Functional Genomic Study of Aging and Aging Interventions

衰老和衰老干预的功能基因组研究

• 批准号: 8335835
• 负责人: Sige Zou
• 金额: $ 51.16万
• 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/8335835
• 关键词: Acids; Acute Myelocytic Leukemia; Aging; Aging-Related Process; American; Analytical Chemistry; Anastrepha ludens; Antioxidants; Biological Models; Biological Process; Biological Sciences; Biology; Biology of Aging; Botanicals; Carbohydrates; Cell Cycle; Cell Cycle Progression; Cells; Collaborations; Consumption; Cranberries; DNA Damage; Detection; Dissociation; Drosophila genus; Drosophila melanogaster; Fatty acid glycerol esters; Fluorescence; Foundations; Free Radicals; Fruit; Future; Genes; Gerontology; Glucose; Goals; Health; Health Benefit; Herb; Human; Human Biology; Intervention; Ions; Journals; Laboratories; Link; Lipids; Long-Term Effects; Longevity; M cell; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Medicine; Methods; Mission; Mississippi; Modification; Molecular; National Institute on Aging; Normal Cell; Nucleic Acids; Oregano spice; Pancreas; Peptides; Phosphopeptides; Phosphorylation; Physiologic pulse; Physiological; Post-Translational Protein Processing; Property; Protein Glycosylation; Proteins; Proteomics; Publications; Publishing; Raman Spectrum Analysis; Rattus; Regulation; Reporter; Research; Rhodamine B; Role; Societies; Supplementation; Surface; Tissues; Universities; Work; age effect; age related; analytical tool; basal insulin; base; cancer type; diabetic patient; fly; fruits and vegetables; functional genomics; functional group; glucose metabolism; glycosylation; improved; insight; macromolecule; mass spectrometer; normal aging; oxidative damage; reproductive longevity; response; tool

Aging is characterized as a gradual decline of various physiological functions and is associated with numerous damage and modifications to macromolecules, including protein, lipid and nucleic acid. Accurate and sensitive measurements of protein modifications, such as glycosylation and phosphorylation, are critical for us to understand the aging processes. To this end, we have collaborated with several laboratories in and outside of the National Institute on Aging (NIA) to develop quantitative tools valuable for aging research. In collaboration with Dr. Dongmao Zhang at the Mississippi State University, we published two quantification methods. One is to use an acid cleavable surface enhanced Raman spectroscopy (SERS) tag to quantify the levels of protein and protein modifications. Our method significantly improves the sensitivity and accuracy of fluorescence based protein detection. This work was published in The Analyst (2011). The other method is to detect carbohydrates using a Rhodamine B derivative as the Surface Enhancement Raman Spectroscopy (SERS) tag. The latter method can be utilized to measure protein glycosylation in aging, which remains quite elusive. This work has been published in Analytical Chemistry (2010). In collaboration with Drs. Rong-fong Shen, Bronwen Martin and Stuart Maudsley at the NIA, we have systematically evaluated the pulsed Q collision induced dissociation (PQD) method for peptide identification in proteomic studies. The PQD method is often employed to facilitate detection of low-mass reporter ions in peptide quantification using an LTQ mass spectrometer. Optimization of the PQD method is particularly valuable for identification of peptides with a labile functional group, such as phosphopeptides, in proteomic studies. This work has been accepted for publication in Journal of the American Society for Mass Spectrometry (2011, in press). To understand basic biological processes in aging, we have identified and characterized a fly gene highly homologous to the mammalian gene Aven. Mammalian Aven is a regulator of the DNA-damage response and G2/M cell cycle progression, and is linked to several types of cancer, such as acute myeloid leukemia. We have found that Drosophila Aven (dAven) is required for normal cell cycle progression in fly fat tissue. This work has been published in Cell Cycle (2011). Future studies will be directed to understand the role of dAven in DNA damage response, which should reveal information that may be relevant to cancer and aging. Taken together, our findings from this study along with analytical tools described above provide a foundation for us to further investigate molecular changes in the aging processes and consequences of these alterations on lifespan and health span. Many botanicals, including fruits and vegetables, are ideal for promoting longevity and health span due to their high antioxidant capacities and numerous bioactivities. However, few botanicals are actually known to possess prolongevity properties. The effective ways to implementing aging interventions remain poorly understood. We have previously demonstrated that supplementation of a fruit extract mixed with cranberry and oregano extracts can promote longevity and reproductive capacity in the Mexican fruit fly. To further investigate the health benefits of cranberry, we have evaluated the effect of long-term cranberry consumption on age-related changes in rat pancreas. We have found that a long-term cranberry consumption protects against an age-related decline in basal insulin release, improves β-cell glucose responsiveness and maintains functional β-cell mass in normal aging rats. Our findings suggest that cranberry consumption can be beneficial for diabetic patients. This work has been published in Journal of Gerontology Serial A: Biological Sciences (2011). To further understand the molecular mechanisms of lifespan regulation by fruits and herbs, we have employed Drosophila melanogaster as the model system. We have determined the effect of nectarine, a globally consumed fruit, on lifespan and health span in Drosophila melanogaster. Our findings suggest that nectarine promotes longevity and health span at least partly through modulating glucose metabolism and reducing oxidative damage. This work provides the first evidence showing the prolongevity effect of nectarine and has been published in Free Radical Biology & Medicine (2011). These findings encourage us to further investigate health benefits of various botanical extracts and the underlying mechanisms related to aging. This will also provide scientific guidance to consumption of fruits and herbs. In summary, we have developed analytic tools for accurate and reliable measurements of protein and protein modifications applicable for investigating molecular changes in aging. In addition, we have demonstrated the effects of two botanical extracts, cranberry and nectarine extracts, in promoting health and longevity in rats and flies, respectively. These studies should prove valuable to advance the objective of the Laboratory of Experimental Gerontology and the mission of the NIA to understand basic biology of aging and develop effect aging interventions. This project should provide insight into basic biology of human aging and facilitate developing effective aging intervention strategies for humans.

