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: 7591991
• 负责人: sige zou
• 金额: $ 68.25万
• 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/7591991
• 关键词: Address; Adult; Affect; Age; Aging; Aging-Related Process; Anastrepha ludens; Animal Model; Anticonvulsants; Antioxidants; Belief; Biological Process; Brain; Caenorhabditis elegans; Classification; Condition; Cranberries; Diet; Dietary Supplementation; Disease; Eating; Energy Intake; Environmental Risk Factor; Evaluation; Excision; Food; Foundations; Fruit; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Screening; Genome; Gerontology; Goals; Human; Individual; Intervention; Invertebrates; Investigation; Knowledge; Life; Longevity; Mammals; Measures; Methods; Mexico; Molecular; Molecular Profiling; Muscle; Mutation; Nematoda; Numbers; Nutraceutical; Nutritional; Organism; Pathway interactions; Pharmacologic Substance; Physiological; Primates; Range; Rate; Regulation; Reproductive system; Resveratrol; Rodent; Source; Supplementation; Surveys; System; Tissues; Transcript; Treatment Protocols; Uncertainty; Yeasts; age effect; anti aging; deprivation; dietary restriction; dietary supplements; feeding; fly; functional genomics; genetic analysis; longevity gene; mimetics; mutant; 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 have systematically investigated tissue-specific factors that affect lifespan and aging processes. We have measured the expression profile of aging for seven tissues from fly, including brain, muscle and tissues in the digestive and reproductive systems, which represent different physiological functions. Hundreds of genes have been identified to show significant changes at the transcript level in aging in each tissue. This survey has provided us a foundation to study the mechanisms of lifespan extension by the longevity genes at the tissue and molecular levels. To address this question, we have chosen to study the methuselah mutant flies, which live longer than control flies. We have measured molecular changes of this mutant across age for the seven tissues described above. We have compared these changes to those in the wild type fly strain at the molecular and tissue levels. Several hundreds of genes have been identified to have tissue-specific changes between wild type and methuselah flies. This assessment elucidates molecular and cellular mechanisms on how the methuselah gene regulates lifespan at the tissue level. Similar approaches will be applied to study mechanisms by which prolongevity interventions extend lifespan at the tissue levels in the future. 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 a screen system by using mexfly in the Moscafrut mass-rearing facility at Tapachula, Chiapas, Mexico. We have assessed the effects of supplementation of more than a dozen of compounds ranging from antioxidants, DR mimetics, fruit extracts and anticonvulsants. We have found that most of these compounds have marginal effects on lifespan extension. However, we have shown that resveratrol can extend lifespan of mexflies only under certain nutritional conditions and some cranberry compounds appears to have positive effects on lifespan. Utilization of the high-throughput system will provide reliable and statistically convincing results on the effects of aging interventions. Systematic evaluation of prolongevity interventions will not only allow identification of effective anti-aging compounds but also uncover mechanisms of lifespan extension by dietary supplementation. This approach should prove valuable to advance the objective of experimental gerontology to investigate and develop aging interventions in mammals. Our understanding of molecular mechanisms of DR comes primarily from studies of genetically amenable systems including yeast, worms, and flies, where DR has been imposed by either diluting the food source