Genetic and environmental factors that regulate aging and longevity

调节衰老和长寿的遗传和环境因素

• 批准号: 7963925
• 负责人: Catherine A Wolkow
• 金额: $ 70.43万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963925
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Affect; Age; Aging; Animals; Apoptosis; Caenorhabditis elegans; Cell Nucleus; Cell physiology; Cells; Cellular Structures; Collaborations; Cytoplasm; Cytoplasmic Vesicles; Data; Deterioration; Development; Disease; Egg Yolk Proteins; Embryo; Endocrine; Environment; Environmental Risk Factor; Food; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Gonadal structure; Growth; Head; Homologous Gene; Human; Human body; Image; Image Analysis; In Situ; Incidence; Insulin; Insulin Receptor; Intestines; Invertebrates; Investigation; Laboratories; Larva; Lead; Life; Ligands; Link; Lipids; Longevity; Maintenance; Metabolic; Metabolism; Molecular; Molecular Genetics; Morphology; Muscle; Nematoda; Nuclear; Nuclear Hormone Receptors; Nutrient; Oocytes; Organ; Organism; Output; Pathway interactions; Patients; Pharyngeal structure; Population; Process; Production; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Publications; Pump; RNA Interference; Reactive Oxygen Species; Reproduction; Research; Resistance; Resources; Rest; Scientist; Signal Pathway; Signal Transduction; Sirtuins; Source; Staging; Stimulus; Stress; Structural Models; Structure; Techniques; Testing; Time; Tissues; Transcript; Vitellogenins; Whole Organism; Work; age effect; age related; aged; biological adaptation to stress; deletion analysis; esterase; experience; functional decline; insulin signaling; interest; neuromuscular; neuronal cell body; novel; promoter; receptor for advanced glycation endproducts; repaired; reproductive; research study; response; transcription factor

The major accomplishment of this year was publication of studies examining age-related changes in tissue morphology of the C. elegans pharynx. The pharynx is a neuromuscular structure in the head that which injests, concentrates and crushes the bacterial food. The pharynx experiences significant changes in both structure and function during aging. In particular, the rate of pharynx muscle pumping declines during aging. In addition, structural deterioration is evident in the aged pharynx. However, it was not known whether these two factors are correlated, or if the functional declines would be the result of other changes in cell function that could not be detected visually. Finally, it was not know whether structural declines themselves were correlated with age. To address these questions, we took advantage of a computational approach for image analyses developed at the NIA. With this approach, it was possible to study the progression of structural aging in the C. elegans pharynx, as reflected in Nomarski images of the pharynx at time points across the adult lifespan. This analysis revealed that structural decline during aging occurs in stages. That is, the structural changes associated with pharynx aging proceed in a step-wise fashion between discreet structural states that can be recognized using mathematical transformations of these images. This finding suggests a model for structural aging in which cellular deterioration competes with cellular maintenance processes. Cellular maintenance processes may attempt to stabilize cellular structure during aging. At some point, we hypothesize that deterioration processes overcome the maintenance processes and cause cellular structure to collapse to a more aged state. We also examined whether structural and functional aging could be correlated. Using image analyses and mathematical transforms of image data, we found that pharynx function was weakly correlated with pharynx structural decline. This is consistent with the idea that functional aging in this organ is reflective partly of muscle deterioration and partly of other processes that are not evident in Nomarski images. These findings provide a context for developing futher experiments for identifying the cellular processes that are most significant for maintaining cellular structure and function during aging. The laboratory also continued work on other projects that will be ready for publication in the near future. A major focus of current work is to identify endocrine pathways that coordinate aging and stress responses throughout the body. One study was undertaken to identify downstream pathways through which DAF-2 insulin receptor and AGE-1 PI3K signaling within a subset of cells regulates development and aging throughout the body. Our previous work suggested that DAF-2 and AGE-1 signaling regulated an endocrine output that controls aging and development in collaboration with DAF-16/FOXO, which is the major direct target of DAF-2 and AGE-1 signaling. To identify this parallel pathway, transcriptional microarrays were used to compared global gene expression in animals lacking AGE-1 PI3K signaling and two strains with AGE-1 PI3K-signaling restricted to specific tissues. This analysis identified specific transcripts that are regulated by endocrine outputs of AGE-1 PI3K signaling. Using RNA-interference and promoter deletion analysis, we identified the signaling pathways that couple to AGE-1 PI3K to regulate these targets. This study is complete and is being submitted for publication. A second focus of our current work is defining molecular pathways that regulate the allocation of metabolic resources between somatic maintenance and other processes, such as reproduction. Aging can be slowed by processes that increase the maintenance and repair of the adult soma. Stressful conditions, such as limiting nutrients, trigger activation of these repair processes. Stress also impedes the distribution of resources to more costly processes, such as reproduction. Two active projects seek to identify pathways that regulate resource distribution under replete and stressful environments. One investigation has examined the factors that regulate synthesis of vitellogenin yolk proteins by intestinal cells. In reproductive adults, vitellogenins are synthesized by the intestine, transported to the gonad and stored by oocytes as a food source for developing embryos. Signaling by the DAF-2 insulin pathway regulates intestinal vitellogenin synthesis through unknown mechanisms. Our work has elucidated factors required for vitellogenin gene expression in response to DAF-2 signaling and other stimuli. This work is nearly complete and will be ready for publication soon. In related work, we are examining cellular responses to nutrient stress. In several publications, we described a novel response to nutrient stress that could be visualized in C. elegans intestinal cells. This response is termed, FIRE, for Fasting-Induced Redistribution of Esterase activity. Under replete conditions with adequate nutrients, intestinal cells contain many cytoplasmic vesicles that are detectable by in situ esterase activity. When nutrients are removed, the cytoplasmic esterase activity is depleted and appears to redistribute to a nuclear, or perinuclear, localization. Using RNA-interference techniques, we have identified genes that regulate this cellular response to nutrient stress. These genes also affect growth, suggesting they provide a link between nutrient levels and growth processes. We are also examining the effects of aging on the FIRE response to determine whether FIRE-regulating genes might be altered during aging.

