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Genetic and environmental factors that regulate aging and longevity

调节衰老和长寿的遗传和环境因素

基本信息

批准号：
7732203
负责人：
Catherine A Wolkow
金额：
$ 112.92万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
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/7732203
关键词：
Adult Affect Agar Age Aging Animals Biological Biological Markers Blueberries Caenorhabditis elegans Characteristics Classification Complement Computers DAF-2 protein Development Disruption Endocrine Environmental Risk Factor Food Future Gene Expression Genes Genetic Goals Human Image Ingestion Insulin Insulin Receptor Invertebrates Laboratories Lead Life Longevity Mammals Mechanics Metabolism Microarray Analysis Mitotic Molecular Profiling Morphology Mus Mutation Nematoda Numbers Organ Organism Output Pathway interactions Pattern Pharyngeal structure Physiological Plants Population Procedures Receptor Signaling Resistance Role Signal Pathway Signal Transduction Soil Source Stilbenes Stress System Time Tissues Week Work age related base cell type coping feeding fly genetic manipulation insulin signaling interest mutant novel response transcription factor tumor growth

项目摘要

Longevity is influenced by genetic pathways and environmental factors. The goals of this project are to (a) elucidate mechanisms by which some genes enhance longevity and (b) identify environmental and physiological factors that can slow aging. These studies focus on aging in the nematode, Caenorhabditis elegans, which is one of the premier organisms for studying aging. The current popularity of C. elegans as a focus for studies of aging comes from its short lifespan (2-3 weeks), ease of cultivation and amenability to genetic manipulation. Insulin-like signaling pathways are important regulators of longevity in several species, from worms to flies to mice, and could also affect human longevity. In C. elegans, lifespan can be increased dramatically by mutations that disrupt signaling downstream of the insulin receptor-like (IR) protein, DAF-2. In addition to regulating lifespan, DAF-2/IR signaling regulates larval development and adult stress resistance and metabolism. Extended lifespan in mutants with disrupted insulin signaling results from activation of DAF-16, a FOXO transcription factor which is a conserved target of insulin-like pathways in many animals. When active, DAF-16/FOXO controls expression of an array of genes that promote longevity and stress resistance. Thus, FOXO transcription factors may be evolutionarily conserved regulators of longevity. Current work aims to define how FOXO transcription factors affect longevity and to identify FOXO-interacting pathways. First, we have described how DAF-2/insulin receptor signaling within a variety of cell types can promote normal lifespan. These findings led to the hypothesis that DAF-2 signaling regulates longevity and development through an endocrine-like output. Using microarray-based analysis of gene expression, we compared global gene expression profiles in long-lived animals lacking insulin signaling and two strains with insulin-signaling restored to specific tissues. This analysis revealed specific transcriptional targets of the insulin pathway that are regulated in response to tissue-restricted insulin signaling. Current work is focused on elucidating the signaling pathways that couple with insulin signaling to regulate these targets. We are also working to identify compounds with prolongevity activity in C. elegans. Lead compounds that clear this screen can be further studied for their effects on aging in mammals, which requires more time-consuming and costly procedures. Previous work focused on polyphenolic proanthocyanins from blueberries. We also recently completed analysis of a panel of stilbene molecules differing in methoxylation at the R groups. Stilbenes are also polyphenolic compounds found in a variety of plants. In contrast to the prolongevity effects of blueberry proanthocyanins, the methoxylated stilbenes were toxic to adult C. elegans. Methoxylated stilbenes also inhibited germline tumor growth in animals carrying a mutation resulting in uncontrolled mitotic proliferation of germcells. This is the first systematic demonstration that stilbene methoxylation can increase bioactivity in a whole animal. Future work will focus on identifying the biological targets of methoxylated stilbenes in C. elegans. These studies are complemented by structural studies of aging-related changes in the C. elegans pharynx, a neuromuscular organ responsible for food ingestion and mechanical disruption. Using computer-based image classification, we examined patterns of structural change in the pharynx during aging. The analysis revealed the existence of several stable morphology states that were associated with characteristic points of the C. elegans lifespan. Particular ages were associated with transitions between sequential morphology states. We hypothesize that the stability of aging morphology states reflects the activity of cellular homeostatic mechanisms coping with aging-related ceellular changes. The identification of these stable aging morphology states introduces a novel biomarker of aging that may be useful for studying the mechanisms leading to aging-related declines.

寿命受到遗传途径和环境因素的影响。这个项目的目标是（a）阐明某些基因增强寿命的机制，（B）确定可以减缓衰老的环境和生理因素。这些研究集中在线虫的衰老上，秀丽隐杆线虫是研究衰老的首要生物之一。目前流行的C.秀丽隐杆线虫作为衰老研究的焦点是因为它的寿命短（2-3周），易于培养和易于遗传操作。胰岛素样信号通路是几个物种长寿的重要调节因子，从蠕虫到苍蝇再到老鼠，也可能影响人类的寿命。 In C.在线虫中，通过破坏胰岛素受体样（IR）蛋白，β-2下游信号传导的突变，可以显著增加寿命。除了调节寿命外，β 2/IR信号传导还调节幼虫发育和成虫的应激抗性和代谢。胰岛素信号传导中断的突变体的寿命延长是由于FOXO-16的激活，FOXO转录因子是许多动物中胰岛素样途径的保守靶点。当激活时，β-16/FOXO控制一系列促进长寿和抗应激的基因的表达。因此，FOXO转录因子可能是进化上保守的长寿调节因子。目前的工作旨在确定FOXO转录因子如何影响寿命，并确定FOXO相互作用的途径。首先，我们已经描述了各种细胞类型中的β-2/胰岛素受体信号传导如何促进正常寿命。这些发现导致了一种假设，即β 2信号通过内分泌样输出调节寿命和发育。使用基于微阵列的基因表达分析，我们比较了缺乏胰岛素信号传导的长寿动物和两种恢复特定组织胰岛素信号传导的菌株的全球基因表达谱。该分析揭示了响应于组织限制性胰岛素信号传导而调节的胰岛素途径的特定转录靶点。目前的工作集中在阐明与胰岛素信号传导耦合以调节这些靶点的信号传导途径。我们还在努力鉴定具有抗衰老活性的化合物。优美的清除这一屏障的铅化合物可以进一步研究其对哺乳动物衰老的影响，这需要更耗时和昂贵的程序。以前的工作集中在蓝莓多酚原花青素。我们最近还完成了一个小组的芪分子在R组甲氧基化不同的分析。芪也是在多种植物中发现的多酚化合物。与蓝莓原花青素的抗衰老作用相反，甲氧基化二苯乙烯类化合物对C.优美的甲氧基化芪类还抑制携带突变的动物中的生殖系肿瘤生长，导致生殖细胞的不受控制的有丝分裂增殖。这是第一次系统地证明，二苯乙烯甲氧基化可以增加整个动物的生物活性。未来的工作将集中在确定甲氧基化芪类化合物在C.优雅的这些研究是补充结构研究的老化相关的变化，在C。线虫咽部，一种负责食物摄取和机械破坏的神经肌肉器官。使用基于计算机的图像分类，我们研究了在老化过程中咽部结构变化的模式。分析表明，存在几个稳定的形态状态，与特征点的C。elegans寿命。特定的年龄与连续形态状态之间的转换。我们推测，衰老形态学状态的稳定性反映了细胞内稳态机制应对衰老相关细胞变化的活性。这些稳定的衰老形态状态的鉴定引入了一种新的衰老生物标志物，可能有助于研究导致衰老相关衰退的机制。