A single-cell view of human tissue aging reveals architectural decline beyond cellular composition

Abstract

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.