Aging biomarkers are crucial for quantifying molecular, physiological, or functional features that vary among individuals as they age. These biomarkers can enhance the prediction of health outcomes beyond just chronological age. In recent years, plasma proteomics have emerged as a method to estimate the biological ages of various human organs. However, there has been a lack of systematic benchmarking against established ageing biomarkers.
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, and various measures of physical function such as grip strength, walk time, and respiratory function, as well as neuroimaging and cognitive assessments. Among the proteomic clocks, accelerated ageing of the liver, immune system, and heart were found to be significantly associated with increased mortality risk. Specifically, the hazard ratios per standard deviation (HRperSD) for liver, immune, and heart ageing were 1.43, 1.42, and 1.38, respectively.
Interestingly, older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function, and poorer cognitive performance exhibited even stronger associations with mortality, with HRperSD values ranging from 1.44 to 1.62.
The second aim of the study 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 research provides a systematic, cross-modal benchmarking of proteomic organ clocks against established ageing biomarkers. It also identifies specific proteins and biological functions that are associated with mortality risk, thereby contributing to the understanding of ageing and health outcomes.
What this study does not show
This study does not establish direct causation between the identified biomarkers and mortality, nor does it provide evidence of clinical utility for specific interventions based on these findings.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established