Evaluating pexophagy as an early cellular marker of aging

项目摘要/摘要 在动物物种中，衰老不仅发生在生物体水平上，也发生在细胞水平上。 了解随年龄变化的细胞过程对于阐明分子基础很重要。 与年龄相关的功能障碍和疾病，并可能指向强大的生物标志物，可以提供 对一个人的生物学年龄的准确测量。在细胞内，细胞器执行复杂的 对细胞健康和生存至关重要的功能。细胞器动态平衡是如何被调节的 老龄化是当前老龄化研究中的一个重要课题，因为它可以提供对 导致年龄相关恶化的细胞事件。在这项提案中，我们将研究一个新的方面 细胞器动态平衡与衰老的关系。也就是说，拟议的研究将集中在食欲不振方面， 或过氧化体的自噬破坏，这是躯体衰老的早期事件。我们的实验室有 生产了一种荧光噬菌体传感器来监测活动性炎患者的过氧化物体周转 优雅女装。记者指出，线虫肠道中发生了大量的过氧化物体周转 在早期衰老过程中；值得注意的是，食性感应器很容易在蠕虫的第一天区分它们 从那些只大几天的人变成成年人。这就提出了一个耐人寻味的问题：食欲不化 衰老的早期生物标志物，如果是这样的话，它与长寿有什么关系？拟议的研究将 开始通过一系列实验来解决这些问题。以确定计时是否 和/或食欲范围随寿命的变化，食欲感应器将在 长寿突变株的肠道，并在不同时间点与野生型动物进行比较 衰老。作为一种补充方法来衡量附着性吞噬作为一种细胞生物标志物的潜力 在肠道中表达食欲感受器的老化的野生动物将被分成两部分 青壮年人群：食欲水平较高的人群和较低水平的人群 嗜食症的程度。随后将对这两个种群进行寿命分析，以 确定这种细胞标志物是否可以预测成年初期的寿命。 最后，对吞噬感应器的分析将扩展到其他含有过氧化物酶体的组织 为了弄清与年龄相关的食欲变化是仅发生在肠道还是发生在肠道 在多个组织中同时存在。这样的分析可能意味着对这一过程的系统性控制，或者 相反，可能在细胞和分子水平上暗示了特定组织在衰老方面的差异。总而言之， 这些研究将提供关于衰老的细胞生物学的基本信息，并将在概念上 促进我们对细胞器生物学中年龄相关修饰的理解。

Project Summary/Abstract In animal species, aging occurs not only at an organismal level, but also at the level of cells. Understanding cellular processes that change with age is important for clarifying the molecular basis of age-related dysfunction and disease, and may point to robust biomarkers that can provide an accurate measure of the biological age of an individual. Within cells, organelles execute complex functions essential for cellular health and survival. How organelle homeostasis is regulated during aging represents an important current topic in aging research, as it may provide insight into the cellular events that drive age-related deterioration. In this proposal, we will investigate a new aspect of organelle homeostasis in relation to aging. Namely, the proposed studies will focus on pexophagy, or the autophagic destruction of peroxisomes, as an early event in somatic aging. Our lab has generated a fluorescent pexophagy sensor to monitor peroxisome turnover in live Caenorhabditis elegans. This reporter indicates that massive peroxisome turnover occurs in the C. elegans intestine during early aging; notably, the pexophagy sensor easily distinguishes worms on their first day of adulthood from those that are just a few days older. This raises an intriguing question: is pexophagy an early biomarker of aging, and, if so, how does it relate to longevity? The proposed studies will begin to address these questions through a series of experiments. To determine whether the timing and/or scope of pexophagy scales with lifespan, the pexophagy sensor will be expressed in the intestine of long-lived mutant strains and compared to wild-type animals at various time points during aging. As a complementary approach to gauge the potential of pexophagy as a cellular biomarker of aging, wild-type animals expressing the pexophagy sensor in the intestine will be segregated into two populations during young adulthood: those with higher levels of pexophagy, and those with lower levels of pexophagy. Subsequent lifespan analysis of the two populations will be performed to determine whether this cellular marker is predictive of lifespan from an early point in adulthood. Lastly, analysis of the pexophagy sensor will be extended to additional peroxisome-containing tissues to clarify whether age-related changes to pexophagy are specific to the intestine or occur synchronously in multiple tissues. Such analysis may suggest systemic control over this process, or may instead hint at tissue-specific differences in aging at the cellular and molecular level. Collectively, these studies will provide fundamental information on the cell biology of aging, and will conceptually advance our understanding of age-dependent modifications to organelle biology.