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Testing direct effects of reproduction on lifespan with controlled feeding in grasshoppers

通过控制饲喂蚱蜢来测试繁殖对寿命的直接影响

基本信息

批准号：
9093113
负责人：
John D. Hatle
金额：
$ 43.25万
依托单位：
UNIVERSITY OF NORTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093113
关键词：
Ablation Academic Research Enhancement Awards Address Affect Aging Aging-Related Process Animal Feed Animals Back Brain Caenorhabditis elegans Carbon Dioxide Cysteine DNA Adducts Data Collection Development Diet Disease Environment Experimental Designs Fat Body Fatty acid glycerol esters Florida Force Feedings Genes Goals Grasshoppers Growth Health Heart Diseases Human Hydrogen Sulfide Invertebrates Lead Life Life Extension Lipid Peroxidation Longevity Malignant Neoplasms Mammals Measures Messenger RNA Modeling Molecular Mus Nutrient One-Step dentin bonding system Ovariectomy Pathway interactions Peptide Receptor Peptides Physiology Production Proteins Publishing RNA Interference Reducing diet Reporting Reproduction Research Role Sirolimus Societies Step Tests Students Sulfur Amino Acids Testing Time United States National Institutes of Health Universities Vitellogenins Work Writing age related cost dietary restriction drug development experience feeding fly follow-up improved knock-down neuropeptide F novel nutrition oxidation public health relevance research study response sham feeding transcriptome undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Increased health span could be accomplished by slowing aging and delaying the onset of age-related diseases. Recent work in C. elegans worms is beginning to reveal how reduced reproduction may extend lifespan. At the same time, reduced feeding (i.e., dietary restriction) also is well known to extend lifespan. The feeding rate of worms upon reduced reproduction was not reported, and it may not be able to be measured reliably. Reduced reproduction can indirectly reduce feeding. Hence, studies on how reduced reproduction extends lifespan in worms may be confounded by inadvertent reductions in feeding. The present project will use a large, low-cost invertebrate to test how reduced reproduction extends lifespan, independent of daily feeding. Grasshoppers with different levels of reproduction (ovariectomized or sham-operated) but on matched daily feeding rates will be used to identify mechanisms of life-extension directly due to reduced reproduction. Because feeding is reduced upon ovariectomy, the sham-operated animals fed the same amount daily will be on dietary restriction. Transcriptomes for fat body and brain for this grasshopper have been acquired, making possible mRNA quantification and RNAi knockdown of many genes. In this way we will examine two pathways known to effect lifespan. For each, we first compare mRNA levels of pathway components in ovariectomized & full diet animals and sham-operated & dietary restricted animals with matched feeding. Second, RNAi will be used to knockdown the pathway to determine if it is required for life-extension upon ovariectomy. Aim 1 will test cellula growth by the Target of Rapamycin (TOR) pathway. Knockdown of TOR extends lifespan in worms, flies, and mice. I predict that components of the TOR pathway will be reduced upon life-extending dietary restriction, but not upon life-extending ovariectomy. Next, I predict that life-extension upon TOR knockdown be additive with life-extension by ovariectomy, but not dietary restriction. Aim 2 will examine the role of the stimulation of feeding by neuropeptide F/Y. This peptide is involved in life-extension in mice, but perhaps not via altering growth pathways. I predict that mRNA levels for neuropeptide F will increase upon dietary restriction, but not upon ovariectomy. Knockdown of neuropeptide F is predicted to increase lifespan and be additive with ovariectomy, but not dietary restriction. In addition, I will test whether neuropeptide F reduces bio-molecular damage (protein carbonyls, lipid peroxidation). A new Aim 3 will test the role of production of gaseous hydrogen sulfide from cysteine in life-extension by dietary restriction. H2S has recently been shown to be essential for the salubrious effects of dietary restriction in mice. I will test whether changes in oxidation and allocation of ingested cysteine are associated with altered H2S production. I predict H2S will be higher upon reduced diet, but not upon reduced reproduction. Understanding how reduced reproduction increases lifespan may reveal an additional target for drug development toward improving human health span. Consistent with the R15 program, students will be involved in all data collection and presentation.

描述（由申请人提供）：可以通过减缓衰老和延迟与年龄有关的疾病的发作来增加健康寿命。最近的工作在C。蠕虫开始揭示减少繁殖如何延长寿命。同时，减少喂食（即，饮食限制）也是众所周知的延长寿命。进料速率没有报告蠕虫在繁殖减少时的死亡率，并且可能无法可靠地测量。减少繁殖可以间接减少进食。因此，研究如何减少繁殖延长寿命的蠕虫可能会混淆无意中减少喂养。目前的项目将使用一个大型的，低成本的无脊椎动物来测试如何减少繁殖延长寿命，独立于日常喂养。蚱蜢与不同水平的生殖（卵巢切除或假手术），但匹配的每日喂养率将被用来确定寿命延长的机制，直接由于减少生殖。由于卵巢切除术后摄食量减少，因此每天喂食相同量的假手术动物将进行饮食限制。已经获得了这种蚱蜢的脂肪体和大脑的转录组，使得许多基因的mRNA定量和RNAi敲除成为可能。通过这种方式，我们将研究已知影响寿命的两种途径。对于每一个，我们首先比较mRNA水平的通路组件在卵巢切除和全饮食动物和假手术和饮食限制的动物与匹配的喂养。第二，RNAi将用于敲除该途径，以确定它是否是卵巢切除术后延长生命所必需的。目的1通过雷帕霉素靶蛋白（TOR）途径检测细胞生长。TOR的敲除延长了蠕虫、苍蝇和小鼠的寿命。我预测，TOR通路的组成部分将减少后，延长寿命的饮食限制，但不是延长寿命的卵巢切除术。接下来，我预测TOR敲低后的寿命延长与卵巢切除术的寿命延长是相加的，但不是饮食限制。目的2：研究神经肽F/Y对摄食的刺激作用。这种肽参与了小鼠的生命延长，但可能不是通过改变生长途径。我预测，神经肽F的mRNA水平将增加饮食限制，但不是卵巢切除术。神经肽F的敲除预计会增加寿命，并与卵巢切除术相加，但不是饮食限制。此外，我将测试神经肽F是否减少生物分子损伤（蛋白质羰基化，脂质过氧化）。一项新的目标3将测试半胱氨酸产生气态硫化氢在通过饮食限制延长寿命中的作用。H2S最近已被证明是必不可少的有益健康的影响，饮食限制在小鼠。我将测试摄入的半胱氨酸的氧化和分配的变化是否与H2S产生的改变有关。我预测H2S在减少饮食时会更高，但在减少繁殖时不会。了解减少生殖如何增加寿命可能会揭示药物开发的另一个目标，以改善人类健康寿命。与R15计划一致，学生将参与所有数据收集和演示。