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.