Th153 - Mechanisms of Inflammation Across the Lifespan in Individuals with down Syndrome

Abstract Text: Aging is accompanied by increased systemic inflammation, a decline in immune responses, and the appearance of several comorbidities. Down syndrome (DS), caused by the trisomy of chromosome 21, presents hyperinflammation across the lifespan, resulting in accelerated biological aging. We examined age (15-60 years old) and sex-matched DS and non-DS controls (n=120) to explore immune dysfunction and aging mechanisms. Multi-omic approaches were applied to cells and plasma samples (bulk RNA-seq, flow cytometry, cytokine array, untargeted metabolomics). Linear and spline functions were fitted to the data to identify age-associated features and differences between groups. We observed that individuals with DS presented increased metabolites related to amino acid catabolism and higher levels of inflammatory cytokines/chemokines (IP-10, IL-10, MIP3 and MCP families) throughout their lifespan. Furthermore, monocytes and natural killer cells from these individuals presented significantly higher expression of post-translational modifications in histones associated with transcriptional activation (H3K9Ac, H3K4me3), indicating a dysregulated profile of trained immunity, which was followed by higher frequencies of inflammatory monocytes (NLRP3, NLRX1, IL1-b, Caspase-1). This hyperactivation was also observed in cells from the adaptive immune compartment, resulting in immune exhaustion (IRF4, TOX). Pathways associated with several diseases (endocarditis, stroke, sepsis) were also significantly upregulated in individuals with DS across ages as compared to non-DS individuals. Understanding the mechanisms at early stages in life related to comorbidities, and common across DS and the aged population, could lead to interventions to modulate those pathways and delay and/or reverse these comorbidities, resulting in better quality of life for the population in general.