How Insulin/IGF-1 Deficiencies Retard Mammalian Aging

描述(由申请人提供)：这个项目定义了衰老的机制、生物学随年龄的变化以及小鼠的寿命如何受到特定的胰岛素和IGF-1途径缺陷的影响。其主要目标是了解胰岛素/IGF-1途径对哺乳动物衰老的影响，并延缓人类随年龄增长的有害变化。测试了下列假设：目的1：在小鼠中，消除特定组织中的胰岛素信号会产生以下益处：(A)Ghrhrlight(LIT/LIT)突变或(B)饮食限制(DR)的胰岛素/IGF-1信号受损；以及(LIT/LIT)突变的影响再现DR的效应；在针对白色脂肪(Firko)、神经组织(NIRKO)和两者(Firko&NIRKO)中缺乏胰岛素受体(IR)的小鼠中，针对白色脂肪(Firko)、神经组织(NIRKO)和两者(Firko&NIRKO)的小鼠，与LIT/LIT突变体以及经DR治疗的小鼠中的衰老相比，(LIT/LIT)突变的效应再现了DR的效应。在这里和在AIMS 2和3中，C57BL/6J X C3H/Hej F1杂交(B6C3HF1)背景为直接比较提供了强大的标准化基础。目的2：减少胰岛素和IGF-1信号的有益作用是相加的。将组合突变体([Firko&LIT/LIT]、[NIRKO&LIT/LIT]和[Firko&NIRKO&LIT/LIT])与AIM 1中的突变体和DR中的突变体进行比较，以确定特定组织中受损的胰岛素途径的益处是多余的、相加的，还是与LIT/LIT突变体减少的胰岛素和IGF-1协同作用的。目的3：胰岛素信号的减少，而不是肥胖，介导了对Firko小鼠衰老的有益影响。肥胖性Lepob(ob/ob)突变与Firko突变相结合，产生肥胖的Firko小鼠，以测试尽管体内脂肪水平增加，衰老速度是否会放缓。与健康相关：在每个目标中，衰老机制和速率都在与临床相关的生物系统中进行测试：对白血病或氧化的抵抗力；胶原、T细胞、身体成分、新陈代谢、葡萄糖、胰岛素、IGF-1、瘦素、红细胞压积和骨组成的衰老速率；寿命和病理损伤。这些实验将胰岛素和IGF-1途径的功能定义为潜在机制的调节，这些机制导致疾病和死亡的易感性随着年龄的增加而增加。了解胰岛素和IGF-1途径功能的降低如何延缓哺乳动物衰老的各个方面，可能会建议随着人类年龄的增长而改善健康的治疗方法。

DESCRIPTION (provided by applicant): This project defines how mechanisms of aging, biological changes with age, and life spans are affected by specific deficiencies in the insulin and IGF-1 pathways in mice. The broad objectives are to understand effects of the insulin/IGF-1 pathways on mammalian aging, and to retard deleterious changes with age in human beings. The following hypotheses are tested: Aim 1: That, in mice, elimination of insulin signaling in specific tissues reproduces the benefits of (a) the combined insulin/IGF-1 signal impairment of the Ghrhrlit (lit/lit) mutation or of (b) diet restriction (DR); also, that the effects of the (lit/lit) mutation reproduce effects of DR. Changes with age in mice targeted to lack the insulin receptor (IR) in white fat (FIRKO), in neural tissue (NIRKO), and in both (FIRKO & NIRKO) are contrasted with aging in the lit/lit mutant, and in the DR-treated mouse. Here and in Aims 2 & 3, the C57BL/6J X C3H/HeJ F1 hybrid (B6C3HF1) background provides a robust standardized foundation for direct comparisons. Aim 2: That the beneficial effects of reduced insulin and IGF-1 signaling are additive. The effects of the combined mutants ([FIRKO & lit/lit\, [NIRKO & lit/lit], and [FIRKO & NIRKO & lit/lit) are compared with the mutants in Aim 1 and with DR, to determine whether the benefits of the impaired insulin pathway in specific tissues are redundant, additive, or synergistic to the diminished insulin and IGF-1 of lit/lit mutants. Aim 3: That reduction in insulin signaling, not adiposity, mediates beneficial effects on aging in FIRKO mice. The hyperphagic Lepob (ob/ob) mutation is combined with the FIRKO mutation, producing obese FIRKO mice, to test if aging rates are retarded despite increased levels of body fat. Health relevance: In each aim, aging mechanisms and rates are tested in biological systems with clinical relevance: resistance to leukemias or oxidation; rates of aging in collagen, T cells, body composition, metabolism, glucose, insulin, IGF-1, leptin, hematocrit and bone composition; life spans and pathological lesions. These experiments define function of the insulin and IGF-1 pathways as regulators of underlying mechanisms causing increases, with age, in vulnerability to disease and death. Understanding how reductions in function of the insulin and IGF-1 pathways delay aspects of mammalian aging may suggest treatments to improve health as human beings age.