Urinary Peptidomics to Address Age-Related Disabilities

Background: The Global Burden Disease 2019 report called for innovation in addressing age-related disabilities. The current study aimed at identifying and validating a urinary peptidomic profile (UPP) differentiating healthy from unhealthy ageing in the general population, to test the UPP predictor in patients, and to search for targetable molecular pathways. 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 internal validation datasets; 219 were examined once and constituted the independent validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Statistical methods included linear and proportional hazard regression. Pathway exploration rested on the Reactome and KEGG databases. The multidimensional UPP signature reflecting ageing was further validated in patients with diabetes, COVID-19 or chronic kidney disease. Findings: With correction for multiple testing and multivariable adjustment, chronological age (C‑age) was associated with 210 sequenced peptides mainly showing 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 internal and independent validation datasets, the trained model explained 76·3%, 54·4% and 65·3% of C‑age. Compared with the derivation data, the UPP-predicted C‑age was greater (p<0·0001) in age-matched patients with diabetes (n=1575), COVID‑19 infection (n=110) or chronic kidney disease (n=202): 50·3 vs 56·9 vs 58·5 vs 62·3 years. In the population, risk carrying biomarkers were associated (p≤0·037) with UPP‑age, independent of C‑age. Over 12·8‑year (median), the incidence of total and cardiovascular mortality and osteoporosis in the population was associated with UPP‑age, independent of C‑age, with hazard ratios per 10‑year higher UPP‑age of 1·54, 1·72 and 1·40, respectively (p≤0.018). The overrepresented proteins were key nodes in collagen and extracellular-matrix (ECM) turnover. Interpretation: Ageing is associated with a specific UPP signature, reflecting fibrosis and ECM remodelling. UPP‑age was associated with risk factors and adverse health outcomes in the population and with accelerated ageing in patients. Innovation in addressing disability should overcome the ontology of diseases and focus on shared disease mechanisms, in particular the bodywide ageing associated fibrosis and ECM remodelling. Funding: European Research Council, Ministry of the Flemish Community, OMRON Healthcare. Declaration of Interest: HM is the co-founder and co-owner of Mosaiques-Diagnostics GmbH, Hannover, Germany, and AL is an employee of Mosaiques Diagnostics. All other authors declare no conflict of interest Ethical Approval: The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) complies with the Helsinki declaration and is registered at the Belgian Data Protection Authority (reference number III 11/1234/13; 22 August 2013). The ethics committee of the University Hospital Leuven, Belgium, approved the secondary use of FLEMENGHO data (national registration number, B32220083510).