mTORC1 signaling in aging and metabolism

项目总结/摘要 许多与衰老有关的信号通路与代谢信号和压力的调节有关 响应路径。例如，雷帕霉素（TOR）通路的靶点是进化上保守的靶点。 营养感应蛋白激酶，调节所有真核细胞的生长和代谢。两个复合体， mTORC 1和2具有重叠的上游调节子和下游效应子。减少mTOR信号传导， 无论是通过基因干预还是使用临床批准的药物雷帕霉素， 如酵母、蠕虫和苍蝇），并延缓许多衰老的病理。鉴于其在老龄化和 因此，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一个主要的下游靶点 mTORC1，4E-BP1。为了证明对4 E-BP 1的强调，增强的4 E-BP活性与寿命相关 在蠕虫和苍蝇中的延伸，我们发现过表达4 E-BP 1的转基因小鼠对高脂肪有抵抗力， 饮食引起的代谢紊乱我们将采用多种4 E-BP 1过表达的小鼠模型， 营养过剩和衰老的研究。初步数据表明，炎症诱导的4 E-BP 1损失 在高脂肪饮食的背景下，表达是雄性变得葡萄糖 不耐受和胰岛素抵抗。我们将确定这种性别二态性的机制及其 对mTOR通路的影响在小鼠模型中，对饮食和衰老的性别特异性反应非常普遍， 在人类中，但性别特异性的根本原因在很大程度上是未知的。此外，我们将确定 为什么4 E-BP 1的肌肉特异性激活在肌肉生长过程中保留了骨骼肌功能和棕色脂肪含量 营养过剩和衰老，重点是最近的发现，将骨骼肌生产的好处， 肌因子FGF 21的分泌。总之，这些研究将产生一些新的见解， 在衰老和代谢的背景下，mTOR信号传导的细节，提供了更好的理解， 这条通路如何调节衰老，以及mTOR通路的调节与其他药理学 干预老龄化。

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.