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: 8148227
• 负责人: Sige Zou
• 金额: $ 51.91万
• 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/8148227
• 关键词: Aging; Intervention; functional genomics

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 understand the aging processes. Previously, we have collaborated with Dr. Dongmao Zhang at the Mississippi State University and published a 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. To continue this line of research, we have recently investigated the Raman spectra of fluorescein isothiocyanate (FITC)-conjugated protein in order to improve the interpretation accuracy of data obtained from biomedical Raman applications. Our recent results have been accepted for publication in Applied Spectroscopy (2010). These studies provide a foundation for us to further investigate molecular changes in the aging processes and consequences of these alterations on lifespan and healthspan. A robust environmental manipulation of lifespan and healthspan is dietary restriction (DR), which has been shown to extend lifespan and healthspan in many species, ranging from invertebrates to mammals. However, it is challenging to impose a long-term DR regime in humans. An alternative strategy would be to utilize pharmaceutical or nutraceutical compounds to induce responses that would mimic DR. Dietary supplements are widely used with the belief that they can forestall disease and increase longevity. A few compounds have been shown to have the DR effect in model organisms. However, the number of such compounds is still small and little is known about the mechanisms by which the compounds extend lifespan. Few systematic attempts have been made to confirm the prolongevity claims, or to investigate potentially effective interventions. We have previously demonstrated a prolongevity screen system to systematically assess the effects of compounds and fruit extracts on lifespan using the Mexican fruit fly (Mexfly) as the model organism. We have recently found that supplementation of a fruit extract mixed with cranberry and oregano can modulate the lifespan of Mexflies in a dietary composition and sex dependent manner. The results have been published in the Journal of Gerontology Biological Sciences (2010). This study supports the anti-aging effects of cranberry and oregano. These findings encourage us to further investigate health benefits and mechanisms of cranberry and oregano consumption related to aging, which will provide scientific guidance to consumption of fruits and herbs. To understand the molecular mechanisms of lifespan regulation by fruits and herbs, we have employed the Drosophila melanogaster as the model system. Acai is a fruit indigenous to the Amazon River area and is thought to possess high anti-oxidant activities, and has anti-inflammatory, anti-cancer and anti-cardiovascular disease properties owing to its high phytochemical content. However, little is known about the potential anti-aging properties of acai especially at the organismal level. We have found that acai supplementation can significantly increase the lifespan of female flies fed a high fat diet compared to the non-supplemented control. We have also measured transcript changes induced by acai for age-related genes. Our findings suggest that acai improves survival of flies fed a high fat diet through activation of stress response pathways and suppression of gluconeogenesis-related pathways. The results have been published in Experimental Gerontology (2010). This study indicates that acai has the potential to antagonize the detrimental effect of fat in the diet and alleviate oxidative stress in aging. Supplementation of acai to the fly diet provides us a system to further investigate the molecular mechanisms of aging. In summary, we have addressed several central issues related to aging. We have developed analytic tools 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 genetically amenable systems, including Drosophila melanogaster and 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，受许多遗传和环境因素影响。对大分子的氧化损伤，包括蛋白质，脂质和核酸，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羰基，酮和/或醛基的形成。蛋白质羰基水平的准确和敏感的测量对于我们了解衰老过程至关重要。以前，我们已经与密西西比州立大学的Dongmao Zhang博士合作，并发表了一种比率的拉曼光谱法（RMRS）方法，用于定量确定蛋白质羰基水平。该方法利用样品中蛋白质的独特光谱作为内部对照，从而显着提高了准确性，以比较样品之间蛋白质羰基水平的差异。为了继续这项研究，我们最近研究了荧光素异硫氰酸荧光素（FITC）偶联蛋白的拉曼光谱，以提高从生物医学拉曼应用中获得的数据的解释准确性。我们最近的结果已被接受用于应用光谱法（2010）的出版物。 这些研究为我们提供了一个基础，以进一步研究这些寿命和健康状况改变的衰老过程的分子变化和后果。 饮食限制（DR）对生命周期和健康状态的强大环境操纵，已显示出许多物种的寿命和健康状态，范围从无脊椎动物到哺乳动物。但是，在人类中强加长期的博士政权是一个挑战。另一种策略是利用药物或营养化合物来诱导模仿DR的反应。饮食补充剂被广泛使用，认为它们可以防止疾病并增加寿命。已经证明了一些化合物在模型生物中具有DR效应。但是，此类化合物的数量仍然很小，对化合物延长寿命的机制知之甚少。很少有系统地尝试确认ProLongevity主张或调查潜在的有效干预措施。我们以前已经证明了使用墨西哥果蝇（Mexfly）作为模型生物体，系统地评估化合物和水果提取物对寿命的影响。我们最近发现，补充酸果莓和牛至混合的水果提取物可以以饮食成分和性依赖性方式调节Mexflies的寿命。结果已发表在《老年病生物学杂志》（2010年）中。这项研究支持蔓越莓和牛至的抗衰老作用。这些发现鼓励我们进一步研究与衰老有关的蔓越莓和牛至消费量的健康益处和机制，这将为消费水果和草药提供科学指导。 为了理解水果和草药的寿命调节的分子机制，我们采用了果蝇杂物剂作为模型系统。 Acai是亚马逊河地区的原住民，被认为具有较高的抗氧化活性，并且由于其高植物化学含量，具有抗炎，抗癌和抗心血管疾病的特性。但是，对于ACAI的潜在抗衰老特性，尤其是在生物水平上，知之甚少。我们发现，与不受补充的对照相比，补充ACAI可以显着增加雌性苍蝇的寿命。我们还测量了ACAI诱导的与年龄相关基因诱导的转录本变化。我们的发现表明，ACAI通过激活压力反应途径和抑制与糖异生有关的途径来提高果蝇的存活。结果已发表在实验老年学（2010年）中。这项研究表明，ACAI有可能拮抗脂肪在饮食中的有害作用并减轻衰老中的氧化应激。将ACAI补充为蝇饮食为我们提供了一个系统，可以进一步研究衰老的分子机制。 总而言之，我们已经解决了与衰老有关的几个核心问题。我们已经开发了分析工具来准确，可靠地测量衰老的分子变化。我们已经采用MEXFLIE来寻找有效的衰老干预措施，这些干预措施将在包括果蝇和啮齿动物在内的遗传性系统中进一步评估。这些研究应证明是有价值的，以促进实验老年度实验室的目标，以调查和发展哺乳动物的衰老干预措施。识别衰老和ProLongevity干预措施中保守的特征对于理解人类衰老而显然很有价值，更重要的是，对于制定人类的有效衰老干预策略。