Matsuno, H. | Search bioRxiv

bioRxiv2026

Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience

Endothelial cells (ECs) express organ-specific gene programs supporting tissue homeostasis and resilience. However, the mechanisms by which aging reshapes these organ-specific endothelial programs and how the resulting changes affect tissue homeostasis, resilience, and disease susceptibility remain largely unknown. Herein, we performed single-cell RNA sequencing of ECs harvested from five organs across the lifespan and found that aging progressively erodes organ-specific endothelial programs while inducing shared interferon-responsive and antigen-presentation programs across organs. Although vascular subtype identity and conserved capillary subset identity were mostly preserved, these organ-specific transcriptional programs were broadly attenuated with aging, indicating erosion of organ-specific endothelial identity to be a fundamental feature of endothelial aging. Importantly, these alterations were associated with declines in specialized EC functions, including alveolar barrier maintenance in the lung, scavenging activity in the liver, angiogenic capacity in the heart, and homeostatic programs in the kidneys and the brain, suggesting that age-related EC alterations compromise tissue homeostasis and resilience in multiple organs. Furthermore, we established a single-cell aging index for alveolar capillary ECs in mice and humans, revealing stress-associated endothelial activation to potentially be an intermediate state linking functional deterioration to cellular senescence, and also demonstrating marked heterogeneity in aging states even among ECs from animals of the same chronological age. Notably, alveolar capillary ECs exhibited progressive functional decline before reaching a senescent-like state, suggesting endothelial dysfunction to precede overt cellular senescence as the organism ages. Collectively, our findings establish progressive erosion of organ-specific endothelial programs as a central feature of vascular aging and provide a conceptual framework for elucidating how endothelial aging contributes to tissue dysfunction and reduced resilience across organs.

physiology↗

bioRxiv2025

Dual Inference Routes for Natural Language Hypothesis Generation in Multimodal Drug Discovery: An Early Experimentation Study

This study presents an early experimentation of a modular AI framework for multimodal drug discovery that integrates natural product based therapies with modern pharmaceuticals. The system combines structured biomedical data, knowledge graphs, and large language models (LLMs) to generate explicit natural language hypotheses. The architecture has four phases: data aggregation, hypothesis generation, dynamic simulation, and in silico evaluation, and supports dual inference routes (compound [->] gene [->] disease/symptom and disease/symptom [->] gene [->] compound). As a case study, Phases 1 and 2 were applied to the Kampo formula Shakuyaku-kanzo-to, a typical example of a multicomponent and multi-target natural therapy. The framework originally arose from challenges in conventional filtering, where important but poorly annotated compounds were often overlooked. However, the focus has since shifted beyond filtering, toward uncovering hidden relationships across fragmented biomedical knowledge. This early implementation demonstrates the potential of natural language hypothesis generation to restructure fragmented knowledge into interpretable insights, providing a blueprint toward future multimodal drug discovery.

bioinformatics↗