Aging regulation by non-autonomous signaling from Drosophila gut enteroendocrine cells

果蝇肠道内分泌细胞非自主信号传导的衰老调节

• 批准号: 10392963
• 负责人: MARC TATAR
• 金额: $ 39.26万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392963
• 关键词: Adult; Affect; Age; Aging; Animals; Behavior; Biological Assay; Biological Models; Brain; Cell Communication; Cells; Chest; Coculture Techniques; Corpora Allata; Data; Diet; Digestion; Distant; Drosophila genus; Enteroendocrine Cell; Fat Body; G-Protein-Coupled Receptors; Goals; Growth; Hormones; Human; Individual; Insulin; Intestines; Juvenile Hormones; Lipids; Longevity; Mammals; Measures; Metabolism; Modeling; Muscle; Neuropeptides; Nutrient; Organism; Peptide Receptor; Peptides; Performance; Peripheral; Physiology; Production; Proteins; Regulation; Reproduction; Signal Transduction; Signaling Molecule; Source; System; Testing; Tissues; Transcriptional Regulation; Work; age related; cytokine; dietary restriction; fly; genetic approach; genetic manipulation; gut microbiome; hormonal signals; insulin-like peptide; mortality; novel; peptide hormone; response; stem cells; transcription factor

Signals produced by a few cells within a single tissue can regulate lifespan and functional aging throughout an animal. These signaling molecules may exert nonautonomous effects at target tissues to induce their protective mechanisms against age-dependent degeneration. Conversely, nonautonomous signals such as insulin/IGF-like hormones may promote somatic functions that favor growth and reproduction, but while being permissive to somatic degeneration. While nonautonomous signaling in aging regulation has been best characterized in terms of centrally produced hormones, and more recently with cytokines and SASP, provocative data from several model systems suggest there are critical, nonautonomous regulators of aging yet to be described. Accordingly, this proposal focuses on small neuropeptide like molecules secreted from specialized cells of the intestine – gut peptides. Enteroendocrine cells of animal guts, including those of Drosophila and humans, produce many gut peptides that have system-wide impacts on behavior, digestion and metabolism. Working with Drosophila, we propose that gut peptides can also affect lifespan and somatic functional aging by nonautonomous signaling across the organism. In Drosophila, gut peptide production appears change with age, some increasing and others decreasing. We also found that depleting a nutrient sensitive transcription factor in fly enteroendocrine cells was sufficient to block longevity extension by dietary restriction, while inducing this factor appears to increase the ability of dietary restriction to slow aging. We propose that gut peptides secreted from these cells provides a mechanism to regulate aging and in particular in response to diet. The work has three objectives. First is to fully characterize changes in the secretion of gut peptides from fly intestines with age and in response to dietary restriction, and to assay their transcriptional controls. From our identified age-dynamic gut peptides, we will use genetic manipulations to robustly infer which gut have the capacity to nonautonomously control life span and functional aging at target tissues. The second goal is to determine if gut peptides modulate aging through direct signaling at target tissues, and notably through G-Protein Coupled Receptors at these tissues. The third aim explores if gut peptides nonautonomously modulate aging by affecting production of a secondary, relay hormone, such as insulin/IGF or juvenile hormone, which in turn control systemic functional aging. Together these aims will describe a novel tissue function for the intestine in aging control through systemic signaling, and provide a model to explore these highly conserved gut peptides in mammals during aging and in response to dietary restriction.

单个组织中的几个细胞产生的信号可以调节整个生命周期和功能老化 动物。这些信号分子可能在靶组织中发挥非自主作用，从而诱导它们的保护作用 抗年龄依赖性退变的机制。相反，非自主信号，如胰岛素/胰岛素样生长因子 荷尔蒙可能会促进有利于生长和生殖的躯体功能，但同时允许 躯体退化。而衰老调节中的非自主信号最好地描述了 集中产生的荷尔蒙，以及最近的细胞因子和SASP，来自几个 模型系统表明，对衰老有一些关键的、非自治的调节因素尚未得到描述。因此， 这项建议关注的是从肠道的特殊细胞分泌的小神经肽类分子。 多肽。动物肠道的肠内分泌细胞，包括果蝇和人类的肠道，会产生许多肠道 对行为、消化和新陈代谢有全系统影响的多肽。与果蝇合作，我们 提出肠肽也可以通过非自主信号影响寿命和躯体功能衰老 在整个生物体中。在果蝇中，肠肽的产生随着年龄的增加而变化，有些增加和 其他人则在减少。我们还发现，耗尽果蝇肠道内分泌中的一种营养敏感转录因子 细胞足以阻止饮食限制延长寿命，而诱导这一因素似乎可以 提高饮食限制延缓衰老的能力。我们认为这些细胞分泌的肠肽 提供一种调节衰老的机制，特别是对饮食的反应。这项工作有三个目标。 第一个是充分描述苍蝇肠道分泌的肠肽随年龄和反应的变化。 饮食限制，并测试他们的转录控制。从我们识别的年龄动态肠肽中， 我们将使用基因操作来有力地推断哪种肠道具有非自主控制生命的能力 靶组织的跨度和功能老化。第二个目标是确定肠肽是否调节衰老。 通过直接向目标组织传递信号，尤其是通过这些组织中的G蛋白偶联受体。 第三个目的是探索肠多肽是否通过影响次级细胞的产生而非自主地调节衰老， 继任激素，如胰岛素/胰岛素样生长因子或保幼激素，进而控制全身功能老化。同舟共济 这些目标将描述肠道通过系统信号控制衰老的新组织功能，以及 提供了一种模型来探索哺乳动物在衰老过程中和在应对 饮食限制。