Amer Johnny, Salhab Ahmad, Safadi Rifaat
Liver Institute, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Liver Institute, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Biomed Pharmacother. 2025 May;186:118000. doi: 10.1016/j.biopha.2025.118000. Epub 2025 Mar 24.
Aging has an impact on Natural Killer (NK) cells surveillance against tumors and infections. Our study aims to assess the aging effects on metabolic and mitochondrial markers influencing NK cell activity.
C57BL/6 J mice aged 12, 24, 48, and 72 weeks were used. Liver injury serum and histological markers, pro-inflammatory cytokines [IL-1β, IL-2, IL-6] and chemoattractant markers [CCL2, CXCL8] were assessed. Moreover, cholesterol metabolic markers [HMG-CoA synthetase, HMG-CoA reductase, mevalonate kinase], mitochondrial biogenesis [PGC1α] and functional gene markers [TFAM, HSPA9, Seahorse, apoptosis] in liver trNK cells, were assessed by RT-PCR. Senescence [p16, p21], exhaustion [PD-1, TIGIT, LAG3], activation [CD107a, NKp46], and chemokine receptor [CCR2, CXCR1] markers were assessed in trNK cells using flow cytometry. Liver trNK cells of aged mice were treated with Rosuvastatin [10μM] for 12 h.
Data showed a linear increase in liver injury markers, pro-inflammatory and chemotaxis along aging. These results were associated with reductions in liver trNK cell counts and activations with a noticeable decrease in their chemoattractant receptor expressions. TrNK cells of aged mice exhibited elevated markers of senescence and exhaustion with a gradual increase in cholesterol accumulation. Mitochondrial biogenesis and functional gene markers showed a decrease in their expressions in aged mice while ameliorated following rosuvastatin treatment. Results were correlated with a decrease in cholesterol metabolism and restoring their NK cell activity.
Our study demonstrates age-related cholesterol accumulation in trNK cells correlated with senescence and functional impairment. Rosuvastatin is suggested to boost, rejuvenate and recover NK cell functionality.
衰老会影响自然杀伤（NK）细胞对肿瘤和感染的监测。我们的研究旨在评估衰老对影响NK细胞活性的代谢和线粒体标志物的作用。
使用12周、24周、48周和72周龄的C57BL/6 J小鼠。评估肝损伤血清和组织学标志物、促炎细胞因子[白细胞介素-1β、白细胞介素-2、白细胞介素-6]和趋化因子标志物[CCL2、CXCL8]。此外，通过逆转录聚合酶链反应评估肝组织常驻NK（trNK）细胞中的胆固醇代谢标志物[3-羟基-3-甲基戊二酰辅酶A合成酶、3-羟基-3-甲基戊二酰辅酶A还原酶、甲羟戊酸激酶]、线粒体生物合成[过氧化物酶体增殖物激活受体γ共激活因子1α]和功能基因标志物[线粒体转录因子A、热休克蛋白家族A成员9、海马实验、凋亡相关基因]。使用流式细胞术评估trNK细胞中的衰老标志物[p16、p21]、耗竭标志物[程序性死亡受体1、T细胞免疫球蛋白和粘蛋白结构域蛋白3、淋巴细胞活化基因3]、活化标志物[CD107a、自然杀伤细胞蛋白46]和趋化因子受体标志物[CCR2、CXCR1]。用瑞舒伐他汀[10μM]处理老年小鼠的肝trNK细胞12小时。
数据显示，随着衰老，肝损伤标志物、促炎和趋化作用呈线性增加。这些结果与肝trNK细胞数量和活化减少有关，其趋化因子受体表达显著下降。老年小鼠的trNK细胞衰老和耗竭标志物升高，胆固醇积累逐渐增加。线粒体生物合成和功能基因标志物在老年小鼠中的表达降低，而在瑞舒伐他汀治疗后有所改善。结果与胆固醇代谢减少和NK细胞活性恢复相关。
我们的研究表明，trNK细胞中与年龄相关的胆固醇积累与衰老和功能损害相关。建议使用瑞舒伐他汀来增强、恢复NK细胞功能。
