Cross-Species Aging Knowledge Integration into Agentic AI Platform Uncovers Conserved Mechanisms

Aging research has been advanced largely through the use of model organisms, where short lifespans and genetic tractability enable the systematic discovery of molecular pathways influencing longevity and age-related decline. However, knowledge about aging remains fragmented across species-specific repositories and domain-focused databases, limiting our ability to identify evolutionarily conserved mechanisms and translate findings to human biology. To address this gap, we developed EvoAge, a unified, multi-species knowledge graph that integrates aging-specific and general biomedical resources into a systems-level framework. EvoAge harmonizes 48 public datasets into a graph comprising 1.04 billion triples across six key species. A human-centric orthology framework reconciles more than 80,000 gene entries, expanding accessible organism-level aging knowledge by up to 1,700-fold compared with existing resources. To operationalize the graph for biological reasoning, we optimized knowledge graph embedding models and deployed a large language model (LLM)-assisted agentic interface that supports natural-language querying, link prediction, and hypothesis testing. In internal benchmarking using recent pre-print aging literature, EvoAge significantly outperformed state-of-the-art LLMs in distinguishing biologically plausible from implausible hypotheses. Importantly, EvoAge recommended a previously unrecognized Alzheimer’s disease (AD) mechanism involving nanoscale redistribution of BACE1 within synaptic compartments. We experimentally validated this EvoAge-supported prediction using patient-derived iPSCs carrying a familial PSEN1 mutation, demonstrating disease-associated remodeling of β-secretase, defined by altered localization, nanoscale clustering, and compartment-specific enrichment. We further confirmed the predicted evolutionary conservation of this BACE1–pathology relationship in additional AD systems, including transgenic mice and postmortem human brain tissue.