A kidney-conditioned urinary peptidomic biological ageing clock predicts all-cause mortality and age-related health outcomes

Background Ageing clocks are promising non-invasive tools to assess biological ageing, but they generally cannot guide intervention. We aimed to develop a urinary peptidomic ageing clock, expected to react to intervention, and to test whether the resulting age acceleration predicts all-cause mortality and adverse health outcomes. Methods In this retrospective multi-cohort study, urinary peptides were measured by capillary electrophoresis-mass spectrometry (CE-MS). An unconditioned clock (UPBioAge) was developed in a kidney function-preserved derivation cohort (n = 1,811), then conditioned on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) by Filtrate-Aware Calibration (FAC) fitted in an independent kidney-diverse cohort (n = 7,798), resulting in k-UPBioAge. Age prediction accuracy was evaluated in three cohorts independent of model development. Kidney-conditioned age acceleration (k-UPBioAgeAcc) was related to all-cause mortality and incident disease in a clinically enriched follow-up cohort (n = 7,469; 625 deaths; median follow-up 3.95 years) using Cox models adjusted for age, sex, comorbidities, body-mass index, mean arterial pressure and eGFR. Findings After standard age-bias correction, k-UPBioAge estimated chronological age with a calibrated holdout mean absolute error of 4.91 years (r = 0.945), and 5.43-5.47 years in two validation cohorts (one population cohort and the other samples analysed in an external site). Each SD increment in k-UPBioAgeAcc was associated with all-cause mortality (HR 1.48, 95% CI 1.35-1.63), incident coronary artery disease (1.44, 1.27-1.63), heart failure (1.27, 1.14-1.42) and chronic kidney disease progression (1.35, 1.05-1.73). The association did not differ by sex (P for interaction = 0.33), and none of four comorbidity interactions survived correction for multiple testing (adjusted P = 0.65-0.72), but no association was evident in participants with an eGFR of 15-29 mL/min/1.73 m2 (n = 433, 84 deaths) or macroalbuminuria (n = 92, 34 deaths). Interpretation Multiple urinary peptides are significantly associated with ageing, enabling the establishment of a robust biological ageing clock. As urine is generated in the kidney, a urinary ageing clock is affected by kidney function, mandating correction. The corrected urinary peptide-based biological ageing clock is affected by disease, and may warrant evaluation for monitoring or guiding personalised interventions.