The impact of mitochondrial dysfunction and cellular senescence on long-term outcomes of sepsis

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, affecting 48 million individuals annually and driving high ICU mortality. Although acute survival has improved, survivors present late impairments, including kidney and liver injuries and susceptibility to secondary infections, resulting in reduced quality of life and greater vulnerability to long-term complications. The hyperinflammation in sepsis links directly to mitochondrial dysfunction, triggering apoptosis, immune compromise, and cellular senescence, leading to the accumulation of senescent cells in tissues following severe insults. These cells, in turn, express the senescence-associated secretory phenotype (SASP), releasing pro-inflammatory, pro-fibrotic, and pro-oxidative factors that drive tissue damage and impede repair.

In this context, the hypothesis is that senescent cell accumulation perpetuates post-acute inflammation and organ failure via SASP, meaning senolytic treatment could reduce chronic septic outcomes. To test this, severe sepsis was induced in C57/BL6 mice using the cecal ligation and puncture (CLP) model with nine 21G needle punctures (CEUA 100/25). Mice were assigned to four groups: Sham, Sham + senolytics (dasatinib + quercetin), CLP, and treated CLP. Spleen, kidney, liver, and lung tissues were harvested at 1, 3, 15, and 30 days to assess immune profiles, senescence markers, and mitochondrial status.

Flow cytometry showed elevated γδT and CD8+ T cell polpulation at 24 hours, remaining high for 15 days in the spleen of septic mice. Senolytic therapy reversed this surge, mitigating sustained immune activation. Additionally, increased p53 protein expression in septic kidneys at day 15 confirmed renal senescence, which trended downward following senolytic treatment. These results indicate that cellular senescence drives persistent post-septic immune dysregulation and organ injury, positioning senolytics as a promising target to improve long-term outcomes.