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: 10608935
• 负责人: Hannah J Smith
• 金额: $ 3.37万
• 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/10608935
• 关键词: Affect; Afferent Neurons; Age of Onset; Aging; Automobile Driving; Auxins; Back; Biological; Caenorhabditis elegans; Categories; Cells; Chimeric Proteins; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Disease; FRAP1 gene; Fertility; Genes; Genetic Models; Goals; Growth; Growth and Development function; Health; Human; Immunoprecipitation; Impairment; Individual; Intervention; Intestines; Knowledge; Longevity; Mediating; Mediator; Metabolic; Metabolic Pathway; Mitochondria; Motor Neurons; Neurons; Neuropeptide Gene; Nutrient; Pathway interactions; Peripheral; Phenotype; Process; Proteins; RNA; RRAGA gene; Regulation; Reproducibility; Reproduction; Resistance; RiboTag; Ribosomes; Risk Factors; Shapes; Signal Induction; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Stress; System; Testing; Therapeutic; Tissues; Vesicle; Work; age related; anti aging; cell growth; cellular development; design; experimental study; healthy aging; human old age (65+); mutant; neurotransmission; neurotransmitter release; pharmacologic; 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.

项目概要 衰老是多种慢性病的主要危险因素，三分之二的人年龄超过 65 岁 与其试图治愈每种疾病，不如尝试健康老龄化。 可以通过靶向调节衰老速率的生物途径来促进。 （雷帕霉素复合物I的机制靶标）信号通路促进细胞生长和发育 当营养丰富时，它的抑制作用可以延长一系列物种的寿命。 mTORC1 抑制作为一种抗衰老疗法受到相关负面副作用的限制，例如 该项目的总体目标是了解生长、发育和发育迟缓。 mTORC1 特异性调节衰老的机制和关键组织 找出针对 mTORC1 通路的方法，从而将长寿与不良健康影响分开。 之前对秀丽隐杆线虫的研究发现，mTORC1 通过神经元调节衰老。 整个体内 mTORC1 信号减弱的突变体，仅在体内恢复 mTORC1 信号 神经元的寿命被抑制回到野生型，然而，这种神经元 mTORC1 拯救对它们没有影响。 无效突变体的生长或发育受损，表明靶向关键组织中的 mTORC1 可能 是一种将衰老调节与其他 mTORC1 功能分离的策略。 神经元 mTORC1 信号传导诱导多种神经肽基因表达的变化并改变 基于这些发现，我们最近研究了外周组织中线粒体网络的形状。 生成的新数据表明，秀丽隐杆线虫中神经元特异性 mTORC1 抑制可延长寿命，而无需 因此，该提案的中心假设是 mTORC1 进行调节。 衰老，独立于其他功能，通过神经元通过调节神经信号传导和 我们将使用一套组织在外周组织中非自主地诱导代谢变化。 特定工具来研究这一假设并探讨 mTORC1 的衰老调节机制 在目标 1 中，我们将评估神经 mTORC1 抑制如何影响表型。 与全身 mTORC1 抑制相关——例如生长、发育、繁殖和压力 抵抗力 - 并测试外周组织中的线粒体网络是否发生变化。 在目标 2 中，我们还确定了神经元 mTORC1 寿命所需的下游生物学途径。 将识别 mTORC1 发挥作用的特定神经元信号分子和神经元类型 总而言之，这项工作将加深我们对代谢途径如何调节衰老的理解。 并让我们能够设计针对这些途径的策略，以促进健康长寿。