E. Abila, Y. Zheng, Z. Bago-Horvath, A. F. Rendeiro
Aging reshapes the human body at the cellular level, yet how cell identity, morphology, and spatial organization remodel across organs and the adult lifespan remains poorly mapped, at a scale and lifespan coverage that molecular spatial assays cannot yet reach. Treating the GTEx histopathology archive as a population-scale, lifespan-resolved resource for spatial biology, we detected over 3.5 billion single cells across 16 human organs from nearly one thousand individuals. Cell density declined pervasively but organ-specifically, and vision-language phenotyping resolved epithelial cells into nine subtypes with divergent aging trajectories, including loss of ovarian granulosa cells at ~45% per decade. Community detection on spatial cell graphs identified functional tissue units, over a quarter of which remodeled with age along a shared trajectory from dense, specialized units toward sparser, stromal- and immune-enriched structures. Critically, this architectural remodeling was largely decoupled from cell composition (R2=0.07), showing that human tissues age along two partly independent axes, a pervasive loss of cells and a distinct remodeling of the architecture they form, with structural decline exceeding what cellular composition alone predicts.