title: Protein carbamylation is a hallmark of aging.
abstract: Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France; Faculty of Medicine, Laboratory of Medical Biochemistry and Molecular Biology, Reims 51100, France;
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Gorisse
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France; Department of Pediatrics (Nephrology Unit), American Memorial Hospital, University Hospital, Reims 51100, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Pietrement
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France; Department of Nephrology and Transplantation, University Hospital, Reims 51100, France; Laboratory of Biopathology, University Hospital, Reims 51100, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuiblet
authors.affiliation: Institute of Pharmacy, Faculty of Natural Sciences I, Martin Luther University Halle-Wittenberg, Halle 24819, Germany;
authors.forename: Christian E H
authors.initials: CE
authors.lastname: Schmelzer
authors.affiliation: Institute of Pharmacy, Faculty of Natural Sciences I, Martin Luther University Halle-Wittenberg, Halle 24819, Germany;
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-0644-4281
authors.initials: M
authors.lastname: Köhler
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Duca
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Debelle
authors.affiliation: Department of Pathology (Forensic Institute), University Hospital, Reims 51100, France;
authors.forename: Paul
authors.initials: P
authors.lastname: Fornès
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France; Faculty of Medicine, Laboratory of Medical Biochemistry and Molecular Biology, Reims 51100, France; Laboratory of Pediatric Biology and Research, Maison Blanche Hospital, University Hospital, Reims 51100, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Jaisson
authors.affiliation: University of Reims Champagne-Ardenne, Extracellular Matrix and Cell Dynamics Unit CNRS UMR 7369, Reims 51100, France; Faculty of Medicine, Laboratory of Medical Biochemistry and Molecular Biology, Reims 51100, France; Laboratory of Pediatric Biology and Research, Maison Blanche Hospital, University Hospital, Reims 51100, France pgillery@chu-reims.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gillery
mesh_terms: D000375:Aging / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*
chemical_list: D011506:Proteins
keywords: carbamylation; longevity; nonenzymatic posttranslational modifications; skin; tissue aging