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信号的减少与不同物种的寿命延长和年龄相关疾病的延迟发病有关。然而，与IGF系统相关的衰老过程的潜在机制仍有待确定。胰岛素样生长因子系统是一个复杂的系统，它具有广泛表达的胰岛素样生长因子受体，介导多种生物学结果。此外，还有一系列IGF结合蛋白(IGFBPs)和IGFBP蛋白，它们最终决定了配体的可用性，从而调节了细胞的反应。最近的体外和体内研究发现了一种新的IGFBP蛋白酶，PAPP-A，它控制着局部IGF的作用。我们的总体假设是哺乳动物的衰老过程是由IGFBPase/PAPP-A调控的。IGFBPase/PAPP-A是一种分泌蛋白，能降解抑制的IGFBP，从而增加可用于受体激活的IGF-I。因此，减少IGFBPase/PAPP-A表达或抑制其蛋白分解活性(从而降低IGF-I的生物利用度)的干预措施应该会延长寿命。我们在IGFBPase/PAPP-A基因敲除小鼠中的数据有力地支持了这一原理，即IGFBPase/PAPP-A的基因缺失延长了小鼠的平均寿命和最长寿命。重要的是要了解这种长寿的机制，以便为潜在的针对IGF-I作用的细胞外调节因子IGFBPase/PAPP-A的抗衰老疗法的开发奠定科学基础。为了实现这一目标，该建议的具体目标是：1)确定野生型和IGFBPase/PAPP-A基因敲除小鼠的死亡率和与年龄相关的病理变化；2)确定与IGFBPase/PAPP-A基因敲除小鼠延长寿命有关的机制成分(例如代谢、抗氧化防御、线粒体DNA损伤)；3)确定IGFBPase/PAPP-A缺陷是否影响免疫能力；以及4)评估IGFBPase/PAPP-A缺陷在胎儿发育过程中对延长寿命的贡献。这些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，并为减缓人类衰老过程和延长高质量寿命的新策略提供启示。

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.