Molecular Heterogeneity of Aging: Insights from Integrated Plasma Proteome

<title>Abstract</title> <p>We conducted an integrative analysis of the plasma proteome and routine clinical blood parameters to identify biomarkers of physiological aging in a cross-sectional cohort of 99 healthy individuals (aged 18–90 years) systematically recruited within the national "RUSS-AGE" project. Plasma proteomic profiling was performed using targeted Selected Reaction Monitoring mass spectrometry with 49 stable isotope-labelled standards, alongside comprehensive clinical biochemistry tests. Our population-level analysis identified strong age-associated correlations for Somatomedin C (IGF-1), Dehydroepiandrosterone sulphate (DHEA-S), and Cystatin C (CST3). Furthermore, we defined an eight-marker signature that reliably distinguishes between younger and older individuals using ML models. This signature indicates a systemic shift from a metabolically active, protective state to one characterized by chronic inflammation and reduced resilience, aligning with established hallmarks of aging. Critically, we found that the inter-individual variability of measured parameters is age-dependent. Protein levels exhibited peak variability in the 28–45 age group, while most clinical parameters showed maximal dispersion later in life (61–80 years). This high variability underscores the following: some older individuals maintain a molecular profile typical of younger population norms, and vice versa. Collectively, integrative plasma proteomic and clinical blood analysis reveal molecular heterogeneity of human aging. These findings may inform future strategies for monitoring and promoting healthy aging on an individualized basis.</p>