Cross-Species Analysis to Identify Conserve Longevity-Related Pathways and Putative Drug Targets

摘要。跨物种分析，以确定保守寿命相关 途径和假定的药物靶点 尽管在基因组学指导和一般“基于组学”的生物医学研究方面进行了大量投资， 研究已经深入了解了影响健康和长寿的因素， 保持健康和延长寿命。这显然是由于数量和复杂性 有助于长寿的因素。我们认为，确定明确有助于 长寿是为了确定物种间进化上保守的基因和途径，这些基因和途径有助于人类的长寿。 不同物种的寿命存在显著差异。然而，在这种情况下， 分析，以及利用哪些化验，是开放的问题，因为是否老化过程中， 一些遥远的物种（例如，酵母，蠕虫和苍蝇），考虑到它们之间明显的生理差异， 人类，可能无法捕获与人类寿命相关的基因和途径。考虑到这一点，我们建议 确定保守的长寿相关基因、途径和药物靶点的最佳方法 包括在非常广泛的温血动物中询问尽可能多的分子表型， 脊椎动物物种（即哺乳动物和鸟类）寿命范围很广。这将确保足够的 变异是寿命可以在表型和分子水平上进行评估， 具有与人类一致的衰老和长寿相关的过程。然而，这种方法 需要制定分析方法，以适应相关的演变现象， 例如介导不同分子表达的基因之间明显的DNA序列差异， 表型，控制物种之间的系统发育关系，以及识别和表征 相关基因和蛋白质之间的正相关关系，以便将任何发现的相关性置于背景中 人类和其他物种。我们建议描述60种差异很大的 在至少5种与衰老和寿命相关的组织中表现出寿命显著变化的物种 （肌肉，心脏，肝脏，大脑，皮肤）与父母相关的研究团队协调努力 UH 2/UH 3赠款。我们将利用这些物种的参考基因组的可用性，或寻求 必要时开发参考基因组，以便于分析。我们还将开发新的分析 方法，利用公共领域的工具和数据进行更全面的分析，并侧重于 我们的发现与人类研究的相关性。这些拟议的研究是第一批 拥护这样一种概念，即不同的科学研究和发现的“三角测量”，即，的尝试 基于生物学一致性，统一不同研究设计的结果，是推进 鉴定长寿相关的保守基因、长寿增强的途径和靶点， 与人类相关的老年保护药物。

ABSTRACT. CROSS-SPECIES ANALYSIS TO IDENTIFY CONSERVED LONGEVITY-RELATED PATHWAYS AND PUTATIVE DRUG TARGETS Despite the massive investment in genomically-guided, and general `omics-based', biomedical research, few studies have generated insights into factors that contribute to health and longevity that can modulated pharmacologically to sustain health and extend longevity. This is clearly due to the number and complexity of factors contributing to longevity. We believe one strategy for identifying factors that unequivocally contribute to longevity is to identify evolutionarily conserved genes and pathways across species that contribute to the pronounced variation in lifespan different species exhibit. However, which species to consider in such analyses, as well as which assays to exploit, are open questions, as is the whether or not aging processes in some distant species (e.g., yeast, worms and flies), given overt physiological differences between them and humans, may not capture genes and pathways relevant to human longevity. With this in mind, we proposed that the best approach to identifying conserved longevity-related genes, pathways and drug targets would involve interrogating as many molecular phenotypes as possible across a very broad range of warm-blooded vertebrate species (i.e. mammals and birds) exhibiting a wide range of lifespans. This will ensure adequate variation is lifespan can be assessed at both the phenotypic and molecular level in species more likely to harbor aging and longevity-related processes consistent with those in humans. However, such an approach would require developing analytical methodology that would accommodate relevant evolutionary phenomena, such as overt DNA sequence differences among genes mediating the expression of different molecular phenotypes, controlling for phylogenetic relationships among species, and identifying and characterizing orthologous relationships among relevant genes and proteins to put into context the relevance of any findings to humans and other species. We propose characterizing the molecular landscape of 60 widely divergent species exhibiting substantial variation in lifespan in at least 5 tissues of relevance to aging and longevity (muscle, heart, liver, brain, skin) in a coordinated effort with the research team associated with the parent UH2/UH3 grant. We will exploit the availability of reference genomes for each of these species, or seek to develop reference genomes where needed, to facilitate analyses. We will also develop novel analytical methods, leverage tools and data from the public domain for more comprehensive analyses, and focus on the relevance of our findings to studies involving humans. These proposed studies are some of the first to champion the notion that the `triangulation' of disparate scientific studies and discoveries, i.e., the attempt to unify results from different study designs based on their biological coherence, is the optimal way to advance identification of longevity-related conserved genes, pathways and targets for longevity-enhancing, geroprotective drugs of relevance to humans.