Defining Molecular Signatures of Normal Human Aortic Ageing

However, the molecular mechanisms underlying physiological human aortic ageing remain poorly defined. We aimed to characterise the proteomic landscape of healthy human aorta across the lifespan to identify age-associated molecular signatures. Method Cryopreserved aortic tissue collected from 15 pre-mortem healthy donor hearts (10–65 years) stored in the Sydney Heart Bank, with no histological evidence of vascular pathology, underwent untargeted proteomics. Age-associated changes in protein abundance were assessed using models incorporating linear and non-linear trends, in combination with pathway enrichment analysis and functional annotation clustering. Results Seventeen proteins demonstrated a significant linear association with age (adjusted p value <0.05), predominately revealing reduced abundance of cytoskeletal (e.g. TUBB2A), focal adhesion and actin binding (e.g. SYNPO2), and extracellular matrix (ECM) (e.g. ITGA7) proteins. In contrast, lysosomal proteins NPC2 and CTSD showed an increase with age. Enrichment analysis identified integrin-mediated cell adhesion, regulation of actin cytoskeleton and metabolic processes as dominant pathways. Fifty-four proteins demonstrated a significant non-linear relationship with age, including RYR2, a regulator of calcium signalling and vascular tone. Functional annotation clustering of significant non-linear proteins demonstrated enrichment for ECM-localised proteins and transcriptional regulation pathways. Conclusion These data provide the first proteomic map of normal human aortic ageing. These changes may represent early molecular signatures of the ageing aorta, offering candidate pathways for early intervention to reduce age-related cardiovascular disease.