Dissection of the IGF-Longevity Connection in a Novel Mouse Model

描述（由申请人提供）：胰岛素样生长因子（IGF）-I信号传导的减少与不同物种的寿命延长和年龄相关疾病的延迟发作有关。然而，与IGF系统相关的衰老过程的潜在机制仍有待确定。IGF系统是复杂的，具有普遍表达的IGF受体，介导不同的生物学结果。还有一种IGF结合蛋白（IGFBP）和IGFBP蛋白酶的补充，最终决定配体的可用性，因此，调节细胞反应。最近的体外和体内研究已经确定了一种新的IGFBP蛋白酶，PAPP-A，控制局部IGF作用。我们的总体假设是，哺乳动物的衰老过程是由IGFBPase/PAPP-A调节的。IGFBPase/PAPP-A是一种分泌蛋白，其降解抑制性IGFBP，从而增加可用于受体活化的IGF-I。因此，降低IGFBPase/PAPP-A表达或抑制其蛋白水解活性（从而降低IGF-I生物利用度）的干预措施应延长寿命。我们在IGFBPase/PAPP-A敲除小鼠中的数据强烈支持这一原则，即，IGFBPase/PAPP-A的遗传缺失延长了小鼠的平均寿命和最大寿命。重要的是要了解这种长寿的机制，以便为靶向IGF-I作用的细胞外调节因子IGFBPase/PAPP-A的抗衰老疗法的潜在开发建立科学基础。为了实现这一目标，该提案的具体目的是：1）确定野生型和IGFBPase/PAPP-A敲除小鼠中的死亡率和年龄相关的病理学，2）定义机制组件（例如，本发明的目的在于提供与IGFBPase/PAPP-A敲除小鼠的延长寿命相关的免疫功能（例如，代谢、抗氧化防御、线粒体DNA损伤）的评估，3）确定IGFBPase/PAPP-A缺乏是否影响免疫能力，和4）评估胎儿发育期间IGFBPase/PAPP-A缺乏对延长寿命的贡献。拟议的研究旨在更好地了解IGFBPase/PAPP-A和IGF系统在衰老的基础生物学中的作用，并对减缓衰老过程和提高人类寿命质量的新策略产生影响。

DESCRIPTION (provided by applicant): A reduction in insulin-like growth factor (IGF)-I signaling has been associated with an extension in lifespan and the delayed onset of age-related disorders in diverse species. However, the underlying mechanisms of the aging process related to the IGF system remain to be determined. The IGF system is complex with ubiquitously expressed IGF receptors that mediate diverse biological outcomes. There is also a complement of IGF binding proteins (IGFBPs) and IGFBP proteases that ultimately determine ligand availability and, therefore, regulate cellular response. Recent in vitro and in vivo studies have identified a novel IGFBP protease, PAPP-A, that controls local IGF action. Our overall hypothesis is that the aging process in mammals is regulated by IGFBPase/PAPP-A. IGFBPase/PAPP-A is a secreted protein that degrades an inhibitory IGFBP thereby increasing IGF-I available for receptor activation. Thus, interventions that decrease IGFBPase/PAPP-A expression or inhibit its proteolytic activity (thereby decreasing IGF-I bioavailability) should increase longevity. Our data in IGFBPase/PAPP-A knock-out mice strongly support this tenet, i.e., genetic deletion of IGFBPase/PAPP-A extends both the mean and maximum lifespan of mice. It will be important to understand the mechanisms underlying this longevity in order to establish a scientific basis for potential development of anti-aging therapies targeting an extracellular regulator of IGF-I action, IGFBPase/PAPP-A. Towards this goal, the Specific Aims of the proposal are to: 1) Determine mortality rates and age-related pathologies in wild-type and IGFBPase/PAPP-A knock-out mice, 2) Define the mechanistic components (e.g., metabolism, antioxidant defenses, mitochondrial DNA damage) associated with the extended lifespan of IGFBPase/PAPP-A knock-out mice, 3) Determine if IGFBPase/PAPP-A deficiency affects immune competence, and 4) Assess the contribution of IGFBPase/PAPP-A deficiency during fetal development to extended lifespan. The proposed studies seek to gain a better understanding of IGFBPase/PAPP-A and the IGF system in the fundamental biology of aging, with implications for novel strategies to slow the aging process and increase quality lifespan in humans.