衰老的特征是各种生理功能的逐渐衰退，并且与包括蛋白质、脂质和核酸在内的大分子的许多损伤和修饰相关。准确和灵敏的蛋白质修饰，如糖基化和磷酸化的测量，是我们了解衰老过程的关键。为此，我们与国家老龄化研究所（NIA）内外的几个实验室合作，开发对老龄化研究有价值的定量工具。我们与密西西比州立大学的张东茂博士合作，发表了两种量化方法。一种是使用酸可裂解的表面增强拉曼光谱（SERS）标签来量化蛋白质和蛋白质修饰的水平。我们的方法显着提高了基于荧光的蛋白质检测的灵敏度和准确性。这篇文章发表在The Analyst（2011）上。另一种方法是使用罗丹明B衍生物作为表面增强拉曼光谱（SERS）标记来检测碳水化合物。后一种方法可用于测量衰老中的蛋白质糖基化，这仍然是相当难以捉摸的。 这项工作已发表在Analytical Chemistry（2010）上。我们与NIA的Rong-fong Shen，Bronwen Martin和Stuart Maudsley博士合作，系统地评估了脉冲Q碰撞诱导解离（PQD）方法在蛋白质组学研究中的肽鉴定。PQD方法通常用于在使用LTQ质谱仪的肽定量中促进低质量报告离子的检测。PQD方法的优化对于在蛋白质组学研究中鉴定具有不稳定官能团的肽（例如磷酸肽）特别有价值。这项工作已被接受发表在Journal of the American Society for Mass Spectrometry（2011年，出版中）。 为了了解衰老的基本生物学过程，我们已经确定并表征了与哺乳动物基因Aven高度同源的苍蝇基因。哺乳动物Aven是DNA损伤反应和G2/M细胞周期进程的调节剂，与几种类型的癌症有关，如急性髓性白血病。 我们发现果蝇Aven（dAven）是果蝇脂肪组织中正常细胞周期进程所必需的。这项工作已发表在Cell Cycle（2011）上。未来的研究将致力于了解dAven在DNA损伤反应中的作用，这将揭示可能与癌症和衰老相关的信息。综上所述，我们从这项研究中获得的发现沿着上述分析工具为我们进一步研究衰老过程中的分子变化以及这些变化对寿命和健康寿命的影响提供了基础。 许多植物，包括水果和蔬菜，由于其高抗氧化能力和许多生物活性，是促进长寿和健康的理想选择。然而，很少有植物实际上是已知的拥有长寿属性。实施老龄化干预措施的有效途径仍然知之甚少。我们之前已经证明，补充一种水果提取物与蔓越莓和牛至提取物的混合物可以促进墨西哥果蝇的寿命和繁殖能力。 为了进一步研究蔓越莓的健康益处，我们评估了长期食用蔓越莓对大鼠胰腺与年龄相关的变化的影响。 我们发现，长期食用蔓越莓可以防止与年龄相关的基础胰岛素释放下降，改善细胞葡萄糖反应性，并保持正常衰老大鼠的功能性细胞质量。ββ我们的研究结果表明，蔓越莓的消费可以对糖尿病患者有益。这项工作已发表在Journal of Gerontology Serial A：Biological Sciences（2011）上。 为了进一步了解水果和草药调节寿命的分子机制，我们采用果蝇作为模型系统。我们已经确定了油桃，一种全球消费的水果，对果蝇寿命和健康寿命的影响。我们的研究结果表明，油桃至少部分通过调节葡萄糖代谢和减少氧化损伤来促进长寿和健康。这项工作提供了第一个证据表明油桃的长寿效应，并已发表在自由基生物学与医学（2011）。这些发现鼓励我们进一步研究各种植物提取物的健康益处以及与衰老相关的潜在机制。这也将为水果和草药的消费提供科学指导。 总之，我们已经开发出适用于研究衰老中分子变化的蛋白质和蛋白质修饰的准确可靠测量的分析工具。此外，我们已经证明了两种植物提取物，蔓越莓和油桃提取物，在促进健康和长寿的大鼠和苍蝇，分别的效果。这些研究应该被证明是有价值的，以推进实验老年学实验室的目标和NIA的使命，以了解衰老的基本生物学和开发有效的衰老干预措施。该项目将提供对人类衰老基本生物学的深入了解，并促进为人类制定有效的衰老干预策略。