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.

项目摘要：蚂蚁是生活在形态和身体上不同的殖民地中的社会昆虫 本质上基本上相同的个体，使蚂蚁成为研究表观遗传学的有吸引力的系统 现象。蚂蚁殖民地包含许多执行大多数任务但不产卵的工人，而皇后区则是 完全负责繁殖。值得注意的是，皇后的寿命比工人长10倍 大多数动物中，高生殖会导致寿命缩短。跳跃的蚂蚁harpegnathos 盐盐表现出高度老化的可塑性：在女王的情况下，一些工人可以成为 伪Queens称为Gamesrgates。 Gamergates急剧改变其行为，产生鸡蛋，重新配置 他们的大脑和最急剧的大脑具有5倍的寿命延长。值得注意的是，当放置在 真正的女王，Gamesrgates随着寿命缩短而过渡到工人。我们 建立的Harpegnathos是可以用CRISPR/CAS9操纵的模型系统，提供了独特的 研究控制衰老的分子机制以及衰老和衰老之间的串扰的机会 生殖。 使用转录组学以及离体和体内药理操作的组合，我们 发现Gamesrgates通过差异调节的胰岛素产生升高 目标时间中胰岛素信号通路（II）的两个分支。 IIS的MA​​PK分支在 gamergate脂肪体和卵巢，而Akt分支则由细胞外“抗胰岛素”蛋白（Impan2）复制。 由于卵子上卵需要MAPK活动，我们假设Akt分支的表达有助于 游戏中的长寿寿命很大。 现在，我们建议研究Imph2功能的分子机制，并测试其在衰老中的作用。第一的， 我们将确定Impl2的源和有机分布，然后在实验中调节其水平和 突变IMPHAT2检查对IIS的影响和卵形成的新陈代谢增加。此外，我们会的 探索Imph2的分子相互作用以及导致特异性抑制的机制 （但不是MAPK）IIS路径。接下来，我们将测试Imph2对操纵动物衰老的影响，评估 老化生物标志物的面板，并将我们的研究扩展到另一种抗胰岛素蛋白ALS。此外，组织 对果蝇中Impl2表达的特定操纵将解决其潜在的对 强大的模型系统中的繁殖和寿命。最后，我们将把研究扩展到大脑重塑 涉及和策划社会过渡的事件。我们将执行单细胞mRNA测序 不同的社会群体/年龄，以调查与年龄相关的Harpegnathos大脑变化并确定 候选监管机构负责延迟游戏的衰老。我们将利用转录组数据进行测试 特定的遗传功能如何调节脑回路和衰老。