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

项目摘要/摘要 衰老通常表现为生物体水平的生理性衰退。然而，老化过程已经 它的根源是细胞水平；分子和细胞隔间的变化最终是基础 生理性衰退与年龄相关疾病病理。阐明衰老的细胞原因具有 有潜力为促进更长、更健康的寿命的战略提供信息，也可能揭示意想不到的 与动物健康和疾病有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：通过 自噬。过氧化物体是膜结合的真核细胞器，对细胞健康和 生物体的生存能力；它们进行基本的氧化反应，并清除毒素。 值得注意的是，我们已经发现，通过自噬(‘Pexphagy’)特异性地 发生在年轻成年动物的早期衰老过程中，这意味着这可能是 启动老化过程中的事件。事实上，以线虫秀丽线虫为模型 我们发现，食欲率可能会随着年龄的增长而增加。动物们展示了 早年加速的过氧化物体降解过早死亡，而在 食欲不振是长寿之道。此外，这种细胞器的周转可能需要独特的管理，因为 我们已经发现，在衰老过程中，就像在饥饿过程中一样，在非典型的自噬过程中也会发生食腐现象。 溶酶体，结构呈管状，形态动态。 我们现在准备在理解食欲癖的监管方面取得重大进展， 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基因筛查，以揭示活体中食欲不振的调节者和效应者 饥饿和衰老期间的动物。到目前为止，我们只知道少数几个调控基因。一个 我们的期望是，我们可以确定在该事件的信号发送中涉及的因素，或者是 在这些情况下，可能会将过氧化物酶体与管状溶酶体联系起来。此外，我们还将详细执行 对基因敲除的分析，我们已经描述了对年龄的调节- 依赖食欲，目的是确定有助于延长寿命的机制 在抑制食欲的基础上。总而言之，这些研究将提供关于以前未探索过的 衰老的细胞方面可能与新的长寿机制有关。

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.