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：蚂蚁是群居昆虫，生活在形态和生理上不同的群体中 本质上基因相同的个体，使蚂蚁成为研究表观遗传学的一个有吸引力的系统 现象。蚂蚁群包含许多工蚁，它们执行大多数任务，但不产卵，而蚁后则 独自负责繁殖。值得注意的是，蜂王的寿命比工蚁长10倍，这与之形成鲜明对比 在大多数动物中，高繁殖率会导致寿命缩短。跳跃的蚂蚁Harpegnathos 跳跃犬表现出高度的老化可塑性：在女王不在的情况下，一些工蚁可能会成为 被称为游戏门的伪女王。玩家门戏剧性地改变了他们的行为，产生了鸡蛋，重新配置了 他们的大脑，最戏剧性的是，寿命延长了5倍。值得注意的是，当放置在 真正的女王，游戏之门重新转变为工人，伴随着寿命的缩短。我们 建立了Harpegnathos作为一个可以用CRISPR/Cas9操作的模型系统，提供了一个独特的 有机会研究控制衰老的分子机制，以及衰老和衰老之间的串扰 繁殖。 结合转录学以及体外和体内的药理操作，我们 研究发现，配子门胰岛素的产生增加，并伴随着对 靶组织中胰岛素信号通路(IIS)的两个分支。IIS的MAPK分支在 Gamergate脂肪体和卵巢，而AKT分支被细胞外的“抗胰岛素”蛋白ImpL2抑制。 由于MAPK活性是产卵所必需的，我们假设AKT分支的抑制有助于 戏剧性地延长了玩家门的寿命。 我们现在建议研究ImpL2功能的分子机制，并测试它在衰老中的作用。第一, 我们将确定ImpL2的来源和组织分布，然后通过实验调节其水平和 突变ImpL2以检测(S)对IIS的影响和增加产卵的代谢。此外，我们还将 探讨ImpL2的分子相互作用及其对AKT的特异性抑制机制 (但不是MAPK)IIS途径。接下来，我们将测试ImpL2对操纵动物衰老的影响，评估 并将我们的研究扩展到另一种抗胰岛素蛋白，ALS。此外，组织- 在果蝇中对ImpL2表达的特异性操作将解决其在 在一个强大的模型系统中实现繁衍和寿命。最后，我们将把我们的研究扩展到大脑重塑 伴随和策划社会转型的事件。我们将进行单细胞mRNA测序 不同的社会群体/年龄调查Harpegnathos大脑的年龄相关变化并确定 对游戏之门延缓衰老负有责任的候选监管机构。我们将利用转录数据进行测试 特定的遗传功能如何调节大脑回路和衰老。