Pan-Organ Spatial Atlas of Immunosenescence: Decoding Immune Aging Across Tissues and Scales

Yale University, New Haven CT

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Abstract

NIH SenNet Administrative Supplement Grant Application Pan-Organ Spatial Atlas of Immunosenescence: Decoding Immune Aging Across Tissues and Scales (PIs: Rong Fan, Katy Börner) SUMMARY Immunosenescence, the progressive decline in immune function due to cellular aging, is a critical contributor to increased vulnerability to infections, chronic inflammation, and immune dysfunction in aging populations. This process is highly heterogeneous, varying across immune organs and tissue environments, but current understanding at the organ- and cell-type-specific level remains limited due to the rarity and diversity of senescent immune cells in situ. We hypothesize that immunosenescent states both reflect and actively remodel local tissue niches, characterized by distinct molecular features including cell cycle arrest markers, metabolic stress signatures, DNA damage indicators, and senescence-associated secretory phenotypes (SASP). To address this, we propose an integrated, multi-modal spatial profiling approach leveraging cutting-edge technologies to comprehensively map senescent immune cells across multiple organs, ages, and physiological conditions in mouse models. Utilizing a high-plex CODEX immunofluorescence panel targeting key senescence and immune markers, we will spatially resolve diverse senescent cell phenotypes (senotypes) across lymphoid and non-lymphoid tissues. This will be complemented by DBiT spatial transcriptomic and epigenomic sequencing to link these senotypic states to their underlying genome-wide molecular mechanisms directly in the tissue context. Building on Dr. Rong Fan’s expertise in spatial multi-omics and Dr. Katy Börner’s computational platforms for data integration and visualization, we will create a comprehensive pan-organ immunosenescence atlas. In addition, we will develop an interactive, multi-scale web platform based on the Cell Distance Explorer framework to enable researchers to explore and compare senescence patterns across organs, ages, sexes, and experimental perturbations. This platform will provide intuitive visualization tools ranging from whole-body organ maps to detailed tissue- and single-cell-level spatial analyses. Validation efforts will ensure the tool’s accuracy and usability through benchmarking with established senescence biomarkers and histological assessments, ultimately making the platform publicly available through the Human Reference Atlas portal (humanatlas.io). By filling a critical knowledge gap in spatial immunosenescence, this project will provide unprecedented insights into the spatial dynamics and systemic effects of immune aging. It promises to transform biomedical research by enabling detailed exploration of senescent immune cell biology at multiple scales, thereby accelerating discoveries in healthy aging, immune function, and therapeutic development.