Pleiotropy and Disease Interactors: The Dual Nature of Genes Linking Ageing and Ageing-related Diseases

Ageing-related diseases (ARDs) exhibit a broad spectrum of phenotypes yet consistently increase in incidence with advancing age. This suggests that, despite their diversity, ARDs could potentially share common biological processes deeply rooted in the mechanisms of ageing, presenting opportunities for unified therapeutic strategies. Using a network approach, we analysed gene proximity to 52 ARDs from the UK Biobank, integrating with protein-protein interaction (PPI), gene coexpression, KEGG pathways, and ageing-related genes. Interestingly, while most ageing-related genes did not associate with ARDs, they were closer to multiple ARDs than random genes. This was mainly due to indirect connections to diverse Communities of ARDs (ARCs), what we call iARC-Interactors, implying indirect association to multiple ARDs through interaction with ARD-related genes, primarily via PPI and KEGG. Genes that are associated with multiple ARCs, i.e., Pleiotropic genes, were predominantly related to immunological disorders. We found a polarizing effect. When compared to multiple ageing- and disease-related genes, high Pleiotropic genes showed the highest tissue specificity and lowest coexpression with themselves and other diseases. In contrast, high iARC-interactive genes (as those of ageing) significantly displayed the exact opposite effects, suggesting two mechanisms for genes to affect multiple ARDs, one operating through modulatory genes that simultaneously affect numerous tissues and processes; and another rather specialised, affecting single tissues that are widespread across the body, as potentially occurring in autoimmune diseases. Lastly, we used Machine Learning (ML) to predict potentially novel ageing-related genes based on each networks iARC-Interactions and genes proximity to ARDs. PPI and KEGG showed the best performance with their top candidate genes enriched for regulation of protein metabolic process, protein stabilization, positive regulation of developmental process, and cellular response to chemical stimulus. This work paints a deeper picture of the multiple types of interactions between ageing-related processes and ARDs.