Aging and rejuvenation: An ant model to study the regulation of longevity

衰老与返老还童：研究长寿调控的蚂蚁模型

• 批准号: 10660241
• 负责人: Claude Desplan
• 金额: --
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10660241
• 关键词: AKT inhibition; Adipose tissue; Affect; Age; Aging; Animals; Ants; Apoptotic; Back; Bees; Behavior; Behavioral; Binding; Biological; Biological Aging; Biological Assay; Biological Markers; Biological Models; Brain; CRISPR/Cas technology; Carbohydrates; Castes; Cells; Chronology; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Methylation; DNA Transposable Elements; Data; Drosophila genus; Epigenetic Process; Event; Exhibits; Experimental Models; Fat Body; Fatty acid glycerol esters; Gene Expression; Genes; Genetic; Genetic Transcription; Hemolymph; Immunoprecipitation; In Vitro; Individual; Insecta; Insulin; Insulin Signaling Pathway; Investigation; Length; Lipids; Liver; Longevity; MAP Kinase Gene; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Microscopy; Modeling; Molecular; Morphology; Mutate; Neurons; Nuclear; Output; Ovary; Pathway interactions; Pattern; Pharmaceutical Preparations; Phosphorylation; Physiological; Physiology; Play; Production; Proliferating; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Regulation; Rejuvenation; Repression; Reproduction; Role; Signal Pathway; Social status; Source; Surveys; System; Testing; Tissues; brain remodeling; candidate identification; cell type; comparative; egg; experience; extracellular; gain of function; in vivo; insulin signaling; insulin-like signaling; knock-down; loss of function; molecular dynamics; mutant; neural circuit; pharmacologic; potential biomarker; reproductive; response; single cell mRNA sequencing; single-cell RNA sequencing; social; social group; synergism; telomere; transcriptomics; treatment effect

Project summary: Ants are social insects that live in colonies of morphologically and physiologically different individuals that are essentially identical genetically, making ants an attractive system to study epigenetic phenomena. Ant colonies contain many workers that perform most tasks but do not lay eggs, while queens are solely responsible for reproduction. Remarkably, queens live up to 10X longer than workers, in sharp contrast with most animals in which high reproduction leads to shortened lifespan. The jumping ant Harpegnathos saltator exhibits a high degree of aging plasticity: In the absence of the queen, some workers can become pseudo-queens called gamergates. Gamergates dramatically change their behavior, produce eggs, reconfigure their brain and most dramatically, have a 5X lifespan extension. Remarkably, when placed in the presence of a genuine queen, gamergates transition back into workers with an accompanying shortened lifespan. We established Harpegnathos as a model system that can be manipulated with CRISPR/Cas9, providing a unique opportunity to study the molecular mechanisms that control aging, as well as the crosstalk between aging and reproduction. Using a combination of transcriptomics as well as both ex vivo and in vivo pharmacological manipulations, we discovered that gamergates have an elevated production of Insulin accompanied by differential regulation of the two branches of the Insulin signaling pathway (IIS) in target tissues. The MAPK branch of IIS is activated in the gamergate fat body and ovary, while the AKT branch is repressed by extracellular “anti-Insulin” proteins, ImpL2. As MAPK activity is required for egg-laying, we hypothesize that repression of the AKT branch contributes to the dramatically extended longevity in gamergates. We now propose to investigate the molecular mechanism of ImpL2 function and test its role in aging. First, we will identify the source and organismal distribution of ImpL2, and then experimentally modulate its levels and mutate ImpL2 to examine the effect(s) on IIS and increased metabolism for egg formation. Furthermore, we will explore the molecular interactions of ImpL2 and the mechanisms that lead to the specific inhibition of the AKT (but not MAPK) IIS pathway. Next, we will test the effect of ImpL2 on aging in manipulated animals, assessing a panel of aging biomarkers and extend our investigations to another anti-Insulin protein, ALS. Moreover, tissue- specific manipulation of ImpL2 expression in Drosophila will address its potentially conserved effect on reproduction and lifespan in a powerful model system. Finally, we will extend our study to the brain remodeling events that accompany and orchestrate the social transition. We will perform single-cell mRNA sequencing of the different social groups/ages to survey age-associated changes in the Harpegnathos brain and identify candidate regulators responsible for delayed aging in gamergates. We will exploit the transcriptomic data to test how specific genetic functions modulate brain circuits and aging.

项目概述：蚂蚁是群居昆虫，生活在形态和生理上不同的群体中。 个体在遗传上基本相同，这使得蚂蚁成为研究表观遗传的一个有吸引力的系统。 现象。蚁群中有许多工蚁，它们执行大多数任务，但不产卵，而蚁后则是 只负责繁殖。值得注意的是，蚁后的寿命是工蚁的10倍， 大多数动物的高繁殖率导致寿命缩短。跳蚁Harpegnathos 跳蚁表现出高度的衰老可塑性：在没有女王的情况下，一些工人可以成为 被称为玩家之门的伪女王Gamergates戏剧性地改变他们的行为，产生鸡蛋，重新配置 他们的大脑，最引人注目的是，寿命延长了5倍。值得注意的是，当被放置在一个 真正的女王，gamergates过渡回工人伴随着缩短的寿命。我们 建立了Harpegnathos作为可以用CRISPR/Cas9操纵的模型系统，提供了一个独特的 有机会研究控制衰老的分子机制，以及衰老和 生殖 使用转录组学以及体外和体内药理学操作的组合，我们 发现gamergates有一个升高的生产胰岛素伴随着不同的调节， 靶组织中胰岛素信号通路（IIS）的两个分支。IIS的MAPK分支被激活， gamergate脂肪体和卵巢，而AKT分支被细胞外“抗胰岛素”蛋白ImpL 2抑制。 由于MAPK活性是产卵所必需的，我们推测AKT分支的抑制有助于 游戏玩家的寿命大大延长。 我们现在建议研究ImpL 2功能的分子机制，并测试其在衰老中的作用。第一、 我们将确定ImpL 2的来源和生物体分布，然后通过实验调节其水平， 突变ImpL 2以检查对IIS的影响和卵形成的代谢增加。此外，我们将 探索ImpL 2的分子相互作用和导致AKT特异性抑制的机制 (but非MAPK）IIS途径。接下来，我们将测试ImpL 2对操作动物衰老的影响，评估其对衰老的影响。 一组衰老生物标志物，并将我们的研究扩展到另一种抗胰岛素蛋白，ALS。另外，组织- 在果蝇中特异性操纵ImpL 2表达将解决其潜在的保守效应， 繁殖和寿命在一个强大的模型系统。最后，我们将把我们的研究扩展到脑重塑 伴随和协调社会转型的事件。我们将进行单细胞mRNA测序， 不同的社会群体/年龄，以调查Harpegnathos大脑中与年龄相关的变化，并确定 候选监管机构负责延迟老化的游戏。我们将利用转录组数据来测试 特定的遗传功能如何调节大脑回路和衰老。