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.

今年的主要成就是发表了一些研究，探讨了与年龄有关的C。[医]咽线虫 咽部是头部的神经肌肉结构，它注入、浓缩和压碎细菌食物。 咽在衰老过程中经历结构和功能的显著变化。 特别地，咽肌泵送的速率在老化期间下降。 此外，老年人咽部的结构退化也很明显。 然而，目前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其他变化的结果，这些变化无法通过视觉检测到。 最后，还不知道结构性衰退本身是否与年龄有关。 为了解决这些问题，我们利用了NIA开发的图像分析计算方法。 用这种方法，有可能研究C.线虫咽部，如Nomarski图像中所反映的咽部在整个成人寿命的时间点。 这一分析表明，老龄化过程中的结构衰退是分阶段发生的。 也就是说，与咽老化相关的结构变化在离散的结构状态之间以逐步的方式进行，这些结构状态可以使用这些图像的数学变换来识别。 这一发现提出了一个结构性衰老的模型，其中细胞退化与细胞维持过程竞争。 细胞维持过程可能试图在老化期间稳定细胞结构。 在某种程度上，我们假设退化过程克服了维护过程，并导致细胞结构崩溃到一个更老化的状态。 我们还研究了结构和功能老化是否相关。 利用图像分析和图像数据的数学变换，我们发现咽功能与咽结构衰退弱相关。 这与这个器官的功能性衰老部分反映了肌肉退化，部分反映了Nomarski图像中不明显的其他过程的想法一致。 这些发现为进一步开展实验提供了背景，以确定在衰老过程中对维持细胞结构和功能最重要的细胞过程。 实验室还继续开展其他项目的工作，这些项目将在不久的将来出版。 目前工作的一个主要重点是确定协调整个身体衰老和压力反应的内分泌途径。 一项研究是为了确定下游途径，通过这些途径，细胞亚群中的AGEs-2胰岛素受体和AGE-1 PI 3 K信号传导调节整个身体的发育和衰老。我们以前的工作表明，β 2和AGE-1信号调节内分泌输出，与β 16/FOXO合作控制衰老和发育，β 16/FOXO是β 2和AGE-1信号的主要直接靶标。 为了鉴定这种平行途径，使用转录微阵列比较缺乏AGE-1 PI 3 K信号传导的动物和两种AGE-1 PI 3 K信号传导仅限于特定组织的菌株的整体基因表达。 该分析鉴定了由AGE-1 PI 3 K信号传导的内分泌输出调节的特定转录物。 使用RNA干扰和启动子缺失分析，我们确定了耦合到AGE-1 PI 3 K调节这些目标的信号通路。这项研究已经完成，正在提交出版。 我们目前工作的第二个重点是定义调节代谢资源在体细胞维持和其他过程（如生殖）之间分配的分子途径。 衰老可以通过增加成年索马的维护和修复来减缓。压力条件，如营养有限，触发这些修复过程的激活。 压力还妨碍将资源分配给成本更高的过程，如生殖。两个活跃的项目试图确定在充满压力的环境下调节资源分配的途径。一项研究已经检验了调节肠细胞合成卵黄蛋白原卵黄蛋白的因素。 在生殖成虫中，卵黄原蛋白由肠道合成，运输到性腺并由卵母细胞储存，作为发育胚胎的食物来源。 胰岛素信号通路通过未知机制调节肠道卵黄蛋白原合成。 我们的工作已经阐明了响应于β 2信号和其他刺激的卵黄蛋白原基因表达所需的因素。 这项工作已接近完成，不久将准备出版。 在相关的工作中，我们正在研究细胞对营养胁迫的反应。在一些出版物中，我们描述了一种新的营养胁迫反应，可以在C。肠细胞 这种反应被称为FIRE，即禁食诱导的酯酶活性再分布。在营养充足的条件下，肠细胞含有许多细胞质小泡，可通过原位酯酶活性检测。 当营养物质被去除时，细胞质酯酶活性被耗尽，并且似乎重新分布到核或核周定位。利用RNA干扰技术，我们已经确定了调节这种细胞对营养胁迫反应的基因。这些基因也影响生长，表明它们在营养水平和生长过程之间提供了联系。 我们也在研究衰老对FIRE反应的影响，以确定FIRE调节基因是否会在衰老过程中发生改变。