Histological aging signatures for monitoring tissue-specific aging and disease

Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.

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Publication Details

Journal
Nature Medicine
Published
2026-08-14
DOI
https://doi.org/10.1038/s41591-026-04566-5
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
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article

Histological aging signatures for monitoring tissue-specific aging and disease

Safwen Kadri, Lisa Kleißl, Sigrid Klotz, Georg Stary et al.
Nature Medicine
Telomeres, Telomerase, and Senescence
article

Histological aging signatures for monitoring tissue-specific aging and disease

Safwen Kadri, Lisa Kleißl, Sigrid Klotz, Georg Stary, Samir Moustafa, Maja Carina Nackenhorst, Philipp Tschandl, Matthias Perkonigg, Rizqah Kamies, Barbara Sterniczky, Anja Michl, Wolfgang Hulla, W WUYTS, Yuri Tolkach, Adelheid Wöhrer, Ernesto Abila, Mathias Drach, Herbert Schiller, Laurens Desadeleer, Matthias Heinig, Andre Rendeiro, Laurens Ceulemans, Zhilong Weng, Iva Buljan, Bart Vanaudenaerde, Daniel Buchanan, Yimin Zheng, Lochlan Fennell, Tamas Veres
article en

Abstract

Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.

Nature Medicine
University of Vienna (AT), The Royal Melbourne Hospital (AU), Austrian Academy of Sciences (AT), Innsbruck Medical University (AT), The University of Melbourne (AU), University of the Sunshine Coast (AU), Universitair Ziekenhuis Leuven (BE), Helmholtz Zentrum München (DE), Fachhochschule Wiener Neustadt (AT), Ludwig Boltzmann Institute for Age Research (AT), Victorian Comprehensive Cancer Centre (AU), German Centre for Cardiovascular Research (DE), CeMM Research Center for Molecular Medicine (AT), German Center for Lung Research (DE), Ludwig Boltzmann Institute Applied Diagnostics (AT), Ludwig Boltzmann Institute for Cancer Research (AT), University Hospital Cologne (DE), Technical University of Munich (DE), Medical University of Vienna (AT), Ludwig-Maximilians-Universität München (DE), KU Leuven (BE)
Openalex Percentile: Top 35%
Telomeres, Telomerase, and Senescence
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