Semaglutide reduces proteomic organ-specific biological age across randomized clinical trials

Semaglutide confers cardiovascular and kidney benefits and reduces all-cause mortality in high-risk populations. Whether biological-age metrics capture these effects and provide mechanistic insight remains unclear. We analyzed proteomics from 10,052 participants across five placebo-controlled semaglutide trials using externally trained organ-specific mortality clocks, proteomic frailty scores and disease-risk models. Semaglutide reduced heart biological age by approximately 2 to 4 years versus placebo, with reductions of 1 to 4 years across kidney, brain, pancreas, lung and multiorgan clocks. Proteomic frailty and cardiometabolic disease-risk scores improved during up to 156 weeks of follow-up. Effects were not fully mediated by weight loss, glycated hemoglobin or C-reactive protein. Exploratory mediation analyses suggested that heart biological-age changes may account for 34% to 49% of effects on selected outcomes. These findings demonstrate reproducible remodeling of mortality-associated proteomic signatures across populations and durations, supporting their potential as treatment-response readouts without establishing biological rejuvenation, causal mediation or surrogate validity.