mTORC1 signaling in aging and metabolism

项目摘要/摘要 许多与衰老相关的信号通路与新陈代谢信号和应激的调节有关 反应途径。例如，雷帕霉素(TOR)途径的靶点是一个进化保守的 在所有真核细胞中调节生长和新陈代谢的营养感应蛋白激酶。两个综合体， MTORC1和2具有重叠的上游调控因子和下游效应器。减少了mTOR信令， 通过基因干预或临床批准的药物雷帕霉素，延长小鼠的寿命(也 例如酵母、蠕虫和苍蝇)，延缓许多衰老的病理过程。鉴于它在衰老和衰老中的核心作用 新陈代谢方面，了解mTOR通路的不同扰动如何影响衰老和 新陈代谢。在这里，我们使用小鼠模型和细胞培养研究来测试主要的下游目标之一 MTORC14E-BP1。强调4E-BP1的合理性，增强的4E-BP活动与寿命相关 在蠕虫和苍蝇中推广，我们发现过度表达4E-BP1的转基因小鼠对高脂肪具有抵抗力 饮食引起的代谢功能障碍。我们将使用多个小鼠模型来研究4E-BP1在两者中的过度表达 营养过剩和衰老研究。初步数据显示，炎症导致的4E-BP1丢失 在高脂肪饮食背景下的表达是男性转化为葡萄糖的特定倾向的基础 不耐受和胰岛素抵抗。我们将确定这种性别二态现象背后的机制及其 对mTOR途径的影响。对饮食和衰老的性别特异性反应在小鼠模型和 在人类中，但性别特异性的潜在原因在很大程度上是未知的。此外，我们将确定 为什么肌肉特异性激活4E-BP1既保留了骨骼肌功能，又保留了棕色脂肪含量 营养过剩和衰老，重点关注最近的发现，将有益于骨骼肌生产和 肌动因子FGF21的分泌。总而言之，这些研究将产生关于 衰老和新陈代谢背景下mTOR信号的特异性，提供了更好的理解 该途径如何调节衰老并将mTOR途径的调节与其他药理作用联系起来 对老龄化的干预。

Project Summary/Abstract Many signaling pathways linked to aging are linked to the regulation of metabolic signaling and stress response pathways. For instance, the target of rapamycin (TOR) pathway is an evolutionarily-conserved nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Two complexes, mTORC1 and 2, have overlapping upstream regulators and downstream effectors. Reduced mTOR signaling, either by genetic intervention or with the clinically approved drug rapamycin, extends longevity in mice (as well as yeast, worms and flies) and delays many pathologies of aging. Given its central role in aging and metabolism, it is critical to understand how different perturbations of the mTOR pathway impact aging and metabolism. Here, we use mouse models and cell culture studies to test one of the major downstream targets of mTORC1, 4E-BP1. Justifying the emphasis on 4E-BP1, enhanced 4E-BP activity is associated with lifespan extension in worms and flies, and we find that transgenic mice overexpressing 4E-BP1 are resistant to high fat diet-induced metabolic dysfunction. We will employ multiple mouse models of 4E-BP1 overexpression in both overnutrition and aging studies. Preliminary data indicates that an inflammation-induced loss of 4E-BP1 expression in the context of a high fat diet underlies the specific propensity of males to become glucose intolerant and insulin resistant. We will determine the mechanisms underlying this gender dimorphism and its impact on the mTOR pathway. Gender-specific responses to diet and aging are rampant in mouse models and in humans, but the underlying causes of gender-specificity is largely unknown. In addition, we will determine why muscle specific activation of 4E-BP1 preserves both skeletal muscle function and brown fat content during overnutrition and aging, focusing on recent findings linking the benefits to skeletal muscle production and secretion of the myokine, FGF21. Together, these studies will yield several new insights regarding the specifics of mTOR signaling in the context of aging and metabolism, providing a better understanding about how this pathway modulates aging and linking modulation of the mTOR pathway to other pharmacologic interventions in aging.