Aging biomarkers are critical in quantifying molecular, physiological, or functional features that vary among individuals as they age. These biomarkers may enhance the prediction of health outcomes beyond merely chronological age. Recent advancements in plasma proteomics have allowed researchers to estimate the biological ages of various human organs. However, systematic benchmarking of these proteomic organ clocks against established ageing biomarkers has been limited.
This study aimed to address this gap by pursuing two complementary objectives. The first was to benchmark proteomic organ clocks against multimodal ageing biomarkers for their associations with 16-year all-cause mortality in the Lothian Birth Cohort 1936 (LBC1936). The study utilized Cox regression analysis involving 861 participants, of whom 444 had died during the follow-up period. The biomarkers examined included the epigenetic clock GrimAge2, telomere length, physical function metrics (such as grip strength, walking time, and respiratory function), neuroimaging, and cognitive assessments.
Among the proteomic clocks evaluated, 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 found to be most strongly 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 associated with mortality. High-risk proteins were notably enriched for immune functions, while low-risk proteins were linked to 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 and identifies specific proteins and biological functions that are associated with mortality risk.
What this study does not show
This research does not establish causal relationships between the identified biomarkers and mortality, nor does it provide evidence of clinical utility in a practical setting.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established