Functional Genomic Study of Aging and Aging Interventions

衰老是一个受遗传和环境因素影响的基本生物学过程。蛋白质、脂质和核酸等大分子的氧化损伤被认为是导致衰老的因素之一。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。准确灵敏地测量蛋白质羰基水平对我们了解衰老过程至关重要。此前，我们与密西西比州立大学的Dongmao Zhang博士合作，发表了一种用于定量测定蛋白质羰基水平的比例拉曼光谱（RMRS）方法。该方法利用样品中蛋白质的独特光谱作为内控，显著提高了样品间蛋白质羰基水平差异比较的准确性。为了继续这条研究路线，我们最近研究了异硫氰酸荧光素（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。我们最近的研究结果已被《应用光谱学》（2010）接受发表。这些研究为我们进一步研究衰老过程中的分子变化及其对寿命和健康的影响提供了基础。

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.