G protein-coupled receptor autoantibody expression patterns in adults with decelerated biological aging mirror...

G protein-coupled receptors (GPCRs) represent the largest and most diverse family of membrane proteins. In addition to their endogenous ligands, functional natural autoantibodies (Aab) have also been shown to bind and modulate GPCRs. Aab concentration is known to increase with chronological age, and several studies demonstrated an association of certain GPCR-binding Aab with chronic inflammation, concretely with specific autoimmune diseases in adults. However, prevalence of GPCR-Aab in pediatric population is not known so far.

In this descriptive study, we investigated the levels of Aab targeting 14 distinct GPCRs across individuals (pediatric, n = 83, adults n = 198) taking into consideration chronological and biological age, as defined by PhenoAge clock.

Our findings suggest, that anti-GPCR Aab are present from childhood through adulthood; however, their expression patterns undergo significant changes over the course of life. Specifically, we observed a significant increase in Aab targeting ACE2, CXCR3, and BDKRB1 in adults and older individuals. Conversely, concentrations of Aab against ATR1, ADRA1A, ADRB2, and ETAR were significantly higher in children compared to adults. We also assessed the impact of age acceleration on Aab levels, defined by a positive Δ age score based on the PhenoAge clock. Distinct GPCR Aab expression signatures correlated with accelerated aging, differing notably from patterns seen in pediatric and adult cohorts. Concretely, the expression profile of GPCR Aab in -Δage adults exhibits similarity to that observed in the pediatric cohort. Furthermore, we found a concordant presence of CXCR3-Aab and expansion of CXCR3 + T cells with increased chronological age.

Because systemic chronic inflammation is a known driver of accelerated aging, we hypothesize that the altered Aab expression profiles observed in biologically older adults may reflect this underlying inflammatory state. Although future research will be essential to evaluate the therapeutic potential of targeting these GPCRs in the context of inflammaging and autoimmune pathophysiology, chronological as well as biological age should be considered when assessing GPCR-Aab patterns.