Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Molecular Medicine, Scripps Research, Jupiter, Florida, USA.
Aging Cell. 2021 Dec;20(12):e13486. doi: 10.1111/acel.13486. Epub 2021 Nov 3.
Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity in oxidative stress-induced senescent mouse embryonic fibroblasts as well as in etoposide-induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1 and Zmpste24 mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2-year-old WT mice. Taken together, these results demonstrate that IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age-related diseases.
组成型 NF-κB 激活与细胞衰老和干细胞功能障碍有关，而 NF-κB 家族成员的罕见变体在百岁老人中更为丰富。我们最近发现了一种新型小分子（SR12343），它通过破坏 IKKβ 和 NEMO 之间的关联来抑制 IKK/NF-κB 激活。在这里，我们研究了 SR12343 在三种不同的小鼠模型中对衰老和老化的治疗效果。SR12343 降低了氧化应激诱导的衰老小鼠胚胎成纤维细胞和依托泊苷诱导的衰老人 IMR90 细胞中衰老相关的β-半乳糖苷酶（SA-β-gal）活性。慢性给予 Ercc1 和 Zmpste24 加速衰老小鼠模型中的 SR12343 可降低细胞衰老和 SASP 的标志物，并改善多种衰老参数。SR12343 还降低了 2 岁 WT 小鼠的衰老标志物并增加了肌肉纤维大小。综上所述，这些结果表明 IKK/NF-κB 信号通路是减少细胞衰老标志物、延长健康寿命和治疗与年龄相关疾病的有希望的靶点。
