Altered monocyte NF-κB signaling is a possible cause of inflammaging and driver of aging, however, evidence from human aging studies is sparse. We assessed monocyte NF-κB signaling across different aging trajectories by comparing healthy older adults to older adults with a recent emergency department (ED) admission and to young adults. 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-κB phosphorylation (pNF-κB p65/RelA; Ser529) and induction of pNF-κB following stimulation with LPS or TNF-α in monocytes. We assessed frailty (FI-OutRef), physical and cognitive function, and plasma levels of IL-6, IL-18, TNF-α, and soluble urokinase plasminogen activator receptor. 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-κB levels than Older Controls (median fluorescence intensity (MFI): 125, IQR: 105–153 vs. MFI: 80, IQR: 71–90, p < 0.0001), and reduced pNF-κB induction in response to LPS (mean pNF-κB 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-α 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-κB MFI did not differ between Older and Young Controls (MFI: 81, IQR: 70–86; p = 0.72). Older Controls had reduced pNF-κB induction in response to LPS and TNF-α compared to Young Controls (LPS: 0.40, 95% CI: 0.35 to 0.44, p < 0.0001; and TNF-α: 0.33, 95% CI: 0.27 to 0.40, p < 0.0001). In Older Controls, basal pNF-κB MFI was associated with FI-OutRef (p = 0.02). Increased basal pNF-κB activity in monocytes could be involved in the processes of frailty and accelerated aging. Furthermore, we show that monocyte NF-κB activation upon stimulation was impaired in frail older adults, which could result in reduced immune responses and vaccine effectiveness.

中文翻译：

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老年医学患者，年龄匹配的对照组和健康的年轻人群中单核细胞NF-κBp65 / RelA信号的变化

单核细胞NF-κB信号改变可能是发炎和衰老的原因，但是，人类衰老研究的证据很少。我们通过比较健康的老年人与最近接受急诊科（ED）的老年人以及与年轻人的比较，评估了不同衰老轨迹中的单核细胞NF-κB信号传导。我们使用以下数据：52名年龄较大（≥65岁）的患者在ED入院时和出院后30天进行随访；52个年龄和性别相匹配的老年对照者，近期没有住院；和60名健康的年轻对照组（20-35岁）。使用流式细胞仪，我们评估了单核细胞中LPS或TNF-α刺激后基础NF-κB磷酸化（pNF-κBp65 / RelA; Ser529）和pNF-κB的诱导。我们评估了体弱（FI-OutRef），身体和认知功能以及血浆中IL-6，IL-18，TNF-α，和可溶性尿激酶纤溶酶原激活剂受体。与老年对照组相比，随访时患者体弱，炎症标志物水平较高，身体和认知功能下降。随访患者的基础pNF-κB水平高于老年对照组（中位荧光强度（MFI）：125，IQR：105-153 vs. MFI：80，IQR：71-90，p <0.0001），pNF降低响应LPS的-κB诱导（平均pNF-κBMFI倍数变化计算为LPS刺激与PBS对照的log10比：0.10，95％CI：0.08至0.12 vs.0.13，95％CI：0.10至0.15 （p = 0.05）和TNF-α刺激（0.02，95％CI：-0.00至0.05 vs. 0.10，95％CI：0.08至0.12，p <0.0001）。老年对照组的炎症标志物水平高于年轻对照组，但基础pNF-κBMFI在老年对照组和年轻对照组之间没有差异（MFI：81，IQR：70-86； p = 0。72）。与年轻对照组相比，老年对照组对LPS和TNF-α的响应降低了pNF-κB诱导（LPS：0.40，95％CI：0.35至0.44，p <0.0001;TNF-α：0.33，95％CI：0.27至0.40，p <0.0001）。在较早的对照中，基础pNF-κBMFI与FI-OutRef相关（p = 0.02）。单核细胞中增加的基础pNF-κB活性可能与脆弱和加速衰老有关。此外，我们表明，在脆弱的老年人中，刺激后单核细胞NF-κB的激活受到损害，这可能导致免疫反应和疫苗效力降低。基础pNF-κBMFI与FI-OutRef相关（p = 0.02）。单核细胞中增加的基础pNF-κB活性可能与脆弱和加速衰老有关。此外，我们表明，在脆弱的老年人中，刺激后单核细胞NF-κB的激活受到损害，这可能导致免疫反应和疫苗效力降低。基础pNF-κBMFI与FI-OutRef相关（p = 0.02）。单核细胞中增加的基础pNF-κB活性可能与脆弱和加速衰老有关。此外，我们表明，在脆弱的老年人中，刺激后单核细胞NF-κB的激活受到损害，这可能导致免疫反应和疫苗效力降低。