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: 10171746
• 负责人: Claude Desplan
• 金额: $ 64.16万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171746
• 关键词: Address; Adult; Age; Aging; Ants; Binding; Biological Models; Brain; Castes; Cells; Chromatin Structure; Clustered Regularly Interspaced Short Palindromic Repeats; Drosophila genus; Epigenetic Process; Exhibits; Fat Body; Female; Fostering; Gene Expression; Gene Expression Profile; Genes; Genetic; Genome; Growth; Individual; Insecta; Insulin; Insulin Antagonists; Insulin Receptor; Knock-out; Length; Longevity; MAP Kinase Gene; Mediating; Modeling; Molecular; Nurses; Organism; Ovary; Pheromone; Physiological; Physiology; Process; Proto-Oncogene Proteins c-akt; Regulation; Rejuvenation; Reproduction; Reproductive Behavior; Role; Signal Pathway; Signal Transduction; Site; Somatic Cell; System; Techniques; Telomerase; Testing; Tissues; cell type; differential expression; epigenetic regulation; histone modification; insulin signaling; insulin-like peptide; longevity gene; mRNA Expression; molecular phenotype; mutant; programs; reproductive; social; telomere; tool; transcriptome

Project summary: Ants are social insects that can be developed as experimentally tractable organisms for probing the dynamic changes in the epigenetic programs that control an array of processes, including aging. Aging is a process of progressive decline in intrinsic physiological functions. There is a well-established trade-off between lifespan and reproduction as higher reproductive activity in females is associated with shorter lifespan. However, in social insects, the reproductive queen has up to 10X longer lifespan than non-reproductive workers. In the ant Harpegnathos saltator, adult individuals that are not exposed to queen pheromones can undergo a reversible switch from non-reproductive workers to reproductive pseudo-queens (gamergates) that exhibit fully developed ovary and, importantly, a 5X increase in lifespan, showing that aging is reversible. Lifespan is shortened again when gamergates are reverted to workers (revertants). Thus, Harpegnathos provides an effective system to study epigenetic regulation of aging and rejuvenation given the adult plasticity that allows switching between castes. We have performed transcriptome analysis of the longevity-regulatory tissues: the fat body, ovary and brain, in workers vs. gamergates vs. revertants. We have identified a group of differentially expressed genes (DEGs), some of which have been implicated in the regulation of longevity, e.g. IIS (insulin and IGF signaling) pathway components. To further analyze the genetic and epigenetic regulation of longevity in ants, we will first compare physiology, lifespan, transcriptome and histone modifications in gamergates derived from young vs. old workers to ascertain the epigenetic regulation of aging and, most intriguingly, rejuvenation. The cellular localization and functions of important DEGs will be further analyzed. Second, we will utilize our newly established genetic tool – CRISPR in ants – to generate knockout (KO) ants in the two DEGs in the ovary, Hs- IMPL2 and Hs-ALS, which likely act as inhibitors of IIS in ants. These KO ants will be used to characterize the role of IIS in the dramatically extended lifespan in gamergates. Third, Hs-ILP1 (insulin-like peptide 1) is differentially expressed in the brain and Hs-ILP2 in the ovary. While both Hs-ILP1 and Hs-ILP2 are strongly increased in gamergates compared to workers, IIS is decreased in the fat body and ovary. To address this paradox, we will analyze (a) the role of Hs-ILP1 and -ILP2 in regulating the two branches of IIS: AKT and MAPK; (b) the role of Hs-ImpL2 and Hs-ALS in regulating activity of Hs-ILPs; and (c) how two insulin receptors (InRs) mediate the role of Hs-ILPs in differentially regulating IIS.

项目概要： 蚂蚁是社会性昆虫，可以发展为实验上易于驾驭的生物体，用于探索动态 控制包括衰老在内的一系列过程的表观遗传程序的变化。衰老是一个 内在生理功能的逐渐衰退。在寿命和健康之间有一个很好的权衡 和生殖，因为雌性的生殖活动越高，寿命越短。但在 在社会性昆虫中，有生殖能力的蚁后的寿命比没有生殖能力的工蚁长10倍。在蚂蚁 Harpegnathos saltator，成年个体不暴露于女王信息素可以经历可逆的 从非生殖性工蚁转变为生殖性假蚁后（gamergates）， 卵巢，更重要的是，寿命增加了5倍，这表明衰老是可逆的。寿命再次缩短 当gamergates被回复为工人（回复突变体）时。因此，Harpegnathos提供了一个有效的系统， 研究衰老和返老还童的表观遗传调节，因为成年人的可塑性允许在衰老和返老还童之间切换。 种姓 我们对长寿调节组织进行了转录组分析：脂肪体，卵巢和大脑， 工蜂对配子对回复突变体。我们已经鉴定了一组差异表达基因（DEG）， 其中一些与长寿的调节有关，例如IIS（胰岛素和IGF信号传导）途径 件.为了进一步分析蚂蚁长寿的遗传和表观遗传调控，我们将首先比较 来自年轻人与老年人的gamergates中的生理学、寿命、转录组和组蛋白修饰 工作人员确定衰老的表观遗传调节，最有趣的是，返老还童。蜂窝 并进一步分析了重要DEG的定位和功能。第二，我们将利用我们的新 已建立的遗传工具-蚂蚁中的CRISPR-在卵巢中的两个DEG中产生敲除（KO）蚂蚁，Hs- IMPL 2和Hs-ALS，它们可能在蚂蚁中作为IIS的抑制剂。这些KO蚂蚁将用于表征 IIS在游戏玩家中显著延长寿命的作用。第三，Hs-ILP 1（胰岛素样肽1）是 Hs-ILP 2在脑中差异表达，Hs-ILP 2在卵巢中差异表达。虽然Hs-ILP 1和Hs-ILP 2都是强的， 与工作者相比，运动员增加，脂肪体和卵巢中的IIS减少。为了解决这个 矛盾，我们将分析（a）Hs-ILP 1和-ILP 2在调节IIS的两个分支：AKT和 MAPK;（B）Hs-ImpL 2和Hs-ALS在调节Hs-ILP活性中的作用;和（c）两种胰岛素受体如何 （InRs）介导Hs-ILP在差异调节IIS中的作用。