How Insulin/IGF-1 Deficiencies Retard Mammalian Aging

描述（由申请人提供）：该项目定义了衰老机制、随年龄变化的生物学变化和寿命如何受到小鼠胰岛素和IGF-1途径特定缺陷的影响。其主要目的是了解胰岛素/IGF-1通路对哺乳动物衰老的影响，并延缓人类随着年龄的增长而发生的有害变化。目的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）的组合胰岛素/IGF-1信号损伤的益处;另外，在一个实施例中，在白色脂肪中缺乏胰岛素受体（IR）的小鼠中，FIRKO）、神经组织（NIRKO）和两者（FIRKO & NIRKO）中的衰老与lit/lit突变体和DR处理的小鼠中的衰老进行对比。在此以及在目标2和3中，C57 BL/6 J X C3 H/HeJ F1杂种（B6 C3 HF 1）背景为直接比较提供了稳健的标准化基础。目的2：减少胰岛素和IGF-1信号传导的有益作用是累加的。将组合突变体（[FIRKO & lit/lit]、[NIRKO & lit/lit]和[FIRKO & NIRKO & lit/lit]）的作用与Aim 1中的突变体和DR进行比较，以确定特定组织中受损的胰岛素途径的益处对于lit/lit突变体的减少的胰岛素和IGF-1是否是多余的、加和的或协同的。目的3：减少胰岛素信号，而不是肥胖，介导对FIRKO小鼠衰老的有益作用。将嗜食性Lepob（ob/ob）突变与FIRKO突变相结合，产生肥胖的FIRKO小鼠，以测试尽管体脂水平增加，但衰老速度是否减慢。健康相关性：在每个目标中，老化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、代谢、葡萄糖、胰岛素、IGF-1、瘦素、血细胞比容和骨组成的老化速率;寿命和病理损伤。这些实验将胰岛素和IGF-1通路的功能定义为导致随着年龄增长而易患疾病和死亡的潜在机制的调节剂。了解胰岛素和IGF-1通路功能的减少如何延迟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.