Bago-Horvath, Z. | bioRxiv Science

bioRxiv2026

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

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.

systems biology↗

bioRxiv2025

Systematic mapping of human tissue microanatomy reveals age-associated remodeling and resilience

Aging disrupts tissue structure at various scales, from cellular alterations to tissue and organ-level integrity. Microanatomical domains - recurrent cellular arrangements essential to organ-specific function, provide a highly physiologically relevant perspective on tissue homeostasis but are severely understudied in human aging. To address this gap, we developed H&E-UTAG, an unsupervised algorithm to detect microanatomical domains in whole slide histopathological images, which enables large-scale, label-free analysis of human microanatomy. Applying it to 24,945 whole-slide images from 40 human tissues of 983 individuals aged 20 to 70 years old, we identified 218 recurrent microanatomical domains categorized into 74 types across tissues. Domain types varied widely in tissue specificity, with 16% shared across 3 or more tissues and 69% restricted to a specific tissue. Age emerged as the dominant factor in influencing domain abundance, with 28% of domains changing significantly over the adult lifespan. By integrating tissue-level pathology annotations, we distinguished structural changes associated with healthy aging from those linked to subclinical disease, revealing that these processes often remodel distinct tissue compartments. Finally, mapping higher-order networks of domain-domain interactions uncovered age-associated reorganization of organ architecture, while a core framework of interactions remained resilient with age. Our novel analytical framework reveals fundamental principles of tissue organization and how they are restructured across the human lifespan, offering new insights into aging biology and tissue architecture in health and in the path to age-associated diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/682110v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1d05840org.highwire.dtl.DTLVardef@151e211org.highwire.dtl.DTLVardef@d0de41org.highwire.dtl.DTLVardef@afb744_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