ABSTRACT: THE LONGEVITY CONSORTIUM (LC). Multiple studies of model organisms and humans have suggested that genetic variants, proteins, metabolites, as well as other biomolecules and molecular- physiologic processes, could play roles in mediating longevity, healthspan, and age-related disease in humans. Unfortunately, the direct relevance of many of these factors to human longevity, healthspan and age-related disease is uncertain, as is the amenability of these factors to pharmacological modulation. Therefore, well-integrated and sophisticated research strategies are needed to determine the degree to which various factors both influence human longevity and are amenable to pharmacological manipulation. The Longevity Consortium (LC) has a history of precedent-setting studies seeking to identify factors that influence human longevity and healthspan and has recently redefined its goals and research strategies to achieve an appropriate level of integration and sophistication to elucidate additional factors affecting longevity, as well as their interactions and translatability into targets for pharmacotherapeutic manipulation. To enable appropriate integration in human longevity research, the LC will exploit a multiple investigator structure with 5 interlinked research projects and 3 integrative cores. These projects and cores will include: A cross-species project focusing on cellular and organismal phenotypes led by Richard Miller (referred to as the Miller-Mice/Cell project hereafter); a metabolomics project led by Oliver Fiehn (Fiehn-Metabolomics); a Centenarians project co-led by Thomas Perls and Paola Sebastiani (Perls- Centenarian); a proteomics project led by Eric Orwoll (Orwoll-Proteomics) and a disease context project led by Nicholas Schork (Schork-Disease Context). The cores include a Systems Biology core led by Nathan Price (Price-Systems), a Chemoinformatics core led by Thomas Girke (Girke-Chemoinformatics), and an administrative core with an overall administrative component led by Steve Cummings (Cummings-Admin) and a scientific integration component led by Nicholas Schork. Drs. Cummings and Schork, as Multiple PIs, will share responsibility for the overall leadership of the LC effort. The proposed LC will complement, and partner with, an NIA-funded U24 project (U24AG051129) involving many LC investigators to construct a website for data dissemination. 1

The Longevity Consortium (LC) renewal proposal is rooted in the belief that integrated approaches to the discovery of factors affecting human longevity must be pursued. The proposed LC research will therefore include 5 research projects and 3 cores, all focusing on, and leveraging, very complementary high-throughput assays, large cohorts and novel analytic methods. An emphasis will be placed on systems biology and chemoinformatics analysis to help place the findings of each project into more coherent views of the molecular pathways and processes affecting longevity and their amenability to pharmacologic manipulation.