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: 7963941
• 负责人: Sige Zou
• 金额: $ 34.59万
• 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/7963941
• 关键词: Address; Age Factors; Aging; Aging-Related Process; Aldehydes; Analytical Chemistry; Animal Model; Belief; Biological; Biological Markers; Biological Process; Classification; Consumption; Cranberries; Disease; Environmental Risk Factor; Fluorescence; Foundations; Genetic; Gerontology; Goals; Health Benefit; Human; Immunoassay; Intervention; Invertebrates; Journals; Ketones; Laboratories; Lipids; Longevity; Mammals; Manuscripts; Mass Spectrum Analysis; Measurement; Measures; Methods; Mexico; Mississippi; Molecular; Nucleic Acids; Nutraceutical; Nutritional; Pharmacologic Substance; Physiological; Post-Translational Protein Processing; Property; Proteins; Publishing; Rattus; Resveratrol; Rodent; Sampling; Supplementation; System; Techniques; Testing; Universities; Urinary tract infection; age effect; age related; anti aging; base; dietary restriction; dietary supplements; effective intervention; fight against; functional genomics; glucose metabolism; improved; internal control; macromolecule; novel; oxidative damage; ratiometric; response; sex; tool

Aging is a fundamental biological process that is influenced by a number of genetic and environmental factors. Oxidative damage to macromolecules, including protein, lipid and nucleic acid, is thought to be one of the causative factors of aging. A commonly used biomarker of protein oxidative damages is the formation of protein carbonyl, ketone and/or aldehyde groups. Accurate and sensitive measurement of the protein carbonyl level is critical for us to understanding the aging process. However, the accuracy of current analytical techniques, including mass spectrometry, fluorescence, and immunoassay based methods, is limited for applications where small changes in the protein modification level are of biological significance. To address this issue, we have collaborated with Dr. Dongmao Zhang at Mississippi State University to develop a novel ratiometric Raman spectroscopic (RMRS) method for quantitative determination of the protein carbonyl level. This method utilizes the unique spectrum of protein in the sample as the internal control, which results in significantly improved accuracy for comparing the difference in the protein carbonyl level among samples. The findings have been published in Analytical Chemistry. This study provides a foundation for us to further investigate molecular changes in the aging process and consequences of these alterations on lifespan and healthspan. A robust environmental manipulation of lifespan is dietary restriction (DR), which has been shown to extend lifespan in many species, ranging from invertebrates to mammals. However, it would be challenging to impose long-term DR in humans. An alternative strategy would be to apply pharmaceutical or nutraceutical compounds to induce responses that would mimic DR. A few compounds have been shown to have this effect in model organisms. However, the number is still small and little is known about mechanisms by which these compounds extend lifespan. Dietary supplements are widely used with the belief that they can forestall disease and increase longevity. Few systematic attempts have been made to confirm prolongevity claims made or to investigate potentially effective interventions. We have developed several prolongevity screen systems and have assessed the effects of more than a dozen of compounds on lifespan in the mexfly. This screen has been conducted in the Moscafrut mass-rearing facility at Tapachula, Chiapas, Mexico. We have published some of our results from this study in Experimental Gerontology showing that resveratrol, a polyphenolic compound, can extend lifespan of the mexflies only under certain nutritional conditions, suggesting the prolongevity effect of resveratrol depends on dietary composition and content. Consumption of cranberry has been shown to have numerous health benefits, especially on fighting against urinary tract infection. However, not much is known about anti-aging effects of cranberry. Considering that cranberry is rich in polyphenolics, we postulate that cranberry has anti-aging properties. To test this hypothesis, we have investigated the prolongevity and anti-aging effects of cranberry supplementation both in rats and mexfly. We have found that long-term supplementation of cranberry can delay some age-related decline of physiological functions, including glucose metabolism. We have also found that cranberry supplementation can modulate the lifespan of mexflies in a dietary composition and sex dependent manner. Two manuscripts describing these results have been submitted for review in scientific journals. These findings encourages us to further investigate health benefits and molecular mechanisms of cranberry consumption related to aging, which will provide scientific guidance to cranberry consumption. In summary, we have addressed several central issues related to aging. We have developed an analytic tool to accurately and reliably measure molecular changes in aging. We have employed mexflies to search for effective aging interventions, which will be further assessed in rodents. These studies should prove valuable to advance the objective of Laboratory of Experimental Gerontology to investigate and develop aging interventions in mammals. Identification of the conserved features in aging and prolongevity interventions are clearly valuable for understanding human aging and more importantly for developing effective aging intervention strategies for humans.

