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

Abstract

Aging, the predominant risk factor for numerous diseases, manifests in various forms across the structure and architecture of tissues of the human body, offering the 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). We analyzed 25,712 images from 40 distinct tissue types across 983 individuals, applying deep learning to quantify the 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 and were associated with telomere attrition, the incidence of 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 external cohorts of both healthy individuals and those with chronic diseases, revealing the organs most differentially affected by aging in disease contexts.

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. These findings underscore the value of histopathological imaging as a tool for understanding human aging and provide a foundation for the exploration of tissue-specific aging processes in age-associated diseases.