D14-10 Age-Related Fragility of the Endothelial Glycocalyx: A Novel Mechanism for the Disproportionate Impact of Sepsis in Older Adults

Abstract Rationale Older age is associated with a dramatically increased incidence and severity of sepsis. Despite this burden, mechanisms underlying heightened vulnerability of older adults to sepsis remain poorly understood, limiting targeted therapeutic strategies. Our laboratory has previously found that severity of heparanase-mediated endothelial glycocalyx degradation during sepsis is associated with risk of acute organ injury, mortality, and persistent cognitive dysfunction. The impact of aging on this biological mechanism remains unexplored. Accordingly, we sought to define the impact of older age on endothelial glycocalyx degradation during sepsis. Methods Plasma heparan sulfate (HS), a marker of heparanase-mediated endothelial glycocalyx degradation, was measured via high performance liquid chromatography tandem mass spectrometry (HPLC MS/MS) in samples collected prospectively from control (n = 25) and septic (n = 100) patients. Multivariate regression analysis was performed to define the impact of age on circulating HS levels in humans. We measured plasma HS in young (8-12 week) and aged (20-24 month) mice during sepsis. Endothelial glycocalyx fragility and composition were evaluated in aged and young mice by measuring HS levels and structure via HPLC MS/MS in plasma after administration of intravenous heparanase analogues. We explored the role of Sulfatase-2 (a secreted glycocalyx modifying enzyme that increases susceptibility to degradation by heparanase) in sepsis-associated glycocalyx degradation using a state-of-the-art glycoanalytical technique and via secondary analyses of human scRNA sequencing and proteomic datasets. Results Plasma HS was higher in older compared to younger septic humans and mice. Multivariate analysis, adjusting for sex and severity of illness, confirmed age as an independent predictor of endothelial glycocalyx degradation in septic humans. The endothelial glycocalyx of aged mice was more susceptible to degradation by heparanase and had structural characteristics that could be driven by secreted Sulfatase-2 expression. Sulfatase activity was elevated in the plasma of aged compared to young animals. Secondary scRNA sequencing and proteomics analyses demonstrated significantly higher Sulfatase-2 expression and circulating levels in older compared to younger patients. Conclusions Our study demonstrates that older age is associated with endothelial glycocalyx fragility during sepsis. This fragility may be driven by specific compositional changes of the endothelial glycocalyx that occur with aging. Elevated circulating Sulfatase-2 in older adults may drive increased systemic sulfatase activity resulting in the endothelial glycocalyx compositional changes that underlie increased fragility. Targeting this novel pathway may be a promising strategy to improve short- and long-term sepsis outcomes in older adults. This abstract is funded by: NIH