Multimodal Ageing Biomarkers and Plasma Proteomic Signatures Associated With All-Cause Mortality

Ageing biomarkers quantify molecular, physiological or functional features that vary between individuals as they age and may improve prediction of health outcomes beyond chronological age. Recently, plasma proteomics have been used to estimate the biological ages of 11 human organs. Although accelerated organ ageing is associated with higher mortality risk, systematic benchmarking against established ageing biomarkers is lacking. Here, we pursued two complementary aims. First, we benchmarked proteomic organ clocks against multimodal ageing biomarkers for associations with 16-year all-cause mortality in the Lothian Birth Cohort 1936 (LBC1936) using Cox regression (861 participants; 444 deaths). Biomarkers included the epigenetic clock GrimAge2, telomere length, physical function (grip strength, walk time and respiratory function), neuroimaging and cognitive measures. Among proteomic clocks, accelerated liver (HR_perSD [95% CI] = 1.43 [1.30-1.58]), immune (1.42 [1.29-1.57]) and heart (1.38 [1.25-1.53]) ageing were most strongly associated with increased mortality risk. However, older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function and poorer cognition showed stronger associations with mortality (HR_perSD = 1.44-1.62). Second, survival analyses of 9703 plasma protein targets identified 368 candidates associated with mortality, with high-risk proteins enriched for immune functions, and low-risk proteins involved in genomic stability and cellular maintenance. GDF15 (HR_perSD [95% CI] = 1.56 [1.42-1.72]), WFDC2 (1.47 [1.33-1.62]) and TIMP1 (1.45 [1.29-1.62]) were the leading proteomic candidates associated with mortality. This study provides a systematic, cross-modal benchmarking of proteomic organ clocks against established ageing biomarkers and identifies proteins and biological functions associated with mortality risk.