Background: Altered monocyte NF-kappa B signaling is a possible cause of inflammaging and driver of aging, however, evidence from human aging studies is sparse. We assessed monocyte NF-kappa B signaling across different aging trajectories by comparing healthy older adults to older adults with a recent emergency department (ED) admission and to young adults.

Methods: We used data from: 52 older (>= 65 years) Patients collected upon ED admission and at follow-up 30-days after discharge; 52 age- and sex-matched Older Controls without recent hospitalization; and 60 healthy Young Controls (20-35 years). Using flow cytometry, we assessed basal NF-kappa B phosphorylation (pNF-kappa B p65/RelA; Ser529) and induction of pNF-kappa B following stimulation with LPS or TNF-alpha in monocytes. We assessed frailty (FI-OutRef), physical and cognitive function, and plasma levels of IL-6, IL-18, TNF-alpha, and soluble urokinase plasminogen activator receptor.

Results: Patients at follow-up were frailer, had higher levels of inflammatory markers and decreased physical and cognitive function than Older Controls. Patients at follow-up had higher basal pNF-kappa B levels than Older Controls (median fluorescence intensity (MFI): 125, IQR: 105-153 vs. MFI: 80, IQR: 71-90,p <0.0001), and reduced pNF-kappa B induction in response to LPS (mean pNF-kappa B MFI fold change calculated as the log10 ratio of LPS-stimulation to the PBS-control: 0.10, 95% CI: 0.08 to 0.12 vs. 0.13, 95% CI: 0.10 to 0.15,p = 0.05) and TNF-alpha stimulation (0.02, 95% CI: - 0.00 to 0.05 vs. 0.10, 95% CI: 0.08 to 0.12,p <0.0001). Older Controls had higher levels of inflammatory markers than Young Controls, but basal pNF-kappa B MFI did not differ between Older and Young Controls (MFI: 81, IQR: 70-86;p = 0.72). Older Controls had reduced pNF-kappa B induction in response to LPS and TNF-alpha compared to Young Controls (LPS: 0.40, 95% CI: 0.35 to 0.44,p <0.0001; and TNF-alpha: 0.33, 95% CI: 0.27 to 0.40,p <0.0001). In Older Controls, basal pNF-kappa B MFI was associated with FI-OutRef (p = 0.02).

Conclusions: Increased basal pNF-kappa B activity in monocytes could be involved in the processes of frailty and accelerated aging. Furthermore, we show that monocyte NF-kappa B activation upon stimulation was impaired in frail older adults, which could result in reduced immune responses and vaccine effectiveness.