Aging biomarkers are crucial for quantifying molecular, physiological, or functional features that change as individuals age. These biomarkers can potentially enhance the prediction of health outcomes beyond merely considering chronological age. Recent advancements in plasma proteomics have allowed 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. Firstly, the researchers benchmarked proteomic organ clocks against multimodal ageing biomarkers to assess their associations with 16-year all-cause mortality in the Lothian Birth Cohort 1936 (LBC1936). This cohort included 861 participants, of whom 444 had died during the follow-up period. The biomarkers evaluated included the epigenetic clock GrimAge2, telomere length, physical function measures (such as grip strength and walk time), neuroimaging, and cognitive assessments.
Among the proteomic clocks analyzed, accelerated ageing of the liver, immune system, and heart were identified as having the strongest associations with increased mortality risk. Specifically, the hazard ratios for these organs were as follows: liver (HRperSD [95% CI] = 1.43 [1.30-1.58]), immune (1.42 [1.29-1.57]), and heart (1.38 [1.25-1.53]). However, it was found that older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function, and poorer cognitive performance exhibited even stronger associations with mortality, with hazard ratios ranging from 1.44 to 1.62.
Secondly, the study conducted survival analyses on 9703 plasma protein targets, identifying 368 candidates associated with mortality. Notably, high-risk proteins were found to be enriched for immune functions, while low-risk proteins were associated with genomic stability and cellular maintenance. Among the leading proteomic candidates linked to 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 comprehensive 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 direct causation between the identified biomarkers and mortality outcomes, nor does it provide a definitive method for predicting individual mortality risk based on these findings.
Evidence scorecard
- Analytic validity: established
- Clinical validity: partial
- Clinical utility: not established
The evidence class for this study is primary_research, and the human status is unclassified.