Mechanisms of Aging Regulation by Neuronal mTORC1 in C. elegans

项目总结 老龄化是多种慢性病的主要风险因素，65岁以上的人中有三分之二 患有多种与年龄相关的疾病。与其试图治愈每一种疾病，健康的老龄化 可以通过靶向调节衰老速度的生物途径来促进。MTORC1 (雷帕霉素复合体I的机制靶点)信号通路促进细胞生长发育 当营养丰富时，它的抑制作用会延长一系列物种的寿命。然而，承诺的是 作为一种抗衰老疗法，mTORC1抑制受到相关负面副作用的限制，如 发育迟缓的生长、发育和生育受阻的本项目的首要目标是了解 MTORC1特异性调节衰老的机制和关键组织 找出针对mTORC1途径的方法，使长寿与不利的健康影响分离。 之前对线虫的研究发现了mTORC1通过神经元调节衰老的证据。在一个长久的生命中 突变体整个身体的mTORC1信号减少，仅在 神经元将寿命抑制回到野生型。然而，这种神经元mTORC1的拯救对 缺失突变体的生长或发育受损，提示在关键组织中靶向mTORC1可能 是一种将衰老调节与其他mTORC1功能分离的策略。最后，本工作发现，恢复 神经元mTORC1信号诱导多种神经肽基因表达的改变 周围组织中线粒体网络的形状。在这些发现的基础上，我们最近 产生的新数据表明，在线虫中抑制神经元特异性mTORC1可以延长寿命 损害生长或发育的。因此，这一提议的中心假设是mTORC1调节 衰老，独立于其他功能，通过神经元调节神经元信号和 诱导代谢改变外周组织中的细胞--非自主的。我们会用一套纸巾- 研究这一假说并探索mTORC1衰老调节机制的特定工具 前所未有的专一性。在目标1中，我们将评估神经元mTORC1抑制如何影响表型。 与全身mTORC1抑制有关--如生长、发育、繁殖和应激 抵抗力-并测试外周组织中的线粒体网络是否发生变化。我们会 还要确定神经元mTORC1长寿所需的下游生物通路。在目标2中，我们 将确定特定的神经元信号分子和mTORC1通过其发挥作用的神经元类型 调节衰老。总之，这项工作将加深我们对代谢途径如何调节衰老的理解 并使我们能够设计策略，以促进健康长寿的方式针对这些途径。

PROJECT SUMMARY Aging is the major risk factor for multiple chronic diseases and two-thirds of individuals over the age of 65 suffer from multiple age-related conditions. Rather than trying to cure each individual disease, healthy aging can be promoted by targeting the biological pathways that regulate the rate of aging. The mTORC1 (mechanistic target of rapamycin complex I) signaling pathway promotes cellular growth and development when nutrients are abundant and its inhibition extends lifespan in a range of species. However, the promise of mTORC1 inhibition as an anti-aging therapeutic is limited by the associated negative side effects such as stunted growth, development, and fertility. The overarching goal of this project is to understand the mechanisms and key tissues through which mTORC1 specifically regulates aging in an effort to identify ways to target the mTORC1 pathway that can uncouple longevity from adverse health effects. Previous work in C. elegans found evidence that mTORC1 regulates aging through the neurons. In a long-lived mutant with decreased mTORC1 signaling throughout its entire body, restoring mTORC1 signaling only in the neurons suppressed the lifespan back to wild type. However, this neuronal mTORC1 rescue had no effect on the impaired growth or development of the null mutant, suggesting that targeting mTORC1 in key tissues may be a strategy to uncouple aging regulation form other mTORC1 functions. Lastly, this work found that restoring neuronal mTORC1 signaling induced changes in the expression of multiple neuropeptide genes and altered the shape of the mitochondrial network in peripheral tissues. Building on these findings, we have recently generated new data showing that neuron-specific mTORC1 inhibition in C. elegans extends lifespan without impairing growth or development. Thus, the central hypothesis of this proposal is that mTORC1 regulates aging, independently of other functions, through the neurons by modulating neuronal signaling and inducing metabolic changes cell-nonautonomously in peripheral tissues. We will use a suite of tissue- specific tools to investigate this hypothesis and probe the mechanisms of aging regulation by mTORC1 with unprecedented specificity. In Aim 1, we will assess how neuronal mTORC1 inhibition affects phenotypes associated with whole-body mTORC1 inhibition – such as growth, development, reproduction, and stress resistance – and test whether there are changes to the mitochondrial network in peripheral tissues. We will also identify downstream biological pathways that are required for neuronal mTORC1 longevity. In Aim 2, we will identify the specific neuronal signaling molecules and types of neurons through which mTORC1 acts to regulate aging. Altogether, this work will deepen our understanding of how metabolic pathways regulate aging and allow us to design strategies to target these pathways in a manner that promotes healthy longevity.