How Insulin/IGF-1 Deficiencies Retard Mammalian Aging

描述（由申请人提供）：本项目定义了小鼠体内胰岛素和IGF-1通路特异性缺陷如何影响衰老机制、随年龄增长的生物学变化和寿命。广泛的目标是了解胰岛素/IGF-1通路对哺乳动物衰老的影响，并延缓人类年龄的有害变化。目标1：在小鼠中，特定组织中胰岛素信号的消除再现了(a) Ghrhrlit （lit/lit）突变或(b)饮食限制（DR）的胰岛素/IGF-1联合信号损伤的益处；此外，（lit/lit）突变的影响再现了dr的影响。在白色脂肪（FIRKO）、神经组织（NIRKO）以及两者（FIRKO和NIRKO）中靶向缺乏胰岛素受体（IR）的小鼠中，随着年龄的变化与lit/lit突变体和dr治疗小鼠的衰老进行了对比。在这里和目标2和3中，C57BL/6J X C3H/HeJ F1混合（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]）的作用与Aim 1和DR中的突变体进行比较，以确定特定组织中受损胰岛素途径的益处是否冗余，附加或协同减少胰岛素和IGF-1的lit/lit突变体。目的3：胰岛素信号的减少，而不是肥胖，介导了FIRKO小鼠衰老的有益作用。暴饮暴食Lepob （ob/ob）突变与FIRKO突变结合，产生肥胖的FIRKO小鼠，以测试是否在体脂水平增加的情况下延缓衰老速度。健康相关性：在每个目标中，衰老机制和速率在具有临床相关性的生物系统中进行测试：对白血病或氧化的抵抗力；胶原蛋白、T细胞、身体组成、新陈代谢、葡萄糖、胰岛素、IGF-1、瘦素、红细胞压积和骨骼组成的衰老率；寿命和病理病变。这些实验将胰岛素和IGF-1通路的功能定义为导致疾病和死亡易感性随年龄增长而增加的潜在机制的调节器。了解胰岛素和IGF-1通路功能的降低是如何延缓哺乳动物衰老的，可能会为改善人类衰老的健康状况提供治疗建议。

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.