Multi-tissue spatial transcriptomics reveals biological age hotspots in mouse and human aging

ABSTRACT Aging proceeds heterogeneously across tissues, yet how biological age varies within the spatial architecture of individual organs remains poorly understood. Here, we introduce stAge, a framework that quantifies localized transcriptomic age (tAge) from spatial transcriptomics data in mouse and human samples during natural aging and in response to injury, infection, neurodegeneration, and cancer. stAge captures age differences among samples and provides a single multi-tissue model for assessing aging within and across organs. Across tissues and conditions, stAge uncovers robust spatial gradients of biological age and shows that injury and neurodegeneration induce pronounced age acceleration, with stronger responses in older organisms and partial normalization during recovery. With advancing age, tissues develop pronounced hotspots of accelerated aging and coldspots of preserved resilience. Hotspots are enriched for metabolic and immune aging signatures, whereas chromatin-related signatures are associated with coldspots. These findings show that aging is spatially structured within tissues and lay a foundation for developing spatially targeted rejuvenation strategies.