Ageing Research Reviews 12 (2013) 685–698 Contents lists available at SciVerse ScienceDirect Ageing Research Reviews j ourna l h om epage: www.elsevier.com/locate/arr Review N-glycomic biomarkers of biological aging and longevity: A link with inflammaging Fabio Dall’Olio a,∗ , Valerie Vanhooren b,c , Cuiying Chitty Chen b,c , P. Eline Slagboom d , Manfred Wuhrer e , Claudio Franceschi a,∗∗ a Department of Experimental Pathology, University of Bologna, via S. Giacomo, 14 I-40126 Bologna, Italy b Department for Molecular Biomedical Research, VIB, Technologiepark 927, B-9052 Ghent, Belgium c Department of Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium d Section Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands e Biomolecular Mass Spectrometry Unit, Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands a r t i c l e i n f o Article history: Received 6 December 2011 Received in revised form 24 January 2012 Accepted 6 February 2012 Available online 14 February 2012 Keywords: Inflammaging Glycosylation Autoimmune disease Rheumatoid arthritis Antibody glycosylation High-throughput glycomic analysis a b s t r a c t Glycosylation is a frequent co/post-translational modification of proteins which modulates a variety of biological functions. The analysis of N-glycome, i.e. the sugar chains N-linked to asparagine, identified new candidate biomarkers of aging such as N-glycans devoid of galactose residues on their branches, in a variety of human and experimental model systems, such as healthy old people, centenarians and their offspring and caloric restricted mice. These agalactosylated biantennary structures mainly decorate Asn297 of Fc portion of IgG (IgG-G0), and are present also in patients affected by progeroid syndromes and a variety of autoimmune/inflammatory diseases. IgG-G0 exert a pro-inflammatory effect through dif- ferent mechanisms, including the lectin pathway of complement, binding to Fc receptors and formation of autoantibody aggregates. The age-related accumulation of IgG-G0 can contribute to inflammaging, the low-grade pro-inflammatory status that characterizes elderly, by creating a vicious loop in which inflam- mation is responsible for the production of aberrantly glycosylated IgG which, in turn, would activate the immune system, exacerbating inflammation. Moreover, recent data suggest that the N-glycomic shift observed in aging could be related not only to inflammation but also to alteration of important metabolic pathways. Thus, altered N-glycans are both powerful markers of aging and possible contributors to its pathogenesis. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Enzymatic glycosylation (not to be confused with non- enzymatic glycosylation, referred to as glycation) represents one of the most frequently occurring co/postranslational modification of proteins. A significant percentage of the human genes encode pro- teins related with biosynthesis, function and degradation of sugar chains. Protein-linked sugar chains play a variety of highly spe- cific roles, acting as a “fine tuning” of the interactions between cells and between molecules (Hart and Copeland, 2010; Ohtsubo and Marth, 2006; Varki, 1993). A brief summary of some biolog- ical functions played by the glycans of glycoproteins is reported in Table 1. The sugar chains linked to glycoproteins are classified ∗ Corresponding author. Tel.: +39 0512094727; fax: +39 0512094746. ∗∗ Corresponding author. Department of Experimental Pathology, University of Bologna, via S. Giacomo, 12 I-40126 Bologna, Italy. Tel.: +39 0512094727; fax: +39 0512094746. E-mail addresses: fabio.dallolio@unibo.it (F. Dall’Olio), claudio.franceschi@unibo.it (C. Franceschi). mainly as N-linked chains, which are bound to the amidic nitro- gen of asparagine, and O-linked chains which are bound to the hydroxyl group of serine or threonine. Glycosylation undergoes profound changes in a variety of pathological conditions, includ- ing cancer [reviewed in Dall’Olio et al., 2012a,b], inflammatory and autoimmune diseases and in the pathophysiological process of aging. Recently developed high-throughput methods of analysis have allowed investigating the whole spectrum of N-linked glycans (N-glycome) present in serum and body fluids of a large number of individuals, revealing characteristic aging-associated N-glycome changes which are reminiscent of those associated with inflamma- tory and autoimmune diseases. These glycosylation changes appear to be associated particularly with the sugar chains linked to Asn297 of immunoglobulin G. In turn, these aberrantly glycosylated anti- bodies might be responsible for the activation and up-regulation of the inflammatory response through different, although ill defined, mechanisms. In this review, we will describe briefly the basic biosynthetic and structural aspects of N-glycosylation and the methods of N-glycome analysis. Then, we will discuss the most relevant N-glycans associated with aging and inflammatory 1568-1637/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.arr.2012.02.002