Plasma Proteomic Profiling of Young and Older Adults Identifies Candidate Biomarkers of Biological Aging at the Intersection of Age and Disease

Aging and chronic diseases intersect at the level of biological aging mechanisms, where age‐related molecular and cellular changes contribute to the development of diverse pathologies. Biomarkers of biological aging could help predict and track the progression of chronic diseases and evaluate the effectiveness of interventions aimed at promoting healthy aging. Here, we aimed to identify biomarkers reflecting biological aging by analyzing protein signatures shared between older age and elevated disease burden. Using the Olink Explore HT platform, we measured 5416 plasma proteins in 52 recently hospitalized Older Patients (≥ 65 years), 52 age‐ and sex‐matched Older Controls, and 20 healthy Young Controls (20–25 years). We identified 797 proteins that differed with chronological age group by comparing Older and Young Controls, and 761 proteins that differed with disease burden by comparing Older Patients and Older Controls. Of these, 311 proteins were differentially expressed across both chronological age and disease burden comparisons and were defined as biological Aging Proteins (APs). We compared the identified APs with findings from prior proteomic studies of aging and disease to uncover previously unreported proteins associated with biological aging. Unsupervised hierarchical clustering analysis of the 5416 proteins revealed eight clusters based on expression patterns, one significantly enriched for APs, suggesting shared regulatory pathways. Our findings highlight known and novel plasma biomarkers associated with biological aging, with potential utility for risk stratification and the development of interventions targeting the aging process.