Matched Plasma and Tissue Proteomics Reveal the Selective Nature of Circulating Biomarkers of Human Aging

Aging is systemic, yet how circulating proteins reflect molecular aging within solid tissues remains unclear. We profiled 5,415 proteins using Olink Explore HT in 178 adults aged 20-87 years, including matched plasma-muscle (n = 56) and plasma-ovary (n = 24) pairs. Plasma-tissue concordance was limited, with 50 muscle and 17 ovarian proteins significantly correlated, indicating that plasma selectively reflects tissue protein abundance. Age-correlated proteins and pathways differed markedly across sex and tissue strata, Including immune/inflammatory signatures in female plasma, vascular and extracellular-matrix pathways in male plasma, and collagen remodeling in the ovary. Expression Variation Analysis further revealed predominantly context-specific age-related changes in protein coordination, including FAS/FADD/TRAIL death-receptor networks in plasma and a TP53-CDKN1A senescence-associated axis in muscle. Exploratory multivariate models identified additional plasma associations with subsets of tissue proteins, including tissue-restricted muscle proteins. Together, these findings define plasma as a selective, context-dependent window into human tissue aging.