Functional Genomic Study of Aging and Aging Interventions

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。寿命是衡量衰老速度的少数几个可靠参数之一。对模式生物的遗传分析揭示了一些可能影响寿命的基因突变。在许多生物体中，包括蠕虫、苍蝇、啮齿动物、灵长类动物和人类，都观察到了衰老过程中基因表达的变化。然而，人们对不同的组织如何衰老，以及长寿基因和长寿干预措施如何影响衰老知之甚少。为了解决组织特异性衰老问题，我们之前已经确定了数百个基因，这些基因在七种不同组织中的转录水平上显示出显著的变化，包括大脑，肌肉以及消化和生殖系统中的组织，这些组织代表了不同的生理功能。这项调查为我们解决老龄化中的几个基本问题提供了基础。首先，我们已经开始在组织和分子水平上研究长寿基因延长寿命的机制。我们已经确定了数百个基因，这些基因在野生型和长寿的果蝇品系玛士撒拉之间显示出组织特异性的变化。这项评估阐明了玛士撒拉基因如何在组织水平上调节寿命的分子和细胞机制。其次，我们研究了不同组织在衰老过程中的共同和不同变化。使用机器学习算法，我们发现大多数与年龄相关的变化都是组织特异性的。线粒体能量产生是所有组织中唯一显示出随年龄显著变化的生物过程，进一步证实了线粒体功能在衰老中的重要性。类似的方法将被应用于研究机制，通过这些机制，长寿干预措施在未来的组织水平上延长寿命。我们将进一步研究哪些与年龄相关的基因和途径在调节D.黑腹菌 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，在人类中实施长期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，并评估了补充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。我们已经证明，白藜芦醇可以延长寿命的墨西哥苍蝇只有在一定的营养条件下，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。因此，我们决定评估蔓越莓提取物在大鼠中的抗衰老作用。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。这一结果鼓励我们研究蔓越莓消费与衰老相关的额外健康益处，这将为蔓越莓消费提供科学指导。 总之，我们利用多物种来解决与寿命调节有关的问题，利用每个系统的独特功能。与D.我们正在研究长寿干预措施和长寿基因在分子和组织水平上延长寿命的机制。我们正在使用墨西哥蝇来确定有效的长寿干预措施，这将在啮齿动物中进一步评估。这种多物种的方法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。识别老化中的保守特征和有效的长寿干预措施对于理解人类老化，更重要的是对于开发有效的人类老化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. Lifespan is one of the few reliable parameters to measure the rate of aging. Genetic analyses of model organisms have uncovered mutations in a number of genes that can affect lifespan. Changes in gene expression in aging have been observed in a number of organisms, including worms, flies, rodents, primates and human beings. However, little is known about how different tissues age, and how longevity genes and prolongevity interventions influence aging. To address tissue-specific aging, we previously have identified hundreds of genes showing significant changes at the transcript level in aging in seven different tissues, including brain, muscle and tissues in the digestive and reproductive systems, which represent different physiological functions. This survey has provided us a foundation to address several basic questions in aging. First, we have started to address the mechanisms of lifespan extension by the longevity genes at the tissue and molecular levels. We have identified hundreds of genes showing tissue-specific changes between the wild type and a long-lived fly strain, methuselah. This assessment elucidates molecular and cellular mechanisms on how the methuselah gene regulates lifespan at the tissue level. Second, we have investigated what are the common and different changes in aging among different tissues. Using a machine learning algorithm, we have found that most of the age-related changes are tissue-specific. The mitochondrial energy production is the only biological process showing significant changes with age in all the tissues, further confirming the current view on the importance of mitochondrial functions in aging. Similar approaches will be applied to study mechanisms by which prolongevity interventions extend lifespan at the tissue levels in the future. We will further investigate which age-related genes and pathways are important in regulating lifespan in D. melanogaster. 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 supplementation 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 shown that resveratrol 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 a numerous health benefits, especially on fighting against urinary tract infection. However, not much is known about anti-aging effects of cranberry. Therefore, we have decided to assess the anti-aging effects of cranberry extracts in rats. We have found that long-term supplementation of cranberry can delay some age-related decline of physiological functions, including glucose metabolism. This result encourages us to investigate additional health benefits of cranberry consumption related to aging, which will provide scientific guidance to cranberry consumption. In summary, we have utilized multi-species to address issues related to lifespan regulation by taking advantage of unique features of each system. With D. melanogaster, we are studying mechanisms by which prolongevity interventions and longevity genes extend lifespan at molecular and tissue levels. We are using the mexflies to identify effective prolongevity interventions, which will be further assessed in rodents. This multi-species approach 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 efficient prolongevity interventions are clearly valuable for understanding human aging and more importantly for developing efficient aging intervention strategies for humans.