Evaluating pexophagy as an early cellular marker of aging

项目总结/摘要 在动物物种中，衰老不仅发生在生物体水平，而且发生在细胞水平。 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，可以提供一个 一个人的生物学年龄的精确测量。在细胞内，细胞器执行复杂的 对细胞健康和生存至关重要。细胞器内稳态是如何调节的 老龄化是老龄化研究中的一个重要的当前主题，因为它可以提供对 导致衰老的细胞事件在这个建议中，我们将研究一个新的方面， 与衰老有关的细胞器内稳态。也就是说，拟议中的研究将集中在食人鲳， 或过氧化物酶体的自噬破坏，作为躯体衰老的早期事件。我们的实验室 产生了荧光pexophagy传感器，以监测过氧化物酶体营业额在活的小杆线虫 优雅这位记者指出，大量的过氧化物酶体周转发生在C。线虫肠 在早期老化;值得注意的是，pexophagy传感器很容易区分蠕虫的第一天， 成年期与成年期的区别。这就提出了一个有趣的问题： 衰老的早期生物标志物，如果是的话，它与长寿有什么关系？拟议的研究将 我们开始通过一系列实验来解决这些问题。为了确定时间是否 和/或范围与寿命的关系，将以 肠的长寿命突变株，并与野生型动物在不同的时间点， 衰老作为一种补充方法来衡量pexophagy作为细胞生物标志物的潜力， 将在肠中表达噬菌感受器的衰老野生型动物分成两组 在年轻的成年人群体：那些具有较高水平的pexophagy，和那些具有较低水平的pexophagy。 吃宠物的水平。随后将对两个人群进行寿命分析， 确定这种细胞标志物是否可以从成年早期预测寿命。 最后，对pexophagy传感器的分析将扩展到其他含有过氧化物酶体的组织 为了阐明与年龄相关的摄食性变化是否是肠道特有的， 同步在多个组织中。这种分析可能表明对这一过程的系统控制，或 相反，这可能暗示在细胞和分子水平上衰老的组织特异性差异。总的来说， 这些研究将为衰老的细胞生物学提供基本信息， 促进我们对细胞器生物学年龄依赖性修饰的理解。

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.