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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相关的疾病的发作来延长健康寿命。最近对秀丽隐杆线虫的研究开始揭示减少繁殖如何延长寿命。与此同时，众所周知，减少进食（即饮食限制）也可以延长寿命。喂料速度尚未报道蠕虫在繁殖减少时的数量，并且可能无法可靠地测量。繁殖减少可以间接减少摄食。因此，关于减少繁殖如何延长蠕虫寿命的研究可能会因无意中减少摄食而受到干扰。目前的项目将使用一种大型、低成本的无脊椎动物来测试减少繁殖如何延长寿命，而不依赖于日常喂养。具有不同繁殖水平（卵巢切除或假手术）但每日饲喂率相匹配的蚱蜢将被用来确定由于繁殖减少而直接延长寿命的机制。因为卵巢切除术后喂养减少，每天喂养相同量的假手术动物将受到饮食限制。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 敲低成为可能。通过这种方式，我们将研究已知影响寿命的两条途径。对于每一个，我们首先比较卵巢切除和全饮食动物以及假手术和饮食限制动物中匹配喂养的途径成分的 mRNA 水平。其次，RNAi 将用于敲低该通路，以确定卵巢切除术后是否需要延长寿命。目标 1 将通过雷帕霉素靶标 (TOR) 途径测试细胞生长。 TOR 的敲低可延长蠕虫、苍蝇和小鼠的寿命。我预测 TOR 通路的成分会因延长寿命的饮食限制而减少，但不会因延长寿命的卵巢切除而减少。接下来，我预测 TOR 敲除后的寿命延长与卵巢切除术的寿命延长相加，但饮食限制则不然。目标 2 将检查神经肽 F/Y 刺激进食的作用。这种肽与小鼠的寿命延长有关，但可能不是通过改变生长途径。我预测神经肽 F 的 mRNA 水平会在饮食限制后增加，但在卵巢切除后不会增加。神经肽 F 的敲低预计会延长寿命，并且与卵巢切除术相辅相成，但不会与饮食限制相结合。此外，我将测试神经肽F是否可以减少生物分子损伤（蛋白质羰基、脂质过氧化）。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。最近研究表明，H2S 对于小鼠饮食限制的健康作用至关重要。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。我预测减少饮食后 H2S 会更高，但减少繁殖后则不会。了解减少繁殖如何延长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。