Core 1: Human Cell Models of Aging Core

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PROJECT SUMMARY – Human Cell Models of Aging Core The SD-NSC Human Cell Models of Aging Core (Human Cell Core) is focused on creating new cellular models of aging from human fibroblasts, including fibroblasts from a unique cohort representing the full breadth of adult chronological age and annotated for physical and functional measures of biological age. Genetic model organisms have long been important for aging research, but there are limitations to the extent to which animal models faithfully represent the molecular and cellular process of human aging. The overarching goal of this Core is to create powerful new human cell-based models to enable a wide range of studies into the molecular and cellular heterogeneities of human aging. Approaches for generating these new human models of aging draw largely from recent advances in creating induced cell types via the direct conversion of skin cell samples. Pioneering work from the Human Cell Core co-Lead, Dr. Gage, has shown that aging characteristics are maintained in these induced cell types. Pairing this approach with equally new approaches for creating 3D organoid cell cultures representative of different organ and tissue microenvironments, enables the creation of unprecedented human cell-based models of tissue aging. These models will enable robust analyses of cellular heterogeneities in human aging processes. As part of this effort, the Core will recruit human subjects ranging in age from 20–70+ years, thereby representing the full breadth of the healthy adult human age span. These participants will be extensively phenotyped for key clinical and physiological features of biological aging, and blood and skin samples will be collected. Skin samples will be used to derive primary dermal fibroblasts, from which both reprogrammed stem cells and directly induced cell types will be created and banked for sharing. The Human Cell Core will develop protocols for the direct inducement of different cell types and for the creation of organoids, including pancreas, kidney, liver, heart, smooth muscle, and vasculature. To promote the uptake of these new human cell models throughout the basic biology of aging research community, the Core will offer workshops and training sessions in conjunction with the Research Development Core. The protocols, specific reagents, and cells will be distributed to NSC affiliates directly from the Human Cell Core, and more broadly through open resources and cell repositories like the NIA Aging Cell Repository at the Coriell Institute and Addgene. Subject phenotype data will be shared along with the cell lines. Importantly, the Human Cell Core is designed to be integrated with the other Research Resource Cores of the SD-NSC, as human cell models (with subject-specific data) can be fed directly into the Heterogeneity of Aging Core for systems-level analysis of aging processes (multi-omic and advanced imaging). These complex datasets can then be fed into the Integrative Models of Aging Core for the application of new and existing integrative analyses. The Human Cell Core, as a stand-alone resource, and as an integrated component of the SD-NSC Core pipeline, will create substantial new opportunities to investigate the influences of cellular heterogeneity in human aging processes.