A urinary proteomic marker indicative of premature ageing.

Abstract

Background: The Global Burden Disease 2019 report called for innovation in addressing age-related disabilities. Here we aimed to identify and validate a urinary peptidomic profile (UPP) differentiating healthy from unhealthy ageing in the general population, to test the UPP predictor in independent patient cohorts, and evaluate whether environmental exposures affect the UPP ageing profile. Methods: In a Flemish population study (n=778; 50.8% women; age, 16.2-82.1 years), 559 participants were examined twice and made up the derivation and time-shifted validation datasets; 219 were examined once and constituted the synchronous validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Statistical methods included linear and proportional hazard regression. The multidimensional UPP signature reflecting ageing was validated in patients with diabetes, COVID-19 or chronic kidney disease. In addition, the UPP ageing signature was associated with residential-modelled chronic air pollution exposure (particulate matter, black carbon, and nitrogen dioxide) Findings: With correction for multiple testing and multivariable adjustment, chronological age (C-age) was associated with 210 sequenced peptides mainly showing the downregulation of collagen fragments. The trained model relating C-age to UPP, derived by elastic net regression, included 54 peptides from 17 proteins. In the derivation and the time-shifted and synchronous validation datasets, the trained model explained 76.3%, 54.4% and 65.3% of C-age. Compared with the C-age, the predicted UPP-age was greater (P<0.0001) in patients with diabetes (50.8 vs 56.9), COVID-19 (53.2 vs 58.5) or chronic kidney disease (CKD; 54.6 vs 62.3). In the Flemish population, independent of C-age, UPP-age was significantly associated with various risk markers related to cardiovascular, metabolic and renal function, and inflammation. In participants with a low vitamin K status, ambient air pollution was associated with a higher UPP-age of 2.00 to 2.22 years per IQR increment (P≤0.0073). Over 12.4 years, the incidence of total and cardiovascular mortality and osteoporosis was associated with UPP-age, independent of C-age, with hazard ratios per 10-year higher UPP-age of 1.54 (95% CI, 1.22–1.95), 1.72 (1.20–2.47) and 1.40 (1.06–1.85), respectively (P≤0.018). Interpretation: The UPP signature indicative of ageing was associated with risk factors, environmental air pollution exposure, and adverse health outcomes in the population and with accelerated ageing in patients and reflects fibrosis and extracellular matrix (ECM) remodelling. Innovation in addressing disability should overcome the ontology of diseases and focus on shared disease mechanisms, in particular the ageing-related fibrotic degeneration.