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: 9925717
• 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/9925717
• 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，可以开发为实验上易驯化的生物体，用于探索动态 控制一系列过程（包括衰老）的表观遗传程序发生变化。衰老是一个过程 内在生理功能进行性衰退。寿命之间存在明确的权衡 和生殖，因为女性较高的生殖活动与较短的寿命有关。然而，在 作为群居昆虫，繁殖蚁后的寿命比非繁殖工蜂的寿命长 10 倍。在蚂蚁里 Harpegnathos salator，未接触蜂王信息素的成年个体可能会经历可逆的 从非生殖工蚁转变为表现出完全发育的生殖伪女王（玩家门） 卵巢，更重要的是，寿命延长了 5 倍，表明衰老是可逆的。寿命再次缩短 当玩家门恢复为工人（恢复者）时。因此，Harpegnathos 提供了一个有效的系统 鉴于成人可塑性允许在衰老和年轻化之间进行切换，研究衰老和年轻化的表观遗传调控 种姓。 我们对长寿调节组织：脂肪体、卵巢和大脑进行了转录组分析。 工人 vs. 玩家门 vs. 回复者。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）通路 成分。为了进一步分析蚂蚁长寿的遗传和表观遗传调控，我们首先比较 年轻与年老玩家门中的生理学、寿命、转录组和组蛋白修饰 研究人员致力于确定衰老的表观遗传调控，以及最有趣的返老还童的调控。蜂窝式 将进一步分析重要DEG的定位和功能。其次，我们将利用我们的新 建立了遗传工具——蚂蚁中的 CRISPR——在卵巢的两个 DEG 中产生敲除（KO）蚂蚁，Hs- IMPL2 和 Hs-ALS，可能是蚂蚁体内 IIS 的抑制剂。这些 KO 蚂蚁将被用来表征 IIS 在显着延长玩家门寿命方面发挥的作用。第三，Hs-ILP1（胰岛素样肽1）是 Hs-ILP2 在大脑中差异表达，而 Hs-ILP2 在卵巢中差异表达。虽然 Hs-ILP1 和 Hs-ILP2 都强烈 与工人相比，游戏玩家增加，脂肪体和卵巢中的 IIS 减少。为了解决这个问题 悖论，我们将分析（a）Hs-ILP1和-ILP2在调节IIS的两个分支：AKT和 MAPK； (b) Hs-ImpL2 和 Hs-ALS 在调节 Hs-ILP 活性中的作用； (c) 两个胰岛素受体如何 (InRs) 介导 Hs-ILP 在差异调节 IIS 中的作用。