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bioRxiv · 10.1101/2025.05.27.656343

Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction

Lee, H. N. R.·Lin, J.·Smith, C. J.·Ware, L. B.·Harrison, F. E.·Bastarache, J. A.·Baer, B.
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Abstract

Sepsis is a life-threatening syndrome marked by a dysregulated immune response to an infection and significant endothelial vascular permeability, often leading to multi-organ failure. Elderly patients are particularly vulnerable to sepsis, with higher morbidity and mortality rates. We hypothesized that advanced age exacerbates sepsis-induced inflammation and endothelial vascular permeability, resulting in a delayed recovery, persistent inflammation, and sustained organ injury. Using a polymicrobial sepsis model in young (3-month-old) and aged (18-month-old) C57BL/6 mice, sepsis was induced via intraperitoneal cecal slurry (CS) injection. Outcomes were assessed during the acute (24-hour; 1.6mg/g CS) and recovery (8-day; 1.0 mg/g CS) phases. During the acute phase, aged mice exhibited worse physiologic dysfunction, higher systemic (plasma TNF-a: young septic 202.1 pg/mL [17.44, 398.9] vs. aged septic 482.6 pg/mL [279.8, 711.7]; p = 0.0352 Mann-Whitney) and organ-specific inflammation, increased endothelial injury and vascular permeability, as well as greater kidney and liver dysfunction compared to young mice. During recovery, aged mice had sustained physiologic dysfunction, prolonged systemic and organ-specific inflammation, and sustained organ injury (kidney tissue NGAL: young septic 291.5 RE [203.7, 373.2] vs. aged septic 821 RE [456, 1258] protein normalized to beta actin; p = 0.0008 Mann-Whitney) compared to young mice. These results support the hypothesis that advanced age worsens sepsis severity and outcomes and delays recovery, emphasizing the need for aged models and multi-organ evaluations to develop effective therapies for this vulnerable population.

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Lee, H. N. R., Lin, J., Smith, C. J., Ware, L. B., Harrison, F. E., Bastarache, J. A., Baer, B.. 2025-05-31. Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction. https://doi.org/10.1101/2025.05.27.656343

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