养摄入如何与长寿基因相互作用。我们有 表明热量限制（CR）增加了艾姆斯侏儒小鼠的寿命， 突变体，但令人惊讶的是，未能延长寿命的另一个长寿的突变体，生长激素（GH） 抗GH受体敲除（GHRKO）小鼠。CR改善了对注射胰岛素的敏感性， 正常和艾姆斯侏儒小鼠中，但在GHRKO动物中没有。我们假设CR不能延长生命 GHRKO小鼠中的胰岛素水平极低，CR无法进一步增加胰岛素 这些动物的敏感性。我们进一步假设应激抵抗与胰岛素敏感性有关， CR将无法提高GHRKO小鼠的应激抵抗力。这些假设将由以下人员进行检验： 确定胰岛素样生长因子-1的胰岛特异性表达是否能改善血糖， 耐受性和胰岛素分泌或用IGF-1或胰岛素的替代疗法将使对 GHRKO小鼠中的短期CR。这些治疗的效果将通过测量胰岛素来评估， 葡萄糖耐量、肝脏、骨骼肌和心脏中胰岛素相关基因的表达（“分子”） 对CR的反应的“签名”），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）和研究与胰岛素作用相关的其他参数， 抗逆性随后，我们将使用治疗，最接近“正常化”的反应，以短- 在GHRKO小鼠中进行术语CR，以确定其是否也将导致GHRKO小鼠恢复以下能力： 通过延长寿命来应对慢性CR。我们还将研究CR在最近开发的 Ghrh-KO小鼠与孤立的GH缺乏症和转基因小鼠表达GH拮抗剂。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， 与各种基因型的长寿相关。研究结果将提供新的见解 研究了CR的抗衰老作用机制以及胰岛素水平与应激反应的关系 抵抗力、衰老和长寿，在当前的背景下，这是一个对公共卫生具有重大意义的问题。 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.