Age-related differences in liver damage and inflammation after femoral osteotomy

Fractures of long bones such as the femur are a common and serious health concern in the elderly, triggering immune responses essential for healing but also affecting remote organs like the liver. With age, the risk of fractures and immune imbalance increases, raising the likelihood of organ damage, infections, and mortality. To better understand age-dependent hepatic responses to bone injury, this study investigates early immune responses in the liver following femoral osteotomy, used here as a reproducible model of fracture. In a mouse model, young (17-26 weeks old) and aged (64-72 weeks old) male C57BL/6J mice received a femoral osteotomy with external fixation (Fx) or a corresponding sham procedure. After 24 h, inflammation, apoptosis, tissue damage, and immune responsiveness of the liver were analyzed. Aged sham animals exhibited a higher inflammatory state in sham-operated animals (neutrophil infiltration, tumor necrosis factor (TNF), interleukin (IL)-1b, chemokine (C-X-C motif) ligand 1 (CXCL1)), without corresponding increases in caspase-3-positive cells, activation of c-Jun N-terminal kinase (JNK), expression of sirtuin (SIRT) 1 or 3, or the receptor for advanced glycation end products (RAGE). Fx did not increase liver damage in young mice but showed a trend toward greater damage in aged mice. Fx significantly increased hepatic neutrophil infiltration and CXCL1 as well as TNF concentrations in both age groups. Aged mice showed weaker activation of pro- and anti-inflammatory signaling pathways after osteotomy, with reduced RAGE expression, JNK activation, and less pronounced induction of SIRT1 and SIRT3. In summary, femur osteotomy induced liver inflammation in both young and aged animals; however, older animals exhibit higher apoptosis and a superimposed inflammatory response on top of already elevated baseline inflammation in sham conditions. Further, they did not adequately activate key regulators like RAGE, SIRT1, and JNK, which coordinate inflammation and repair. Observed dysregulations may underlie the increased vulnerability to post-traumatic complications in the elderly. Understanding these age-related deficits is essential to improving therapeutic strategies.