Most mortality acceleration unexplained by measured biomarkers in observational analysis of 23,512 participants

Researchers used a Markov generator-matrix model fitted to biomarker and mortality data from NHANES (n=23,512) and replicated in the Health and Retirement Study to test whether measured blood biomarkers account for, cause, and reverse with aging reversal. The analysis found that 92.7% of the Gompertz rise in mortality is assigned to a latent component not captured by measured biomarkers (89.1% under mean-field re-specification; 91.5% on replication). Mendelian-randomization analysis found known causal proteins but null results for inflammatory, renal, and growth-signalling markers. Cellular reprogramming reversed a chronological clock (−9.7 to −22.4 years) but not a damage clock enriched for causality.