Buljan, I. | bioRxiv Science

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↗

bioRxiv2024

Tissue clocks derived from histological signatures of biological aging enable tissue-specific aging predictions from blood

Aging, the leading risk factor for numerous diseases, manifests through diverse structural and architectural changes in human tissues, providing an opportunity to quantify and interpret tissue-specific aging. To address this, we present a comprehensive assessment of tissue changes occurring during human aging, utilizing a vast array of whole slide histopathological images from the Genotype-Tissue Expression Project (GTEx), primarily reflecting non-diseased tissue samples. Using deep learning, we analyzed 25,712 images from 40 distinct tissue types across 983 individuals, quantifying nuanced morphological changes that tissues undergo with age. We developed tissue clocks--predictors of biological age based on tissue images--which achieved a mean prediction error of 4.9 years. These clocks were associated with established aging markers, including telomere attrition, subclinical pathologies, and comorbidities. In a systematic assessment of biological age rates across organs, we identified pervasive non-uniform rates of aging across the human lifespan, with some organs exhibiting earlier changes (20-40 years old) and others showing bimodal patterns of age-related changes. We also uncovered several associations between demographic, lifestyle, and medical history factors and tissue-specific acceleration or deceleration of biological age, highlighting potential modifiable risk factors that influenced the aging process at the tissue level. Finally, by combining paired histological images and gene expression data, we developed a strategy to predict tissue-specific age gaps from blood samples. This approach was validated in independent cohorts covering eight diseases, ranging from acute conditions like stroke to chronic diseases such as cystic fibrosis and Alzheimers disease. It successfully recovered significant associations with disease-relevant organs and revealed patterns of systemic and tissue-specific aging that may reflect broader physiological changes in health and disease. This work offers a new perspective on the aging process by positioning tissue structure as an integrator of cellular and molecular changes that reflect the physiological state of organs in health and disease. It underscores the value of histopathological imaging as a tool for understanding human aging and provides a foundation for the monitoring of tissue-specific aging processes in age-associated diseases.

physiology↗