Age-Dependent FoxO1–Trim63 Axis Shapes Sepsis Outcomes in Mice

In a polymicrobial sepsis mouse model, researchers show that aging alters disease tolerance rather than resistance: young mice rely on cardiac FoxO1 and its target Trim63 (MuRF1) to protect the heart and other organs, promoting survival, while in aged mice the same axis worsens organ damage and mortality. FoxO1 inhibition or Trim63 loss improves outcomes in aged animals but worsens them in young ones, demonstrating antagonistic pleiotropy and underscoring the need for age-tailored therapies in sepsis.