Protein Carbamylation is Associated with Aging
Chemical reactions leading to modification of long-lived proteins in tissues, such as those making up the extracellular matrix or that occupy important positions in nerve cells, are a source of damage and dysfunction. Proteins can only perform correctly when they possess the right structure: modify that structure and problems arise. Degenerative aging is, at root, nothing more than an accumulation of damage, but there remains a lot of room to debate which specific types of damage might be more or less important than others over the present span of human life. One of the better known classes of damaging modification to proteins is produced by reactions with sugar compounds, particularly advanced glycation end-products (AGEs) such as glucosepane, but this is far from the only type of modification that occurs in the complex biology of a living individual. In the research noted here, for example, the authors add data to what is know about carbamylation of proteins.
Definitively establishing the relative degrees of significance of different forms of protein modification will probably require a means of clearing out and reversing each of these chemical reactions: given that technology, run the test and see what happens. This is somewhat complicated by the fact that species with different life spans tend to have radically different relationships with the various types of damaging protein modification. This has been amply demonstrated over the past twenty years of work on AGEs: those relevant to long-term health in mice and rats are not particular relevant in humans, and vice versa, a unfortunate circumstance that led to failure for the first efforts to produce treatments capable of clearing AGEs.
Chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, 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.