Pleiotropy and disease interactors: the dual nature of genes linking ageing and ageing-related diseases.

Ageing-related diseases (ARDs) display diverse phenotypes yet share an age-dependent rise in incidence, suggesting mechanistic links with ageing processes. We examined whether ageing-related genes differ systematically from genes associated with multiple ARD clusters. Across 57 ARDs from UK Biobank, network analyses showed that ageing-related genes, although rarely ARD-associated, lie significantly closer to many ARDs through greater-than-chance proximity in protein-protein interaction (PPI) and KEGG networks. Consistent with this network overlap, ageing-related genes tend to occupy intermediate tiers in KEGG signalling cascades and exhibit strong coexpression with disease-associated genes as well as low tissue specificity, supporting that they play regulatory roles across multiple tissues. In contrast, genes associated with multiple ARDs are enriched for immune disorders and tend to have fewer ARD-associated neighbors in PPI networks. Accordingly, genes associated with multiple ARDs also tend to be located in terminal branches of KEGG pathways and show high tissue specificity coupled with weak coexpression with other ARD genes. Lastly, machine learning integration based on gene-disease network topology identified candidate ageing-related genes enriched for intracellular signal transduction and programmed cell death. Altogether, this work reveals two genetic architectures of multi-ARD influence: a cross-tissue regulatory mechanism enriched in ageing-related genes, and a tissue-specific, immune-driven mechanism among pleiotropic disease-related genes.