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

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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.