Mechanisms of Aging in C. elegans

线虫的衰老机制

• 批准号: 8437842
• 负责人: STUART K KIM
• 金额: $ 32.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437842
• 关键词: Accounting; Adult; Age; Aging; Aging-Related Process; Animal Model; Animals; Belief; Binding; Biological Clocks; Biological Models; Caenorhabditis elegans; Cell Lineage; Cells; Cessation of life; ChIP-seq; Climacteric; DNA Microarray Chip; Data; Development; Disease; Elderly; Engineering; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Human; Image; Individual; Insulin; Intestines; Lead; Life; Longevity; Molecular Profiling; Mutation; NuRD complex; Pathogenesis; Pathway interactions; Physiology; Poison; Population; Regulatory Pathway; Role; Signal Pathway; Skin; Specific qualifier value; System; Testing; Tissues; Transgenic Organisms; Work; age related; dietary restriction; improved; juvenile animal; mutant; normal aging; novel; programs; public health relevance; research study; theories; tool; transcription factor; transcriptome sequencing; young adult

DESCRIPTION (provided by applicant): This proposal is about intrinsic mechanisms of aging, which are inherent and always occur during the normal aging process. Intrinsic mechanisms involve an internal clock that specifies lifespan during normal aging. Besides damage accumulation, another mechanism for intrinsic aging has recently been found in C. elegans termed developmental drift. Developmental pathways are established in the young adult to guide the formation of different tissues. Key regulators of these developmental pathways become aberrantly expressed in old age, leading to a cascade of changes in expression of downstream genes that has detrimental effects on tissue function and that limits lifespan. Developmental drift is conceptually novel because it proposes that that old worms are not the same as young worms with damage accumulation. Rather, old worms have inherent, programmed differences that make them more susceptible to degeneration and death. This proposal uses C. elegans as a model system because of its short two week lifespan and powerful genetic tools. DNA microarray experiments have been used to define a molecular signature for aging that includes 1254 genes that differ in expression between young and old worms. Seven transcription factors have previously been identified as candidates that may be responsible for these age-related changes. All seven transcription factors are key regulators of development in diverse tissues, such as the intestine and the skin. This proposal will use ChIP SEQ experiments to determine whether these transcription factors are directly responsible for causing expression of their downstream genes to change with age. Expression experiments using an automatic cell lineage analyzer to digitize images of GFP-expressing worms will be used to extract precise expression data from individual cells. These data will show how expression of the seven transcription factors changes with age. Transgenic worms will be engineered to convert old worms into young worms; specifically, expression of the seven aging regulators in old worms will be altered to resemble expression found in young worms, and then lifespan experiments will be used to test whether converting worms to their younger state is beneficial. A key prediction of the developmental drift hypothesis is that changes in old age should resemble changes that occur during development. This will be tested by finding out if the network of genes directly downstream of a transcription factor during aging are the same as its downstream network during development.

描述（由申请人提供）：本提案是关于衰老的内在机制，这是固有的，总是在正常的衰老过程中发生的。内在机制包括在正常衰老过程中指定寿命的内部时钟。除了损伤积累外，最近在秀丽隐杆线虫中发现了另一种内在衰老机制，称为发育漂变。发育途径在青年成人中建立，以指导不同组织的形成。这些发育途径的关键调控因子在老年时异常表达，导致下游基因表达的级联变化，对组织功能产生有害影响，并限制寿命。发育漂移在概念上是新颖的，因为它提出了老蠕虫与具有损伤积累的年轻蠕虫不同。相反，年老的蠕虫具有内在的、程序化的差异，使它们更容易退化和死亡。本研究以秀丽隐杆线虫作为模型系统，因为它的寿命只有两周，而且具有强大的遗传工具。DNA微阵列实验已经被用来定义衰老的分子特征，其中包括1254个基因，这些基因在年轻和年老的蠕虫之间表达不同。七个转录因子先前被确定为可能负责这些年龄相关变化的候选因子。这七种转录因子都是肠道和皮肤等不同组织发育的关键调控因子。本提案将使用ChIP SEQ实验来确定这些转录因子是否直接导致其下游基因的表达随年龄变化。使用自动细胞谱系分析仪对表达gfp的蠕虫图像进行数字化的表达实验将用于从单个细胞中提取精确的表达数据。这些数据将显示七种转录因子的表达如何随年龄变化。转基因蠕虫将被改造成将年老的蠕虫转化成年轻的蠕虫；具体来说，这7种衰老调节因子在老虫体内的表达将被改变为与年轻虫体内的表达相似，然后使用寿命实验来测试将蠕虫转化为更年轻的状态是否有益。发展漂变假说的一个关键预测是，老年的变化应该类似于发育过程中发生的变化。这将通过发现转录因子在衰老过程中直接下游的基因网络是否与其在发育过程中的下游网络相同来验证。