Aging biomarkers are vital in quantifying the molecular, physiological, or functional features that vary among individuals as they age. They may enhance the prediction of health outcomes beyond merely chronological age. Recent advancements in plasma proteomics have enabled researchers to estimate the biological ages of various human organs. However, a systematic comparison of these proteomic organ clocks against established ageing biomarkers is still lacking.
This study aimed to address this gap by pursuing two complementary objectives. First, the researchers benchmarked proteomic organ clocks against multimodal ageing biomarkers to assess their associations with all-cause mortality over a 16-year period in the Lothian Birth Cohort 1936 (LBC1936). The analysis involved 861 participants, of whom 444 had died during the follow-up period. The biomarkers evaluated included the epigenetic clock GrimAge2, telomere length, physical function indicators (such as grip strength, walking time, and respiratory function), neuroimaging, and cognitive measures.
Among the proteomic clocks analyzed, accelerated ageing of the liver, immune system, and heart were found to be significantly associated 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, the study 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 HRs ranging from 1.44 to 1.62.
The second aim of the study involved survival analyses of 9703 plasma protein targets, which led to the identification of 368 proteins associated with mortality. Notably, high-risk proteins were primarily enriched for immune functions, while low-risk proteins were linked to genomic stability and cellular maintenance. Among these, GDF15, WFDC2, and TIMP1 emerged as leading proteomic candidates associated with mortality, with hazard ratios of 1.56, 1.47, and 1.45, respectively.
This research provides a systematic and 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, contributing valuable insights to the field of aging research.
What this study does not show
This study does not establish causation between the identified biomarkers and mortality risk, nor does it provide a comprehensive evaluation of all potential biomarkers.
Evidence scorecard
- Analytic validity: Established
- Clinical validity: Partial
- Clinical utility: Not established