Immunoglobulin G and Aging: Biological Functions and Its Crosstalk with the Gut Microbiota

Aging is characterized by a progressive decline in physiological integrity, often accompanied by chronic inflammation and immune dysregulation. Immunoglobulin G (IgG), a key effector of humoral immunity, undergoes substantial structural and functional remodeling with age, particularly through changes in its glycosylation profile. These modifications shift IgG toward a proinflammatory state, linking it to inflammaging and multiple age-related diseases. This review synthesizes recent advances in understanding how IgG contributes to immune aging, with a specific focus on its glycosylation-dependent functions, tissue accumulation, and bidirectional crosstalk with the gut microbiota. We also highlight the potential of IgG as a biomarker and therapeutic target in aging-related interventions. We discuss the dual functional architecture of IgG and how age-related glycan shifts-namely, increased agalactosylation, afucosylation, and bisecting N-acetylglucosamine (GlcNAc)-enhance binding to activating Fcγ receptors, amplifying proinflammatory signaling. Experimental studies demonstrate that IgG accumulation in adipose tissue contributes to metabolic dysfunction via Neonatal Fc Receptor (FcRn)-dependent pathways. Additionally, sex hormones modulate IgG glycosylation patterns, partially explaining sex-specific differences in immune aging. The concept of "glycan clocks" has emerged as a tool to assess biological age and intervention responsiveness. Moreover, the gut microbiota plays a critical role in shaping the IgG repertoire, and aging disrupts this IgG-microbiota axis, resulting in altered mucosal immunity and systemic inflammation. Interventions targeting this axis-including microbiota modulation and glycoengineering-offer promising translational avenues for immune rejuvenation. Finally, we review emerging therapeutic strategies that leverage the gut-immune interface to mitigate aging-associated cardiovascular and metabolic diseases. IgG is not merely a biomarker but an active participant in the aging process, functioning at the intersection of immune regulation, microbial symbiosis, and systemic inflammation. Its age-associated transformation reflects broader changes in host immunity and highlights new opportunities for precision interventions in immunosenescence.