Identifying natural products that modify aging and lifespan in vivo

识别体内可改变衰老和寿命的天然产品

• 批准号: 7963926
• 负责人: Catherine A Wolkow
• 金额: $ 69.55万
• 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/7963926
• 关键词: Adult; Adverse effects; Affect; Aging; Alzheimer' s Disease; Animals; Benign; Biological; Biological Assay; Biological Availability; Biological Factors; C. elegans genome; Caenorhabditis elegans; Cancer Model; Cells; Chemical Structure; Collection; Disease; Dose; Elderly; Equipment; Ethics; Exhibits; Family; Gene Expression; Gene Targeting; Genes; Genetic; Genome; Genomics; Goals; Growth; Homologous Gene; Hydroxylation; Institutionalization; Intervention; Laboratories; Life; Longevity; Malignant Neoplasms; Mammalian Cell; Marketing; Mediating; Microarray Analysis; Mitosis; Molecular; Mutation; Nematoda; Organism; Pathway interactions; Phenotype; Poison; Positioning Attribute; Proliferating; Publications; Reporter; Research; Research Design; Resistance; Resveratrol; Rodent Model; Screening procedure; Series; Severities; Stilbenes; Structure; Study Subject; Time; Toxic effect; Work; age related; anti aging; cost; gene conservation; human subject; in vivo; interest; intervention effect; mature animal; mutant; prevent; protective effect; research study; response; tumor

Our major accomplishment this year was the publication of a study comparing the bioactivities of a series of stilbene compounds in C. elegans. The collection of stilbenes examined different by the presence of methoxylation or hydroxylation substitutions at four positions. In C. elegans, treatment with the hydroxylated stilbenes was generally benign in an adult lifespan assay. However, increasing methoxylation caused compounds to become toxic, and shorten adult survival. We next compared bioactivities in a C. elegans cancer model. Animals carrying a mutation in the gld-1 gene exhibit a germline tumor phenotype resulting from the inability of the germcells to exit mitosis. As for adult survival, the methoxylated stilbenes exhibited inhibitory activity on the growth of gld-1(q20) germline tumors, while hydroxylated stilbenes had minimal activity in this assay. Together, these results show that methoxylation enhanced stilbene bioactivity in C. elegans, both in terms of toxicity towards terminally-differentiated cells in adult animals and in proliferating cells in the germline tumors. This publication has generated great interest, and was flagged as Highly Accessed by the publisher. We hypothesize that the bioactivity differences between methoxylated and hydroxylated stilbenes reflect differences in bioavailability and/or target interactions. To examine these possibilities, transcriptional microarrays were used to compare gene expression in response to short-term exposures at high concentrations of resveratrol, an hydroxylated stilbene, and pterostilbene, a methoxylated stilbene. Preliminary results indicate that a resveratrol and pterostilbene may regulate some overlapping targets, which would be consistent with the idea that their differing bioactivities reflect bioavailability differences. In addition, pterostilbene affects expression of additional genes unaffected by resveratrol, which may reflect target-specific differences in these compounds. Analysis of the microarray results is ongoing. We are currently working on a second project which aims to identify compounds with hormetic activity in C. elegans. Hormesis is the ability of a toxic compound to induce beneficial, protective effects at subtoxic doses. Using C. elegans, we conducted a small screen to identify natural products that exerted hormetic activity in a C. elegans lifespan assay. This screen identified one compound which is able, in some experiments, to extend lifespan at a non-toxic dose. A parallel screen was conducted by collaborators in the LNS to identify compounds that induce a Nrf transcriptional response in cultured mammalian cells. The Nrf response screen identified the same compound, suggesting that prolongevity activity in C. elegans may be mediated by the homologous gene. Current work aims to identify the structural aspects of this compound required for prolongevity activity. In addition, we are examining target genes induced in C. elegans by this compound.

我们今年的主要成就是发表了一项研究，比较了一系列芪类化合物在C。优雅的 通过在四个位置处存在甲氧基化或羟基化取代来检查芪类的集合。 In C.在线虫中，用羟基化芪类处理在成虫寿命测定中通常是良性的。 然而，增加甲氧基化导致化合物变得有毒，并缩短成虫存活时间。 我们接下来比较了C. elegans癌症模型。 携带gld-1基因突变的动物表现出生殖细胞不能退出有丝分裂而导致的生殖细胞肿瘤表型。 至于成虫存活，甲氧基化的芪类化合物对gld-1（q20）生殖系肿瘤的生长表现出抑制活性，而羟基化的芪类化合物在该试验中具有最小的活性。 总之，这些结果表明甲氧基化增强了C. elegans，无论是在对成年动物的终末分化细胞的毒性和生殖系肿瘤中的增殖细胞。 该出版物引起了极大的兴趣，并被出版商标记为高度访问。 我们假设甲氧基化和羟基化芪类之间的生物活性差异反映了生物利用度和/或靶向相互作用的差异。 为了研究这些可能性，转录微阵列被用来比较基因表达的短期暴露在高浓度的白藜芦醇，羟基化的芪，和紫檀芪，甲氧基化的芪。 初步结果表明，白藜芦醇和紫檀芪可能会调节一些重叠的目标，这将是一致的想法，他们不同的生物活性反映生物利用度的差异。 此外，紫檀芪影响不受白藜芦醇影响的其他基因的表达，这可能反映了这些化合物的靶特异性差异。 微阵列结果的分析正在进行中。 我们目前正在进行第二个项目，其目的是在C.优美的 毒物兴奋效应是有毒化合物在亚毒性剂量下诱导有益的保护作用的能力。 利用C.在秀丽隐杆线虫中，我们进行了一个小筛选以鉴定在C.线虫寿命测定。该筛选确定了一种化合物，在某些实验中，该化合物能够以无毒剂量延长寿命。 LNS的合作者进行了平行筛选，以鉴定在培养的哺乳动物细胞中诱导Nrf转录反应的化合物。Nrf反应筛选鉴定出相同的化合物，表明C. elegans可能是由同源基因介导的。 目前的工作旨在确定这种化合物的结构方面所需的长寿活动。此外，我们正在研究在C中诱导的靶基因。elegans通过这种化合物。