衰老是一个基本的生物学过程，受到许多遗传和环境因素的影响。蛋白质、脂质和核酸等大分子物质的氧化损伤被认为是衰老的原因之一。蛋白质氧化损伤的常用生物标志物是蛋白质羰基、酮和/或醛基的形成。蛋白质羰基水平的准确和灵敏的测量对于我们了解衰老过程至关重要。然而，目前的分析技术，包括质谱法，荧光，和免疫分析为基础的方法，是有限的应用程序中的蛋白质修饰水平的小变化是生物学意义的准确性。为了解决这个问题，我们与密西西比州立大学的Dongmao Zhang博士合作开发了一种新的比率拉曼光谱（RMRS）方法，用于定量测定蛋白质羰基水平。该方法利用样品中蛋白质的独特光谱作为内部对照，从而显著提高了比较样品之间蛋白质羰基水平差异的准确度。研究结果发表在Analytical Chemistry上。这项研究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的影响提供了基础。 一个强大的环境操纵寿命是饮食限制（DR），这已被证明可以延长许多物种的寿命，从无脊椎动物到哺乳动物。然而，对人类实施长期DR将具有挑战性。另一种策略是应用药物或营养化合物来诱导模拟DR的反应。一些化合物已被证明在模式生物中具有这种作用。然而，这个数字仍然很小，而且对这些化合物延长寿命的机制知之甚少。膳食补充剂被广泛使用，相信它们可以预防疾病和延长寿命。很少有系统的尝试，以确认长寿的索赔或调查潜在的有效干预措施。我们已经开发了几种寿命筛选系统，并评估了十几种化合物对墨西哥果蝇寿命的影响。该筛选是在墨西哥恰帕斯州塔帕丘拉的Moscafrut大规模饲养设施中进行的。我们已经在实验老年学上发表了这项研究的一些结果，表明白藜芦醇，一种多酚化合物，只有在一定的营养条件下才能延长墨西哥果蝇的寿命，这表明白藜芦醇的长寿效果取决于膳食组成和含量。 蔓越莓的消费已被证明有许多健康益处，特别是在对抗尿路感染方面。然而，人们对蔓越莓的抗衰老作用知之甚少。考虑到蔓越莓富含多酚类物质，我们假设蔓越莓具有抗衰老特性。为了验证这一假设，我们已经研究了蔓越莓补充剂在大鼠和墨西哥果蝇中的长寿和抗衰老作用。我们发现，长期补充蔓越莓可以延缓一些与年龄相关的生理功能下降，包括葡萄糖代谢。我们还发现，蔓越莓补充剂可以以饮食组成和性别依赖的方式调节墨西哥蝇的寿命。描述这些结果的两份手稿已提交科学期刊审查。这些发现鼓励我们进一步研究蔓越莓消费与衰老相关的健康益处和分子机制，这将为蔓越莓消费提供科学指导。 总之，我们讨论了与老龄化有关的几个核心问题。我们开发了一种分析工具，可以准确可靠地测量衰老过程中的分子变化。我们已经雇用墨西哥苍蝇来寻找有效的衰老干预措施，这将在啮齿动物中进一步评估。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，调查和开发衰老干预哺乳动物。识别衰老和长寿干预措施中的保守特征对于理解人类衰老，更重要的是对于制定有效的人类衰老干预策略显然是有价值的。