A number of drugs and interventions have been identified that curb morbidities associated with individual age-related diseases, and a few compounds have been identified that increase longevity in mice and other nonhuman species. However, few, if any, have been definitively shown to work by slowing the aging process and thereby simultaneously delaying the onset of multiple diseases and ultimately extending human longevity. Thus, current searches for drug and intervention targets that can lead to the development of longevity-enhancing ?geroprotectors,? i.e., interventions which stave off multiple age-related diseases and increase longevity by slowing or disrupting aspects of the aging process, need to be improved. Only very integrated approaches are likely to lead to successful searches given the need to reconcile complexities surrounding the pathogenesis of age-related diseases with processes contributing to the synchronized decay of multiple systems that defines aging. We believe that such integration can be achieved practically by: 1. pursuing multiple human longitudinal studies focusing on the discovery of metabolites and proteins associated with a biologically-compelling definition of slow and healthy human aging in different tissues; 2. exploiting novel cross-species longevity studies involving multiple tissues to obtain insights into conserved pathways impacting longevity whose elements may be consistent with factors discovered in human studies and hence validate them as truly related to longevity and not just disease; and 3. aggregating data arising from items 1-2 along with relevant available public domain data to generate/validate hypotheses, in addition to pursuing a GWAS to identify protective factors for disease and using novel statistical and inferential methods. Our 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 human targets for longevity-enhancing geroprotective drugs and interventions. Importantly, although we believe that each of the individual studies we are proposing is itself powerful enough to identify potential geroprotector targets, their collective and integrated use with novel analytic methods will have unprecedented power and provide a paradigm for anti-aging drug discovery research within the academic community. For example, we are proposing the first human longitudinal study to search for druggable factors associated with the epigenetic clock and other validated measures of the aging rate/healthy aging in thousands of individuals; the largest metabolomics and proteomic cross-species multi-tissue study (N=60 species) of factors associated with lifespan; the largest human longitudinal comparative tissue study of aging exploring blood, muscle, fat and skin samples; and the largest study of aggregated data from public domain sources for association analyses including standard GWAS and a unique polygenic risk score-based healthy genome GWAS.
We will pursue a very integrated ?geroprotector? drug target identification program that will exploit the use of longitudinal human cohorts, epigenetic clock and other measures of the human aging rate, cross-species comparisons, massive public data aggregation, metabolomics/proteomic assays and novel analytic methods.
