Contrastive Deep Learning Reveals Age Biomarkers in Histopathological Skin Biopsies

Aging clocks aim to estimate biological age, a measure of physiological state distinct from chronological age, from observable biomarkers, and are widely used for health assessment and disease analysis. DNA methylation is a particularly informative biomarker due to its stability and strong association with aging, and recent learning-based approaches have improved predictive performance. However, most existing methods treat CpG sites as independent features, overlooking the complex and heterogeneous biological relationships among them. We propose RelAge-GNN, a multi-relational graph neural network framework for DNA methylation-based age prediction. Our method constructs three complementary graphs capturing co-methylation patterns, genomic co-localization, and gene-level associations among CpG sites. Each graph is modeled by an independent GNN branch, and a learnable gating mechanism adaptively fuses the resulting representations. Experiments on large-scale datasets show that RelAge-GNN achieves competitive accuracy and stronger correlation with chronological age compared to state-of-the-art methods. Moreover, the model exhibits improved sensitivity in detecting age acceleration across diverse disease cohorts, highlighting its potential utility for disease characterization. Finally, through post hoc interpretability analyses, we quantify the contributions of different relational structures and CpG sites, providing biologically meaningful insights and suggesting potential directions for aging-related research. Our code is available at: https://anonymous.4open.science/r/RelAge-GNN-F1E3/.

Whole-body dual-energy X-ray absorptiometry (DXA) scans are routinely acquired to measure bone density and regional body composition, leaving their spatial structure largely unused. Here, we show that self-supervised learning (SSL) can convert raw DXA images into representations of systemic health. We introduce LeDXA, a vision model based on a joint-embedding predictive architecture (JEPA) that learns by predicting latent representations rather than reconstructing pixels. Trained from scratch on 11,540 unlabeled Human Phenotype Project scans, LeDXA was evaluated internally and on 47,400 external UK Biobank (UKBB) scans. It improved cross-cohort prediction of prevalent diseases and biomarkers beyond scanner-derived DXA measurements and DINOv3, a state-of-the-art general-purpose model, despite approximately 150,000-fold fewer training images and nearly 40-fold fewer parameters. Over a median 4.3-year UKBB follow-up, LeDXA improved incident disease prediction over tabular DXA measures, with the largest gains for hip and knee arthrosis and type 2 diabetes. For hip arthrosis, 66% of incident cases occurred in the highest-risk quartile versus 41% for tabular measures. Its representations predicted chronological age externally (r = 0.88; mean absolute error = 2.90 years), and the biological-age gap tracked broader disease burden and a 45% higher mortality hazard in the oldest-appearing quartile. The gap also decreased in women after starting hormone-replacement therapy, suggesting it may be modifiable. Genome-wide associations recovered mostly known body-composition and bone-density loci, and LeDXA embeddings were more heritable than DINOv3's. These findings reveal prognostic information in DXA images that conventional readouts discard, learnable with relatively little data and modest compute.

DNA methylation (DNAm) serves as one of the most robust molecular biomarkers of biological aging. While conventional epigenetic clocks accurately predict chronological age from high-dimensional CpG profiles, they treat aging as a static regression task, meaning they can only output a single score rather than simulating how an entire profile continuously changes over time. To reconstruct these continuous dynamics, we frame lifelong human epigenetic aging as a trajectory inference problem across discrete age snapshots derived from widely available cross-sectional data. We introduce a two-stage computational pipeline: first, an age-regularized Variational Autoencoder (VAE) maps high-dimensional CpG profiles onto a chronologically ordered latent manifold while preserving a generative decoder bridge back to the original methylation space. Second, we model the continuous movement across this latent space via Regularized Unbalanced Optimal Transport (RUOT) that unifies deterministic drift, random diffusion, and non-conservative mass changes. By resolving this RUOT formulation using the DeepRUOT framework, our model fluidly accommodates population-level density shifts like survivorship bias and cellular attrition without requiring rigid biological priors. Evaluated on a large-scale, 80-year pan-tissue dataset, our model demonstrates robust distribution interpolation and uncovers a prominent late-life surge in the learned growth field that mathematically captures the variance expansion driven by stochastic epigenetic drift. Finally, by decoding continuous latent paths back to individual CpG sites, we reconstruct and empirically verify distinct biological aging archetypes, offering a rigorous, generative paradigm for simulating human molecular aging.