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: 7732209
• 负责人: Sige Zou
• 金额: $ 45.42万
• 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/7732209
• 关键词: Address; Affect; Age; Aging; Algorithms; Anastrepha ludens; Animal Model; Belief; Biological Process; Brain; Classification; Condition; Consumption; Cranberries; Disease; Environmental Risk Factor; Foundations; Future; Gene Expression; Genes; Genetic; Gerontology; Goals; Health Benefit; Human; Intervention; Invertebrates; Laboratories; Life; Longevity; Machine Learning; Mammals; Measures; Mexico; Mitochondria; Molecular; Muscle; Mutation; Numbers; Nutraceutical; Nutritional; Organism; Pathway interactions; Pharmacologic Substance; Physiological; Primates; Production; Range; Rate; Rattus; Regulation; Reproductive system; Resveratrol; Rodent; Supplementation; Surveys; System; Tissues; Transcript; Urinary tract infection; age effect; age related; anti aging; dietary restriction; dietary supplements; fight against; fly; functional genomics; genetic analysis; glucose metabolism; longevity gene; response

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.

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。寿命是衡量老龄化速度的为数不多的可靠参数之一。对模式生物的遗传分析发现了一些基因的突变，这些基因可能会影响寿命。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，关于不同组织如何衰老，以及长寿基因和长寿干预如何影响衰老，人们知之甚少。为了应对组织特异性衰老，我们先前已经在七个不同的组织中发现了数百个基因，这些基因在衰老过程中表现出显著的转录水平变化，包括大脑、肌肉以及消化系统和生殖系统中的组织，它们代表着不同的生理功能。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解决长寿基因延长寿命的机制。我们已经确定了数百个基因，这些基因显示了野生型苍蝇和长寿苍蝇品系Matuselah之间的组织特异性变化。这项评估阐明了甲氧西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是特定于组织的。线粒体的能量产生是所有组织中唯一随年龄发生显著变化的生物过程，进一步证实了目前关于线粒体功能在衰老中的重要性的观点。未来，类似的方法将被用于研究延寿干预在组织水平上延长寿命的机制。我们将进一步研究哪些与年龄相关的基因和途径在调节黑腹果蝇寿命方面起重要作用。 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，并评估了补充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。我们发现白藜芦醇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。 食用小红莓被证明对健康有许多好处，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。因此，我们决定评估小红莓提取物对大鼠的延缓衰老作用。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。这一结果鼓励我们研究与衰老相关的小红莓消费的额外健康益处，这将为小红莓的消费提供科学指导。 总而言之，我们利用多物种通过利用每个系统的独特功能来解决与寿命调节相关的问题。我们正在研究延寿干预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苍蝇来确定有效的延长寿命的干预措施，这将在啮齿动物身上进一步评估。这种多物种的方法应该被证明是有价值的，以促进实验老年学实验室研究和发展哺乳动物衰老干预的目标。识别衰老中的保守特征和有效的延寿干预显然对理解人类衰老具有重要价值，更重要的是为人类制定有效的衰老干预策略。