Mechanisms of Aging Regulation by Neuronal mTORC1 in C. elegans

线虫神经元 mTORC1 的衰老调节机制

• 批准号: 10386130
• 负责人: Hannah J Smith
• 金额: $ 3.85万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386130
• 关键词: Affect; Afferent Neurons; Age of Onset; Aging; Automobile Driving; Auxins; Back; Biological; Caenorhabditis elegans; Cells; Chimeric Proteins; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Developmental Delay Disorders; Disease; FRAP1 gene; Fertility; Genes; Genetic Models; Goals; Growth; Growth and Development function; Health; Human; Impairment; Individual; Intervention; Intestines; Knowledge; Lead; Longevity; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Mitochondria; Motor Neurons; Neurons; Neuropeptide Gene; Nutrient; Pathway interactions; Peripheral; Pharmacology; Phenotype; Process; Proteins; RNA; RRAGA gene; Regulation; Reproduction; Resistance; RiboTag; Ribosomes; Risk Factors; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Stress; System; Testing; Therapeutic; Tissues; Vesicle; Work; age related; anti aging; base; cell growth; design; experimental study; healthy aging; human old age (65+); mutant; neurotransmission; neurotransmitter release; prevent; sensor; side effect; therapy design; tool; transcriptome sequencing

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.

项目摘要 老龄化是多种慢性病的主要危险因素，三分之二的65岁以上的人 患有多种与年龄有关的疾病。与其试图治愈每一种疾病， 可以通过靶向调节衰老速度的生物途径来促进。mTORC1 （雷帕霉素复合物I的机制靶点）信号通路促进细胞生长和发育 当营养物质丰富时，它的抑制会延长一系列物种的寿命。然而，承诺 作为抗衰老治疗剂的mTORC 1抑制受到相关负面副作用的限制， 生长发育和生育能力受到阻碍。本项目的首要目标是了解 mTORC 1特异性调节衰老的机制和关键组织， 确定针对mTORC 1通路的方法，该通路可以将寿命与不良健康影响分开。 以前的工作在C。elegans发现了mTORC 1通过神经元调节衰老的证据。在一个长寿的 mTORC 1信号在整个身体中减少的突变体，仅在 神经元将寿命抑制回野生型。然而，这种神经元mTORC 1拯救对 无效突变体的生长或发育受损，这表明在关键组织中靶向mTORC 1可能 是一种将衰老调节与其他mTORC 1功能分离的策略。最后，这项工作发现， 神经元mTORC 1信号转导诱导多种神经肽基因表达的变化， 周围组织中线粒体网络的形状。基于这些发现，我们最近 产生了新的数据，显示在C. elegans延长寿命， 损害生长或发展。因此，该提议的中心假设是mTORC 1调节 衰老，独立于其他功能，通过调节神经元信号传导， 诱导外周组织中细胞非自主的代谢变化。我们会用一套纸巾- 研究这一假设的特定工具，并探索mTORC 1的衰老调节机制， 前所未有的特殊性。在目标1中，我们将评估神经元mTORC 1抑制如何影响表型 与全身mTORC 1抑制相关-如生长、发育、生殖和应激 抵抗力-并测试周围组织中的线粒体网络是否发生变化。我们将 还确定了神经元mTORC 1寿命所需的下游生物学途径。在目标2中， 将确定特定的神经元信号分子和神经元类型，mTORC 1通过这些神经元发挥作用， 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 并允许我们设计策略，以促进健康长寿的方式针对这些途径。