Aging biomarkers are crucial for quantifying the molecular, physiological, or functional changes that occur as individuals age. These biomarkers can enhance the prediction of health outcomes beyond mere chronological age. Recent advancements in plasma proteomics have enabled researchers to estimate the biological ages of 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 for their associations with all-cause mortality over a 16-year period in the Lothian Birth Cohort 1936 (LBC1936). This cohort consisted of 861 participants, of whom 444 had died by the end of the study. The biomarkers evaluated included the epigenetic clock GrimAge2, telomere length, physical function measures (such as grip strength, walking time, and respiratory function), neuroimaging, and cognitive assessments.
The findings revealed 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 strongly associated with increased mortality risk. However, traditional biomarkers such as older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function, and poorer cognitive performance showed 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. Notably, high-risk proteins were 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 associated with mortality risk.
What this study does not show
This study does not establish a causal relationship between the identified biomarkers and mortality risk, nor does it provide evidence for the clinical utility of these biomarkers in predicting individual health outcomes.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established