Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging mice. These included both sexes of GHRKO and Snell Dwarf mutant mice, and in females only of PAPPA KO mice. P65 is also lower in both sexes of mice treated with rapamycin, canagliflozin, meclizine, or acarbose, and in mice undergoing caloric restriction. Two drugs that extend lifespan of male mice, i.e. 17α-estradiol and astaxanthin, however, did not produce lower levels of p65. We also measured other canonical NF-κB signaling regulators, including the activators IKKα and IKKβ and the inhibitor IκB-α. We found that those regulators do not consistently change in a direction that would lead to of NF-κB inhibition. In contrast, we found that NCoR1, an HDAC3 cofactor and a transcription co-repressor that regulates p65 activity, was also downregulated in many of these mouse models. Finally, we report downregulation of three p65 target proteins that regulate the metabolic and inflammatory states of the liver (HNF4α, IL-1β, and CRP) in multiple slow-aging mouse models. Together, these data suggest that NF-κB signaling, might be inhibited in liver of multiple varieties of slow aging mice. This establishes p65 as a potential target for novel longevity interventions.

小鼠和人类炎症的许多方面会随着年龄的增长而增加。转录组学分析显示，许多小鼠抗衰老干预措施产生的促炎蛋白水平较低。在这里，我们探讨了不同的长寿干预措施会降低 NF-κB 水平的假设，从而可能介导延长寿命干预的一些抗炎益处。我们发现 NF-κB 蛋白 p65 在几种慢衰老小鼠的肝脏中显着下调。这些包括 GHRKO 和 Snell Dwarf 突变小鼠的两性，以及仅在 PAPPA KO 小鼠的雌性中。在接受雷帕霉素、卡格列净、美克洛嗪或阿卡波糖治疗的小鼠以及接受热量限制的小鼠中，P65 在两性中也较低。然而，两种延长雄性小鼠寿命的药物，即 17α-雌二醇和虾青素，并没有产生较低水平的 p65。我们还测量了其他经典的 NF-κB 信号调节因子，包括激活剂 IKKα 和 IKKβ 以及抑制剂 IκB-α。我们发现这些调节因子并不一致地朝着导致 NF-κB 抑制的方向变化。相比之下，我们发现 NCoR1 是一种 HDAC3 辅因子和调节 p65 活性的转录共阻遏因子，在许多这些小鼠模型中也被下调。最后，我们报道了在多种慢衰老小鼠模型中调节肝脏代谢和炎症状态的三种 p65 靶蛋白 （HNF4α 、 IL-1β 和 CRP） 的下调。总之，这些数据表明 NF-κB 信号传导可能在多种慢衰老小鼠的肝脏中受到抑制。这使 p65 成为新型长寿干预的潜在靶点。