Reduced NK cell frequency in older patients with evolving fractures is linked to a distinct inflammatory cytokine profile

BACKGROUND: Proximal hip fractures represent a profound acute physiological stress in older adults and are often followed by infections, delayed recovery, and functional decline. These complications occur more frequently in frail individuals with reduced physiological resilience and impaired immune responses. As natural killer (NK) cells are central to early immune defense, we aimed to define how acute fracture, hospitalization and frailty shape NK cell homeostasis and function in older patients. METHODS: We conducted a prospective study including older patients (> 65 years) with acute fractures (SMART cohort; n = 103) and compared them to matched healthy older people from the RESIST senior individuals (SI) cohort (n = 550). A subset of SMART patients (n = 55) was longitudinally followed-up post-surgery. NK cell frequency, phenotype and function were investigated using multiparametric flow cytometry, and plasma soluble immune mediators (SIMs) were analyzed. RESULTS: SMART patients were clinically frailer than matched SI individuals, as indicated by reduced grip strength and lower Barthel scores, and exhibited an inflammatory state with elevated CRP levels and leukocyte counts. NK cell frequencies were significantly reduced in SMART patients and inversely correlated with grip strength and systemic inflammation. Furthermore, NK cells from SMART patients showed a distinct immune phenotype and altered chemokine receptor expression compared with SI individuals. Of note, differences between frail and non-frail patients within the SMART cohort were modest and substantially smaller than those observed between SMART patients and SI individuals. Functionally, frail patients displayed reduced baseline expression of cytotoxic molecules, whereas cytokine-induced NK cell responses were preserved. Furthermore, longitudinal analyses revealed stable NK cell frequencies but surgical intervention remodeled NK cell subset distribution and marker expression. CONCLUSIONS: In conclusion, our findings indicate that NK cell alterations in older patients with fractures are likely driven by the combined impact of acute injury, hospitalization and surgery rather than by frailty alone.