今年的主要成就是研究研究秀丽隐杆线虫咽的组织形态变化的研究。 咽是头部的神经肌肉结构，可损害，浓缩和粉碎细菌食物。 咽部在衰老过程中的结构和功能都发生了重大变化。 特别是，咽部肌肉泵送的速率在衰老期间下降。 另外，在老化的咽部中，结构恶化是明显的。 但是，尚不清楚这两个因素是否相关，或者功能下降是否是细胞功能上无法视觉检测的其他变化的结果。 最后，不知道结构上的衰落是否与年龄相关。 为了解决这些问题，我们利用了一种计算方法来用于在NIA开发的图像分析。 通过这种方法，可以研究秀丽隐杆线虫咽的结构衰老的进展，如在成人寿命的时间点上的咽nomarski图像所反映的那样。 该分析表明，衰老期间的结构下降是在阶段发生的。 也就是说，与咽衰老相关的结构变化以谨慎的结构状态在可以使用这些图像的数学变换识别的谨慎结构状态之间进行。 这一发现提出了一个结构性老化的模型，其中细胞恶化与细胞维持过程竞争。 细胞维持过程可能会试图在衰老过程中稳定细胞结构。 在某个时候，我们假设劣化过程克服了维护过程，并导致细胞结构塌陷至更老的状态。 我们还检查了结构和功能衰老是否可以相关。 使用图像数据的图像分析和数学变换，我们发现咽功能与咽结构下降较弱相关。 这与以下想法一致：该器官中的功能衰老部分反映了肌肉恶化的一部分，部分是在Nomarski图像中不明显的其他过程。 这些发现为开发未实现的实验提供了一个背景，用于识别对于在衰老过程中维持细胞结构和功能最重要的细胞过程。 该实验室还继续研究其他项目，这些项目将在不久的将来准备出版。 当前工作的主要重点是确定内分泌途径，以协调整个身体的衰老和压力反应。 进行了一项研究，以鉴定下游途径，在细胞子集中，DAF-2胰岛素受体和1岁的PI3K信号通过该途径调节整个体内的发育和衰老。我们以前的工作表明，DAF-2和1岁的信号传导调节了与DAF-16/FOXO合作控制衰老和发育的内分泌输出，DAF-16/FOXO是DAF-2和Age-1信号传导的主要直接目标。 为了识别这种平行的途径，使用转录微阵列比较缺乏1岁PI3K信号传导的动物中的全球基因表达和两种菌株，其中限于特定组织的年龄1年龄PI3K信号。 该分析确定了特定的成绩单，这些成绩单受年龄1 PI3K信号传导的内分泌产量调节。 我们使用RNA的介入和启动子缺失分析，确定了夫妇到1岁PI3K以调节这些目标的信号传导途径。这项研究已经完成，正在提交出版。 我们当前工作的第二个重点是定义分子途径，该途径调节体细胞维持和其他过程（例如繁殖）之间代谢资源的分配。 通过增加成年躯体维护和修复的过程可以减慢衰老。压力条件（例如限制营养素）会触发这些修复过程的激活。 压力还阻碍了资源分配到更昂贵的过程，例如生殖。两个活跃的项目旨在确定在充满压力和压力环境下的资源分配的途径。一项研究检查了调节肠细胞合成卵黄蛋白蛋白蛋白的因素。 在生殖成年人中，卵黄蛋白是由肠道合成的，被肠道传输到性腺，并由卵母细胞储存，作为发育胚胎的食物来源。 DAF-2胰岛素途径的信号传导通过未知机制来调节肠道卵黄蛋白的合成。 我们的工作已经阐明了对DAF-2信号传导和其他刺激的响应卵黄蛋白基因表达所需的因素。 这项工作几乎完成了，很快就会准备出版。 在相关工作中，我们正在研究细胞对营养应激的反应。在几个出版物中，我们描述了对秀丽隐杆线虫肠细胞中可以看到的对营养应激的新反应。 这种反应称为禁食诱导的酯酶活性重新分布的火灾。在充满养分的充气条件下，肠细胞包含许多可通过原位酯酶活性检测的细胞质囊泡。 去除营养时，细胞质酯酶活性会耗尽，并且似乎将其重新分配到核或核周定位。使用RNA干扰技术，我们确定了调节这种细胞对营养应激的反应的基因。这些基因也会影响生长，这表明它们在营养水平和生长过程之间提供了联系。 我们还在研究衰老对火灾反应的影响，以确定在衰老过程中是否可能改变燃烧基因。