Functional Genomic Study of Aging and Aging Interventions

衰老是一个基本的生物过程，受到许多遗传和环境因素的影响。对蛋白质、脂肪和核酸等大分子的氧化损伤被认为是衰老的原因之一。蛋白质氧化损伤的一个常用的生物标志物是蛋白质的羰基、酮和/或醛的形成。准确和灵敏地测量蛋白质的羰基水平对于我们理解衰老过程至关重要。然而，目前的分析技术，包括基于质谱学、荧光和免疫分析的方法的准确性，对于蛋白质修饰水平的微小变化具有生物学意义的应用是有限的。为了解决这个问题，我们与密西西比州立大学的张东茂博士合作，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的羰基水平。该方法利用样品中独特的蛋白质光谱作为内对照，显著提高了比较样品间蛋白质羰基水平差异的准确度。这一发现发表在《分析化学》杂志上。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寿命的影响提供了基础。 一种强有力的对寿命的环境控制是饮食限制(DR)，它已被证明在从无脊椎动物到哺乳动物的许多物种中都能延长寿命。然而，将长期DR强加给人类将是一项挑战。另一种策略是应用药物或营养品化合物来诱导模拟博士的反应。一些化合物已被证明在模型生物体中具有这种作用。然而，这个数字仍然很小，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，人们相信它们可以预防疾病，延长寿命。几乎没有系统性的尝试来证实所提出的延长寿命的说法或调查潜在有效的干预措施。我们已经开发了几种延寿筛选系统，并评估了十几种化合物对粘蝇寿命的影响。这一筛选是在墨西哥恰帕斯州塔帕丘拉的莫斯法鲁特大规模饲养设施中进行的。我们在《实验老年学》杂志上发表了这项研究的一些结果，表明白藜芦醇是一种多酚化合物，只有在特定的营养条件下才能延长苍蝇的寿命，这表明白藜芦醇的延寿作用取决于食物的组成和含量。 食用小红莓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，人们对小红莓的抗衰老作用知之甚少。考虑到小红莓富含多酚类物质，我们推测小红莓具有抗衰老作用。为了验证这一假设，我们研究了补充小红莓对大鼠和苍蝇的延寿和延缓衰老的作用。我们发现，长期补充小红莓可以延缓一些与年龄相关的生理功能的下降，包括葡萄糖代谢。我们还发现，小红莓补充剂可以通过饮食组成和性别依赖的方式来调节墨西哥苍蝇的寿命。描述这些结果的两份手稿已提交科学期刊审阅。这些发现鼓励我们进一步研究小红莓消费与衰老相关的健康益处和分子机制，为小红莓消费提供科学指导。 总而言之，我们已经解决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老化过程中的分子变化。我们已经使用了墨西哥苍蝇来寻找有效的衰老干预措施，这将在啮齿类动物身上进一步评估。这些研究对于推进实验老年学实验室研究和发展哺乳动物衰老干预措施的目标具有重要意义。识别衰老和延寿干预中的保守特征对于理解人类衰老，更重要的是为人类制定有效的衰老干预策略，显然是有价值的。

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.