In a 16-year follow-up of 861 older adults, epigenetic age (GrimAge2), brain and grey matter volume, respiratory function and cognitive performance predicted all-cause mortality more strongly than plasma proteomic organ clocks. Among 9703 protein targets, 368 were linked to mortality, with GDF15, WFDC2 and TIMP1 leading; elevated-risk proteins clustered in immune signalling while protective ones mapped to genomic stability and cellular maintenance.
Key Points
- Epigenetic age, brain volume, lung function predicted mortality better than organ clocks
- Liver, immune and heart proteomic clocks led among organ-specific measures
- GDF15, WFDC2, TIMP1 topped 368 mortality-associated plasma proteins
Longevity Analysis
Measurement hierarchy matters: inexpensive functional capacity — how well a person breathes, thinks and moves — carried more prognostic weight than high-dimensional plasma panels, which argues for interpreting proteomic organ ages as complements rather than replacements. The protein signatures point in a consistent biological direction, with chronic immune activation marking elevated risk and intact genome repair and cellular housekeeping marking lower risk, reinforcing inflammatory load and repair capacity as the central levers. Practical implication: track respiratory function, cognition and brain structure alongside any molecular clock, and treat persistent immune signalling as a modifiable target rather than an incidental marker.
Original published by Wiley Aging Cell, by Maira Pyrgioti, Ines Mesa Eguiagaray, Paul Redmond, Janie Corley, Mark E. Bastin, Maria Valdés Hernández, Tom C. Russ, Joanna M. Wardlaw, Eilis Hannon, Ian J. Deary, Keenan A. Walker, Elliot M. Tucker‐Drob, Simon R. Cox, Riccardo E. Marioni, Sarah E. Harris .