A kidney-conditioned urinary peptidomic biological ageing clock predicts all-cause mortality and age-related health outcomes
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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.
Funding
This work received funding from the European Union’s Horizon Europe Marie Skłodowska-Curie Actions Doctoral Networks programme through the PICKED project (HORIZON-MSCA-2023-DN-01, Grant Agreement No. 101168626). This work was also supported in part by the German Federal Ministry of Education and Research (BMBF) through the ERA PerMed SIGNAL project (01KU2307), and by the PerMediK COST Action (CA21165).
Research in context
Evidence before this study
We searched PubMed for studies published in English up to August 6, 2026. Two searches defined the primary evidence base: urinary peptidomic ageing signatures (“urinary peptidome” OR “urine peptidome” OR “urinary proteome”, combined with “biological age” OR “ageing clock” OR “age prediction” OR ageing OR aging; 11 records) and urinary peptidomic markers of kidney function (combined with “glomerular filtration” OR albuminuria OR “kidney function”; 24 records); all 35 records were screened in full. A bounded context search for ageing clocks and mortality in other tissues returned 303 records. Most published ageing clocks are based on DNA methylation or on serum/plasma proteomics. We identified a single CE–MS urinary peptidomic age predictor (UPP-age). To our knowledge, no previous study recognised the urinary peptidome as a filtered biofluid whose biological age signal can be structurally confounded by kidney function (as reflected by glomerular filtration and albuminuria). Furthermore, no studies explicitly conditioned a urinary ageing clock on kidney function before evaluating its association with mortality and adverse health outcomes. Existing urinary ageing clocks have reported associations with chronological age, disease phenotypes, and mortality; however, the biological age signal has not been separated from the age-related kidney function component that urine inevitably carries.
Added value of this study
We show that a urinary peptidomic ageing clock contains an age- and mortality-associated signal that is partly masked by kidney physiology. We therefore introduce Filtrate-Aware Calibration (FAC) to re-orient systematic kidney-associated prediction error and derive a kidney-conditioned urinary peptidomic ageing clock and its age acceleration metric (k-UPBioAge and k-UPBioAgeAcc). The kidney-conditioned k-UPBioAgeAcc was more strongly associated with all-cause mortality and incident disease. Because mortality and disease outcome data were not used during model development, the observed association represents an independent validation of the model. More broadly, our findings suggest that ageing clocks derived from organ-filtered biofluids may benefit from accounting for the physiology of the filtering organ to reduce organ-specific physiological confounding.
Implications of all the available evidence
Urinary peptidomics is an attractive, non-invasive tool for the assessment of biological ageing, disease and mortality risk, but its signal must be interpreted in the context of kidney physiology. Conditioning a urinary peptidomic age clock and its age acceleration on kidney function produces a robust mortality-associated biomarker after clinical adjustment, suggesting that Filtrate-Aware Calibration warrants independent prospective evaluation for urinary ageing clocks. The principle of conditioning ageing clocks for the physiology of the filtering organ may also be applicable to other organ-filtered biofluids, including saliva, cerebrospinal fluid and sweat.
