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学过程，受许多遗传和环境因素影响。寿命是测量衰老率的少数可靠参数之一。模型生物的遗传分析在许多可能影响寿命的基因中发现了突变。在许多生物中，包括蠕虫，蝇，啮齿动物，灵长类动物和人类在内的许多生物中都观察到了衰老中基因表达的变化。然而，关于不同的组织年龄以及寿命基因和延长性干预措施如何影响衰老的方式知之甚少。为了解决组织特异性衰老，我们以前已经确定了数百个基因在七个不同组织中的衰老中显示出显着变化，包括脑，肌肉和组织中的消化和生殖系统中，代表了不同的生理功能。这项调查为我们提供了一个基础，以解决衰老中的几个基本问​​题。首先，我们已经开始通过组织和分子水平的寿命基因来解决寿命延伸的机理。我们已经确定了数百个基因，显示了野生型与长寿命菌株Methuselah之间组织特异性变化。该评估阐明了甲壳虫基因如何调节组织水平的寿命的分子和细胞机制。其次，我们研究了不同组织之间衰老的常见和不同变化。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。线粒体能量产生是唯一显示所有组织中年龄发生重大变化的生物学过程，进一步证实了目前对线粒体功能在衰老中重要性的看法。类似的方法将应用于研究机制，通过这些方法，ProLongevity干预措施将来会在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对于调节D. melanogaster的寿命很重要。 饮食限制（DR）对寿命的强大环境操纵（DR）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。但是，将长期DR施加在人类中是一项挑战。另一种策略是将药物或营养化合物应用于模仿DR的反应。已经证明了一些化合物在模型生物中具有这种作用。但是，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。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。很少有系统地尝试确认提出的ProLongevity主张或调查潜在的有效干预措施。我们已经开发了多个Prolongevity屏幕系统，并评估了补充多种化合物对MexFly寿命的效果。该屏幕是在墨西哥Chiapas Tapachula的Moscafrut群众群体中进行的。我们已经表明，白藜芦醇只能在某些营养条件下延长Mexflies的寿命，这表明白藜芦醇的延长效应取决于饮食中的成分和含量。 蔓越莓的消费量已被证明具有许多健康益处，尤其是在与尿路感染作斗争时。但是，关于蔓越莓的抗衰老作用知之甚少。因此，我们决定评估大鼠蔓越莓提取物的抗衰老作用。我们发现，长期补充蔓越莓可以延迟某些与年龄相关的生理功能下降，包括葡萄糖代谢。该结果鼓励我们调查与衰老有关的蔓越莓消费的其他健康益处，这将为蔓越莓消费提供科学指导。 总而言之，我们利用多种物种来利用每个系统的独特功能来解决与寿命调节有关的问题。借助D. melanogaster，我们正在研究延长的干预措施和寿命基因在分子和组织水平上延长寿命的机制。我们正在使用Mexflies来识别有效的Prolongevity干预措施，这将在啮齿动物中进一步评估。这种多物种方法应该证明是有价值的，以促进实验性老年病的实验室，以调查和发展哺乳动物的衰老干预措施。鉴定衰老和有效的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。