or by using genetic mutations that reduce feeding efficiency. However, a major drawback of these approaches is that there remains substantial uncertainty in determining the exact caloric intake of individuals under these DR paradigms, unlike this ability in studies of higher organisms. We have developed an alternative dietary paradigm that can extend lifespan in C. elegans. We have found that a dietary deprivation (DD) regimen, in which the food source is completely removed from adults, can prolong adult lifespan by 45%. Since this regimen involves complete removal of the food source, the problem of controlling food intake, which has hampered interpretation of past studies, is alleviated. Using this unambiguous method, we have investigated the genetic pathways necessary for lifespan extension by diet. We have measured genome-wide transcript profiles of DD response and have identified hundreds of candidates for further genetic studies. In addition, we have conducted a small scale genetic screen to identify which genes are required for DD response. This analysis should reveal mechanisms governing longevity under different environmental especially dietary conditions. Considering the similarities between DD and DR, some of the DD mechanisms should be evolutionarily conserved, which will advance knowledge about effects of diet on aging and longevity in mammals. In summary, we have applied three different invertebrate species to address issues related to dietary regulation of lifespan 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 mexflies to identify effective prolongevity interventions, which should provide guidance for further investigation of aging interventions in mammals. By utilizing a unique and robust dietary regimen in C. elegans, we are dissecting molecular mechanisms of dietary regulation of lifespan. Identification of the conserved features in aging and efficient prolongevity interventions are clearly critical for us understand human aging and more importantly to develop 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。寿命是衡量衰老速度的少数可靠参数之一。对模型生物体的遗传分析发现了许多可能影响寿命的基因突变。在许多生物体中都观察到了衰老过程中基因表达的变化，包括蠕虫、苍蝇、啮齿动物、灵长类动物和人类。然而，人们对不同组织如何衰老，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，我们系统地研究了影响寿命和衰老过程的组织特异性因素。我们测量了果蝇七种组织的衰老表达谱，包括大脑、肌肉以及消化系统和生殖系统的组织，它们代表了不同的生理功能。数百个基因已被发现在每个组织的衰老过程中在转录水平上显示出显着的变化。本研究为我们从组织和分子水平研究长寿基因延长寿命的机制奠定了基础。为了解决这个问题，我们选择研究 methuselah 突变果蝇，它们比对照果蝇寿命更长。我们测量了上述七种组织中这种突变体随年龄变化的分子变化。我们在分子和组织水平上将这些变化与野生型果蝇品系的变化进行了比较。已鉴定出数百个基因在野生型果蝇和玛苏塞拉果蝇之间具有组织特异性变化。该评估阐明了 methuselah 基因如何在组织水平上调节寿命的分子和细胞机制。未来，类似的方法将应用于研究延长组织水平寿命的干预机制。 对寿命的一个强有力的环境控制是饮食限制（DR），它已被证明可以延长从无脊椎动物到哺乳动物等许多物种的寿命。然而，在人类身上实施长期的 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仿 DR 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，数量仍然很少，而且人们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并延长寿命。很少有系统性的尝试来证实所提出的长寿主张或调查潜在有效的干预措施。我们在墨西哥恰帕斯州塔帕丘拉的 Moscafrut 大规模饲养设施中使用 mexfly 开发了一种筛选系统。我们评估了补充十多种化合物的效果，包括抗氧化剂、DR 模拟物、水果提取物和抗惊厥药。我们发现大多数这些化合物对延长寿命具有边际效应。然而，我们已经证明，白藜芦醇只有在某些营养条件下才能延长墨西哥果蝇的寿命，并且一些蔓越莓化合物似乎对寿命有积极影响。高通量系统的利用将为衰老干预措施的影响提供可靠且统计上令人信服的结果。对长寿干预措施的系统评估不仅可以识别有效的抗衰老化合物，还可以揭示通过膳食补充剂延长寿命的机制。这种方法对于推进实验老年学研究和开发哺乳动物衰老干预措施的目标具有重要意义。 我们对 DR 分子机制的理解主要来自对包括酵母、蠕虫和苍蝇在内的遗传适应性系统的研究，其中 DR 是通过稀释食物来源或使用降低喂养效率的基因突变来实施的。然而，这些方法的一个主要缺点是，在这些 DR 范式下确定个体的确切热量摄入仍然存在很大的不确定性，这与高等生物研究中的这种能力不同。我们开发了一种替代饮食模式，可以延长线虫的寿命。我们发现，饮食剥夺 (DD) 疗法（即完全去除成年人的食物来源）可以将成年人的寿命延长 45%。由于该方案涉及完全去除食物来源，因此阻碍了对过去研究的解释的控制食物摄入的问题得到了缓解。使用这种明确的方法，我们研究了通过饮食延长寿命所需的遗传途径。我们测量了 DD 反应的全基因组转录谱，并确定了数百个候选者用于进一步的遗传学研究。此外，我们还进行了小规模遗传筛选，以确定 DD 反应所需的基因。该分析应该揭示不同环境尤其是饮食条件下控制长寿的机制。考虑到 DD 和 DR 之间的相似性，一些 DD 机制在进化上应该是保守的，这将增进人们对饮食对哺乳动物衰老和长寿影响的认识。 总之，我们利用三种不同的无脊椎动物物种的独特特征来解决与寿命饮食调节相关的问题。我们正在利用黑腹果蝇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。我们正在利用墨西哥果蝇来确定有效的长寿干预措施，这将为进一步研究哺乳动物的衰老干预措施提供指导。通过利用线虫独特而强大的饮食方案，我们正在剖析饮食调节寿命的分子机制。识别衰老中的保守特征和有效的长寿干预措施显然对于我们了解人类衰老至关重要，更重要的是为人类制定有效的衰老干预策略。