Aging biomarkers are crucial for quantifying molecular, physiological, or functional features that vary among individuals as they age. These biomarkers can potentially enhance the prediction of health outcomes beyond just chronological age. Recent advancements in plasma proteomics have enabled researchers to estimate the biological ages of various human organs.
In this study, the authors aimed to benchmark proteomic organ clocks against established multimodal ageing biomarkers to assess their association with all-cause mortality. The research utilized data from the Lothian Birth Cohort 1936 (LBC1936), involving 861 participants and 444 recorded deaths over a 16-year period. The biomarkers examined included the epigenetic clock GrimAge2, telomere length, physical function metrics (such as grip strength and respiratory function), neuroimaging, and cognitive assessments.
The findings revealed that among the proteomic clocks, accelerated ageing of the liver, immune system, and heart were significantly correlated with increased mortality risk. Specifically, the hazard ratios (HR) indicated that accelerated liver ageing had an HR of 1.43, immune ageing had an HR of 1.42, and heart ageing had an HR of 1.38. However, older epigenetic age, smaller brain volumes, reduced respiratory function, and poorer cognitive performance exhibited even stronger associations with mortality, with HRs ranging from 1.44 to 1.62.
Furthermore, the study conducted survival analyses on 9703 plasma protein targets and identified 368 proteins linked to mortality risk. Notably, high-risk proteins were predominantly associated with immune functions, while low-risk proteins were involved in genomic stability and cellular maintenance. Among the leading candidates associated with mortality were GDF15 (HR of 1.56), WFDC2 (HR of 1.47), and TIMP1 (HR of 1.45).
This comprehensive study provides a systematic 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 study does not establish a causal relationship between the identified biomarkers and mortality risk, nor does it provide evidence for the efficacy of interventions based on these biomarkers.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established