Aging biomarkers are crucial in quantifying molecular, physiological, or functional features that vary among individuals as they age. They may enhance the prediction of health outcomes beyond chronological age. Recent advancements in plasma proteomics have enabled the estimation of biological ages for various human organs. However, there has been a lack of systematic benchmarking against established ageing biomarkers.
This study, published in Aging Cell, aimed to address this gap by pursuing two complementary objectives. The first objective was to benchmark proteomic organ clocks against multimodal ageing biomarkers in relation to 16-year all-cause mortality within the Lothian Birth Cohort 1936 (LBC1936). The analysis involved 861 participants, of whom 444 had died during the follow-up period. The biomarkers assessed included the epigenetic clock GrimAge2, telomere length, physical function (such as grip strength, walking time, and respiratory function), neuroimaging, and cognitive measures.
Results indicated that among the proteomic clocks, accelerated ageing of the liver (HRperSD [95% CI] = 1.43 [1.30-1.58]), immune system (1.42 [1.29-1.57]), and heart (1.38 [1.25-1.53]) were most significantly associated with increased mortality risk. However, older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function, and poorer cognitive performance demonstrated even stronger associations with mortality (HRperSD = 1.44-1.62).
The second objective involved survival analyses of 9703 plasma protein targets, which identified 368 candidates linked to mortality. Notably, high-risk proteins were enriched for immune functions, while low-risk proteins were associated with genomic stability and cellular maintenance. Among the leading proteomic candidates associated with mortality were GDF15 (HRperSD [95% CI] = 1.56 [1.42-1.72]), WFDC2 (1.47 [1.33-1.62]), and TIMP1 (1.45 [1.29-1.62]).
This study provides a systematic, cross-modal benchmarking of proteomic organ clocks against established ageing biomarkers, identifying proteins and biological functions associated with mortality risk. The findings may have implications for future research in ageing and mortality prediction.
What this study does not show
This study does not establish a direct causal relationship between the identified biomarkers and mortality, nor does it provide evidence for the effectiveness of interventions based on these biomarkers.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established