PROJECT SUMMARY – Overall Since aging is the biggest risk factor of most human diseases and the overall functional decline in individuals, there is great interest in understanding its biological underpinnings, with the ultimate goal of increasing the number of healthy and productive years of human life (i.e., healthspan). Conserved mechanisms of aging and longevity have been identified via investigations into the basic biology of aging. These include studies in model organisms that have also shown that aging is pliable, opening the door for healthspan-promoting interventions. However, a major complicating factor that impedes our understanding of aging and our ability to intervene is the intrinsic and induced heterogeneity of the process. Distinct cell types have intrinsically different aging modalities, and even identical cell types age at different rates depending on physiological context or environmental exposures. These and other cellular heterogeneities (e.g., altered epigenetic states and gene expression) can drive tissue dysfunction and age-related pathology that ultimately impact healthspan and lifespan. Unravelling this complexity experimentally requires application of robust single-cell and imaging approaches to address the heterogeneity of cellular aging head-on, as well as computational and mathematical modelling approaches to illuminate aging networks and pathway interactions that involve known hallmarks of aging. Another major gap in aging research is the need for new and better human cell and tissue models to allow basic research directly relevant to human aging. Thus, the overarching premise of the proposed San Diego Nathan Shock Center (SD-NSC) is to create the requisite infrastructure to facilitate and promote the systematic study of cellular heterogeneity in aging and to provide novel cell and tissue models for basic human aging studies. The SD-NSC will establish cutting-edge Research Resource Cores focused on: 1) novel human cell and organoid models of aging, including from a unique human aging cohort that is annotated for physical and functional measures of biological age, 2) single-cell and high resolution -omics and imaging techniques, and 3) computational modelling of aging networks. The SD-NSC Research Resource Cores will provide scientific services to the NSC Network and the aging research community, and disseminate samples, datasets protocols, and computational tools. These resources will be complemented by a Research Development Core and Center outreach activities that will provide: 1) pilot grants and customized mentoring programs to encourage and support early-stage and established investigators new to aging research, 2) innovative in- person and virtual training in advanced methods and technologies to address cellular heterogeneity, and 3) intellectual leadership through novel programming to encourage collaboration and the dissemination of knowledge related to the basic biology of aging. The SD-NSC will bring togethe...