PROJECT SUMMARY/ABSTRACT Fundamental aging processes appear to be root-cause contributors to most of the disorders and diseases across the lifespan that account for the bulk of disability, mortality, and health costs. The goal of the nation-wide Translational Geroscience Network (TGN) is to accelerate translation of geroscience-guided lifestyle, nutritional, and drug interventions that target these aging processes from biological discovery and pre-clinical validation to testing in humans. The TGN is motivated by the hypothesis that clinical interventions targeting fundamental mechanisms of aging can delay, prevent, alleviate, or treat age-related diseases and disabilities as a group, instead of one at a time (the Geroscience Hypothesis). During the next grant period, the aims of TGN are: Aim 1) Accelerate development of a diverse portfolio of interventions targeting fundamental aging processes (gerotherapeutic interventions) by leveraging TGN expertise and infrastructure in terms of study design, outcome measures selection, quality control, regulatory compliance, biostatistics, data management, gerodiagnostic assays, and biobanking for translational early phase gerotherapeutic clinical studies. The current 81 endorsed or planned studies linked to the TGN now include lifestyle and nutritional interventions, metformin, rapalogs, anti- inflammatories, MitoQ, senolytics, &/or NAD precursors for several indications as well as observational studies. Aim 2) Discover, develop, select, optimize, and validate gerodiagnostic measures of aging mechanisms across studies and optimize reference analytical capabilities of the Facilities for Geroscience Analysis (FGA). The >150 gerodiagnostics and indicators of organ & immune dysfunction that are or will be tested in response to interventions include analytes in blood, urine, saliva, synovial fluid, buccal swabs, CSF, biopsies, & other samples from TGN clinical studies. Aim 3) Provide statistical and data management support to select efficient designs, facilitate sample size estimates, and incorporate FDA-compliant network-wide data capture, allowing cross-study comparisons. Sensitive, specific, and reliable phenotypic signatures responsive to interventions that are based on body fluid analytes, questionnaires, exam findings, physical & cognitive function, imaging, and biopsies will be refined and composite scores/ signatures integrating these analytes, clinical scales, and physical function tests developed. Aim 4) Expand TGN biobanking of samples from across studies to facilitate reverse translation, exploratory analyses, and new ancillary research as hypotheses develop and assays become available. We will continue to work with the NIA Biobank to ensure sample storage and distribution, even beyond the terms of this award. Blood (plasma, serum, PBMCs), urine, buccal swabs (& as available, CSF, saliva, biopsies, aqueous humor, synovial fluid, hair & nail clippings, microbiome), ECG, imaging, medical record (diagno...