Immunoglobulin G glycosylation and its alterations in aging-related diseases

Abstract

Immunoglobulin G (IgG) is an important serum glycoprotein and a major component of antibodies. Glycans on IgG affect the binding of IgG to the Fc receptor or complement C1q, which in turn affects the biological activity and biological function of IgG. Altered glycosylation patterns on IgG emerge as important biomarkers in the aging process and age-related diseases. Key aging-related alterations observed in IgG glycosylation include reductions in galactosylation and sialylation, alongside increases in agalactosylation, and bisecting GlcNAc. Understanding the role of IgG glycosylation in aging-related diseases offers insights into disease mechanisms and provides opportunities for the development of diagnostic and therapeutic strategies. This review summarizes five aspects of IgG: an overview of IgG, IgG glycosylation, IgG glycosylation with inflammation mediation, IgG glycan changes with normal aging, as well as the relevance of IgG glycan changes to aging-related diseases. This review provides a reference for further investigation of the regulatory mechanisms of IgG glycosylation in aging-related diseases, as well as for evaluating the potential of IgG glycosylation changes as markers of aging and aging-related diseases.

1. Introduction

Aging is a multifaceted biological process involving a gradual overall decline in physiological function and homeostasis over time, making individuals increasingly susceptible to a spectrum of chronic and degenerative conditions [1]. This progressive decline encompasses various cellular, molecular, and systemic changes, including genomic instability, telomere shortening, epigenetic alterations, mitochondrial dysfunction, and proteostasis and inflammatory pathway dysregulation [2]. Aging is jointly regulated by a variety of genetic and epigenetic factors, including the abnormal expressions of aging-related genes, increased DNA methylation levels, altered histone modifications, and disrupted protein translation homeostasis [3]. This regulation exhibits significant variability, heterogeneity, and plasticity, reflecting the complex interplay between genetic predispositions and epigenetic influences [3].

Age-related diseases, such as Alzheimer's disease, cardiovascular disease, metabolic disorders, and chronic inflammation, represent significant burdens on global health and pose formidable challenges to healthcare systems worldwide [4]. These diseases often share common risk factors and pathological mechanisms with aging, suggesting intricate connections between the aging process and disease pathogenesis [5,6].

Protein glycosylation refers to the enzymatic process of attaching carbohydrate molecules via covalent bonds to specific functional groups on proteins [7]. The "paracentral dogma" hypothesis, which proposes glycosylation as a third fundamental life code after DNA/RNA and proteins [8], underscores the crucial role of sugar codes in co- and post-translational modifications (PTMs). Glycosylation enhances the classical central dogma by providing an additional layer of regulation and information that is crucial for protein folding, stability, cell‒cell communication, and signaling. Protein glycosylation, which is influenced by both genetic and epigenetic factors, plays a pivotal role in numerous cellular signaling and communication events [9]. Glycomedicine refers to glycomics- and glycoproteomics-based biomarkers and therapeutic target discovery; therefore, it has great potential to provide a new dimension of medical science toward better disease diagnosis and drug discovery [10].