Tavenier Juliette, Rasmussen Line Jee Hartmann, Houlind Morten Baltzer, Andersen Aino Leegaard, Panum Inge, Andersen Ove, Petersen Janne, Langkilde Anne, Nehlin Jan O
Department of Clinical Research, Copenhagen University Hospital Hvidovre, 2650, Hvidovre, Denmark.
Department of Psychology and Neuroscience, Duke University, Durham, NC, 27708, USA.
Immun Ageing. 2020 Sep 4;17(1):25. doi: 10.1186/s12979-020-00197-7.
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.
单核细胞中核因子κB（NF-κB）信号通路的改变可能是炎症衰老的一个原因及衰老的驱动因素，然而，来自人类衰老研究的证据并不充分。我们通过比较健康老年人、近期入住急诊科的老年人和年轻人，评估了不同衰老轨迹中的单核细胞NF-κB信号通路。
我们使用了以下数据：52名年龄较大（≥65岁）的患者，在急诊科入院时及出院后30天随访时收集；52名年龄和性别匹配、近期未住院的老年对照；以及60名健康的年轻对照（20 - 35岁）。我们使用流式细胞术评估单核细胞中基础NF-κB磷酸化（pNF-κB p65/RelA；Ser529）以及用脂多糖（LPS）或肿瘤坏死因子-α（TNF-α）刺激后pNF-κB的诱导情况。我们评估了衰弱程度（FI-OutRef）、身体和认知功能，以及白细胞介素-6（IL-6）、白细胞介素-18（IL-18）、TNF-α和可溶性尿激酶型纤溶酶原激活剂受体的血浆水平。
随访时的患者比老年对照更衰弱，炎症标志物水平更高，身体和认知功能下降。随访时的患者基础pNF-κB水平高于老年对照（中位荧光强度（MFI）：125，四分位间距（IQR）：105 - 153 vs. MFI：80，IQR：71 - 90，p < 0.0001），并且对LPS刺激的pNF-κB诱导降低（LPS刺激与磷酸盐缓冲液对照的log10比值计算的平均pNF-κB MFI倍数变化：0.10，95%置信区间（CI）：0.08至0.12 vs. 0.13，95% CI：0.10至0.15，p = 0.05）以及对TNF-α刺激的pNF-κB诱导降低（0.02，95% CI： - 0.00至0.05 vs. 0.10，95% CI：0.08至0.12，p < 0.0001）。老年对照的炎症标志物水平高于年轻对照，但老年和年轻对照之间基础pNF-κB MFI无差异（MFI：81，IQR：70 - 86；p = 0.72）。与年轻对照相比，老年对照对LPS和TNF-α刺激的pNF-κB诱导降低（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）。在老年对照中，基础pNF-κB MFI与FI-OutRef相关（p = 0.02）。
单核细胞中基础pNF-κB活性增加可能参与衰弱和加速衰老过程。此外，我们表明衰弱的老年人在刺激后单核细胞NF-κB激活受损，这可能导致免疫反应和疫苗效力降低。
