Pexophagy regulation in live animals and its role in aging and longevity

活体动物的 Pexophagy 调节及其在衰老和长寿中的作用

• 批准号: 10566172
• 负责人: Kenneth Adam Bohnert
• 金额: $ 29.79万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566172
• 关键词: Acceleration; Affect; Age; Aging; Animals; Autophagocytosis; Binding; Biology; Caenorhabditis elegans; Cell Culture Techniques; Cells; Cellular biology; Collection; Digestion; Disease; Elements; Ensure; Event; Excision; Genes; Genetic; Genetic Screening; Goals; Health; Impairment; Intestines; Knowledge; Life; Link; Lipids; Longevity; Longevity Pathway; Lysosomes; Mammalian Cell; Molecular; Morphology; Mutagenesis; Mutation; Nematoda; Organelles; Participant; Pathology; Physiological; Plants; Positioning Attribute; Process; Proteins; Reaction; Regulation; Regulator Genes; Reporter; Research Project Grants; Role; Route; Signal Transduction; Specific qualifier value; Specificity; Starvation; Stimulant; Structure; Subcutaneous Tissue; System; Testing; Time; Tissues; Toxin; Tubular formation; Yeasts; age related; expectation; gene function; human old age (65+); knock-down; longevity gene; macromolecule; mature animal; model organism; mutant; novel; peroxisome; peroxisome membrane; premature; prevent; screening; support network; tool; uptake; young adult

Project Summary/Abstract Aging often manifests as physiological decline at an organismal level. However, the aging process has its roots at the level of cells; changes to molecules and cellular compartments ultimately underlie physiological decline and age-related disease pathology. Clarifying cellular causes of aging has the potential to inform strategies to promote longer, healthier lives, and may also reveal unexpected elements of cell biology relevant to animal health and disease. My lab has begun analysis of a new aspect of cell biology in aging: degradation of peroxisomes by autophagy. Peroxisomes are membrane-bound eukaryotic organelles that are critical to cell health and organismal viability; they carry out essential oxidative reactions, and they also eradicate toxins. Remarkably, we have found that peroxisome degradation by autophagy (‘pexophagy’) specifically occurs in young-adult animals during early aging, signifying that this may be one of a collection of initiating events in the aging process. Indeed, using the nematode Caenorhabditis elegans as a model organism, we have discovered that the rate of pexophagy may scale with aging. Animals that show accelerated peroxisome degradation in early age die prematurely, whereas animals in which pexophagy is inhibited live long. Moreover, turnover of this organelle may entail unique regulation, as we have found that pexophagy during aging, as during starvation, occurs at non-canonical autophagic lysosomes, which are tubular in structure and morphologically dynamic. We are now poised to make significant advancements in understanding the regulation of pexophagy, particularly in a live-animal system, and its role in aging and longevity. In the proposed research project, we will perform unbiased genetic screens to uncover regulators and effectors of pexophagy in live animals during starvation and aging. To date, we know of only a handful of regulatory genes. An expectation is that we may identify factors involved in the signaling of this event, or adapters that potentially link peroxisomes to tubular lysosomes in these contexts. In addition, we will perform detailed analysis of gene knockdowns that we have already described to feed into the regulation of age- dependent pexophagy, with the goal of determining mechanisms that contribute to lifespan extension upon pexophagy inhibition. In sum, these studies will provide information on a previously unexplored cellular aspect of aging possibly relevant to novel longevity mechanisms.

项目总结/摘要 衰老通常表现为生物体水平上的生理衰退。然而，老龄化过程 其根源在细胞水平;分子和细胞区室的变化最终导致 生理衰退和与年龄相关的疾病病理。阐明衰老的细胞原因， 潜在的信息战略，以促进更长，更健康的生活，也可能揭示意想不到的 与动物健康和疾病相关的细胞生物学要素。 我的实验室已经开始分析衰老过程中细胞生物学的一个新方面： 自噬过氧化物酶体是膜结合的真核细胞器，对细胞健康至关重要， 生物体的生存能力;他们进行必要的氧化反应，他们也消除毒素。 值得注意的是，我们已经发现，过氧化物酶体降解的自噬（“pexophagy”），特别是 发生在成年动物的早期衰老，这意味着这可能是一个集合， 引发衰老过程中的事件。事实上，用秀丽隐杆线虫作为模型， 在研究生物体时，我们发现食腐的速度可能随着年龄的增长而增加。动物表现出 早期过氧化物酶体加速降解过早死亡，而 食欲抑制长寿。此外，这种细胞器的周转可能需要独特的调节， 我们发现，衰老过程中的自噬现象与饥饿时一样，发生在非典型的自噬细胞中。 溶酶体，其在结构上是管状的并且在形态上是动态的。 我们现在正准备在理解食粪的调控方面取得重大进展， 特别是在活体动物系统中，以及它在衰老和长寿中的作用。在拟议的研究项目中， 我们将进行无偏见的遗传筛选，以揭示调节和pexophagy的效应，在生活中， 饥饿和衰老期间的动物。到目前为止，我们只知道少数调控基因。一个 期望的是，我们可以确定参与该事件信号传导的因素，或 潜在地将过氧化物酶体连接到管状溶酶体。此外，我们还将详细 我们已经描述了基因敲除的分析，以调节年龄- 依赖性食粪，目的是确定有助于延长寿命的机制 抑制了摄食。总之，这些研究将提供以前未探索的信息， 衰老的细胞方面可能与新的长寿机制有关。