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.

项目摘要： 蚂蚁是社交昆虫，可以作为实验可探测动态的实验性诱因的生物而开发 控制一系列过程（包括衰老）的表观遗传程序的变化。衰老是一个过程 内在生理功能的逐步下降。寿命之间有一个完善的权衡 随着女性中较高的生殖活性，繁殖与寿命较短有关。但是，在 社会昆虫的生殖女王的寿命比非生殖工人长10倍。 Harpegnathos Saltator，不接触女王信息素的成年人可以经历可逆的 从非生产工人转变为曝光完全开发的生殖伪Queens（Gamergates） 卵巢，重要的是，寿命增加了5倍，表明衰老是可逆的。寿命再次缩短 当gamergates恢复为工人（恢复剂）时。那，Harpegnathos提供了一个有效的系统 鉴于允许在成人的可塑性之间切换的成人可塑性，研究衰老和恢复活力的表观遗传调节 种姓。 我们已经对寿命调节组织进行了转录组分析：脂肪体，卵巢和大脑，在 工人与Gamergates vs.还原。我们已经确定了一组不同表达的基因（DEG）， 其中一些是在调节寿命时暗示的，例如IIS（胰岛素和IGF信号传导）途径 成分。为了进一步分析蚂蚁寿命的遗传和表观遗传调节，我们将首先比较 源自年轻与老年的生理学，寿命，转录组和组蛋白修饰 工人确定衰老的表观遗传调节，最有趣的是恢复活力。细胞 重要DEG的本地化和功能将进一步分析。其次，我们将利用新的 建立的遗传工具 - 蚂蚁的CRISPR - 在卵巢中产生敲除（KO）蚂蚁，HS- Impl2和HS-AL可能是蚂蚁中IIS的抑制剂。这些ko蚂蚁将用于表征 IIS在游戏中急剧延长的寿命中的角色。第三，HS-ILP1（胰岛素样肽1）为 在卵巢中在大脑和HS-ILP2中表达不同。而HS-ILP1和HS-ILP2都强烈 与工人相比，Gamesrgates的增加，脂肪体和卵巢的IIS减少。解决这个问题 悖论，我们将分析（a）HS -ILP1和-ILP2在确定IIS的两个分支：AKT和AKT和 MAPK; （b）HS-IMPL2和HS-AL在确定HS-ILP活性中的作用； （c）两个胰岛素受体如何 （INR）介导HS-ilps在不同调节IIS中的作用。