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; 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 衰老是多种慢性疾病和三分之二的人的主要危险因素65岁 患有多种与年龄有关的条件。健康衰老而不是试图治愈每种疾病 可以通过靶向调节衰老率的生物学途径来促进。 mtorc1 （雷帕霉素复合物的机械靶标i）信号通路促进了细胞的生长和发育 当营养丰富并且其抑制作用会延长一系列物种的寿命。但是，承诺 MTORC1抑制作用作为抗衰老疗法受到相关的负副作用的限制，例如 发育不良，发育和生育能力。该项目的总体目标是了解 MTORC1特异性调节衰老的机制和关键组织以努力 确定靶向MTORC1途径的方法，该途径可以使寿命与不良健康效应相关。 秀丽隐杆线虫的先前工作发现了MTORC1通过神经元调节衰老的证据。长寿 MTORC1整个身体的MTORC1信号传导降低的突变体，仅恢复MTORC1信号传导 神经元抑制了寿命回到野生型。但是，这种神经元MTORC1救援对 零突变体的生长或发育受损，表明在关键组织中靶向MTORC1可能 成为脱离衰老调节的策略，形成其他MTORC1功能。最后，这项工作发现还原 神经元MTORC1信号传导诱导多个神经肽基因表达的变化，并改变了 外围组织中线粒体网络的形状。在这些发现的基础上，我们最近有 生成了新数据，表明秀丽隐杆线虫中的神经特异性MTORC1延长了寿命 损害增长或发展。这是该提议的核心假设是MTORC1调节 通过调节神经元信号传导和 诱导的新陈代谢在外周组织中的细胞不可改变。我们将使用一套组织 研究这一假设并探究MTORC1老化调节机制的特定工具 空前的特异性。在AIM 1中，我们将评估神经元MTORC1抑制如何影响表型 与全身MTORC1抑制相关 - 例如生长，发育，繁殖和压力 耐药性 - 并测试外围组织中线粒体网络是否发生变化。我们将 还可以确定神经元MTORC1寿命所需的下游生物学途径。在AIM 2中，我们 将识别特定的神经元信号分子和类型的神经元类型 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 并允许我们以促进健康寿命的方式设计策略来针对这些途径。