Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Identification of ageing-associated naturally occurring peptides in human urine

Esther Nkuipou-Kenfack, Akshay Bhat, Julie Klein, Vera Jankowski, William Mullen, Antonia Vlahou, Mohammed Dakna, Thomas Koeck, Joost P. Schanstra, Petra Zürbig _, Karl L. Rudolph, Björn Schumacher, Andreas Pich and Harald Mischak

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Oncotarget. 2015; 6:34106-34117. https://doi.org/10.18632/oncotarget.5896

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Abstract

Esther Nkuipou-Kenfack1,2, Akshay Bhat1,3, Julie Klein4,5, Vera Jankowski6, William Mullen7, Antonia Vlahou8,9, Mohammed Dakna1, Thomas Koeck1, Joost P. Schanstra5,6, Petra Zürbig1, Karl L. Rudolph10, Björn Schumacher11, Andreas Pich2 and Harald Mischak1,7

1 Mosaiques Diagnostics GmbH, Hannover, Germany

2 Hannover Medical School, Core Facility Proteomics, Hannover, Germany

3 Charité-Universitätsmedizin Berlin, Med. Klinik IV, Berlin, Germany

4 Institut National de la Santé et de la Recherche Médicale (INSERM), Institut of Cardiovascular and Metabolic Disease, Toulouse, France

5 Université Toulouse III Paul-Sabatier, Toulouse, France

6 University Hospital RWTH Aachen, Institute for molecular cardiovascular research (IMCAR), Aachen, Germany

7 BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom

8 Biotechnology Division, Biomedical Research Foundation Academy of Athens, Athens, Greece

9 School of Biomedical and Healthcare Sciences, Plymouth University, Plymouth, UK

10 Leibniz Institute of Age Research, Fritz Lipmann Institute, Jena, Germany

11 Institute for Genome Stability in Ageing and Disease and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center, University of Cologne, Cologne, Germany

Correspondence to:

Petra Zürbig, email:

Keywords: ageing, urine, peptidomics, collagen, proteases, systems biology, Gerotarget

Received: September 10, 2015 Accepted: September 16, 2015 Published: September 29, 2015

Abstract

To assess normal and pathological peptidomic changes that may lead to an improved understanding of molecular mechanisms underlying ageing, urinarypeptidomes of 1227 healthy and 10333 diseased individuals between 20 and 86 years of age were investigated. The diseases thereby comprised diabetes mellitus, renal and cardiovascular diseases. Using age as a continuous variable, 116 peptides were identified that significantly (p < 0.05; |ρ|≥0.2) correlated with age in the healthy cohort. The same approach was applied to the diseased cohort. Upon comparison of the peptide patterns of the two cohorts 112 common age-correlated peptides were identified. These 112 peptides predominantly originated from collagen, uromodulin and fibrinogen. While most fibrillar and basement membrane collagen fragments showed a decreased age-related excretion, uromodulin, beta-2-microglobulin and fibrinogen fragments showed an increase. Peptide-based in silico protease analysis was performed and 32 proteases, including matrix metalloproteinases and cathepsins, were predicted to be involved in ageing. Identified peptides, predicted proteases and patient information were combined in a systems biology pathway analysis to identify molecular pathways associated with normal and/or pathological ageing. While perturbations in collagen homeostasis, trafficking of toll-like receptors and endosomal pathways were commonly identified, degradation of insulin-like growth factor-binding proteins was uniquely identified in pathological ageing.


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