Aging biomarkers are crucial for quantifying molecular, physiological, or functional features that change as individuals age. They can potentially enhance the prediction of health outcomes beyond what chronological age offers. Recent advancements in plasma proteomics have enabled researchers to estimate the biological ages of various human organs. However, the relationship between these proteomic organ clocks and established ageing biomarkers in predicting mortality risk has not been thoroughly investigated.
This study, published in Aging Cell, aimed to achieve two primary objectives. Firstly, it sought 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 involved 861 participants, of whom 444 had died by the end of the follow-up period. The ageing biomarkers examined included the epigenetic clock GrimAge2, telomere length, physical function measures (such as grip strength, walk time, and respiratory function), neuroimaging, and cognitive assessments.
Among the proteomic clocks evaluated, accelerated ageing of the liver (hazard ratio per standard deviation [HRperSD] = 1.43), immune system (1.42), and heart (1.38) were found to be strongly associated with increased mortality risk. However, older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function, and poorer cognitive performance exhibited even stronger associations with mortality (HRperSD = 1.44-1.62).
The second objective involved survival analyses of 9703 plasma protein targets, leading to the identification of 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 = 1.56), WFDC2 (1.47), and TIMP1 (1.45).
This study represents a systematic, cross-modal benchmarking of proteomic organ clocks against established ageing biomarkers. It identifies specific proteins and biological functions that are associated with mortality risk, contributing to the understanding of how biological aging processes relate to health outcomes.
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 specific recommendations for clinical practice.
Evidence scorecard
- Analytic validity: established
- Clinical validity: partial
- Clinical utility: not established
The evidence is based on primary research with human participants.