Department of Endocrinology, the Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Mol Med. 2023 Nov 28;29(1):161. doi: 10.1186/s10020-023-00752-0.
Liver aging, marked by cellular senescence and low-grade inflammation, heightens susceptibility to chronic liver disease and worsens its prognosis. Insulin-like growth factor 2 (IGF2) has been implicated in numerous aging-related diseases. Nevertheless, its role and underlying molecular mechanisms in liver aging remain largely unexplored.
The expression of IGF2 was examined in the liver of young (2-4 months), middle-aged (9-12 months), and old (24-26 months) C57BL/6 mice. In vivo, we used transgenic IGF2; Alb-Cre mice and D-galactose-induced aging model to explore the role of IGF2 in liver aging. In vitro, we used specific short hairpin RNA against IGF2 to knock down IGF2 in AML12 cells. D-galactose and hydrogen peroxide treatment were used to induce AML12 cell senescence.
We observed a significant reduction of IGF2 levels in the livers of aged mice. Subsequently, we demonstrated that IGF2 deficiency promoted senescence phenotypes and senescence-associated secretory phenotypes (SASPs), both in vitro and in vivo aging models. Moreover, IGF2 deficiency impaired mitochondrial function, reducing mitochondrial respiratory capacity, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD)/NADH ratio, increasing intracellular and mitochondrial reactive oxygen species levels, and disrupting mitochondrial membrane structure. Additionally, IGF2 deficiency markedly upregulated CCAAT/enhancer-binding protein beta (CEBPB). Notably, inhibiting CEBPB reversed the senescence phenotypes and reduced SASPs induced by IGF2 deficiency.
In summary, our findings strongly suggest that IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling. These results provide compelling evidence for considering IGF2 as a potential target for interventions aimed at slowing down the process of liver aging.
肝脏衰老的特征是细胞衰老和低度炎症，这会增加患慢性肝病的易感性，并使其预后恶化。胰岛素样生长因子 2 (IGF2) 与许多与衰老相关的疾病有关。然而，其在肝脏衰老中的作用和潜在的分子机制在很大程度上仍未得到探索。
检测了年轻（2-4 个月）、中年（9-12 个月）和老年（24-26 个月）C57BL/6 小鼠肝脏中 IGF2 的表达。在体内，我们使用转基因 IGF2; Alb-Cre 小鼠和 D-半乳糖诱导的衰老模型来探索 IGF2 在肝脏衰老中的作用。在体外，我们使用针对 IGF2 的特异性短发夹 RNA 敲低 AML12 细胞中的 IGF2。使用 D-半乳糖和过氧化氢处理诱导 AML12 细胞衰老。
我们观察到衰老小鼠肝脏中 IGF2 水平显著降低。随后，我们证明 IGF2 缺乏促进了衰老表型和衰老相关分泌表型（SASPs），无论是在体外还是体内衰老模型中。此外，IGF2 缺乏会损害线粒体功能，降低线粒体呼吸能力、线粒体膜电位和烟酰胺腺嘌呤二核苷酸（NAD）/NADH 比值，增加细胞内和线粒体活性氧水平，并破坏线粒体膜结构。此外，IGF2 缺乏明显上调 CCAAT/增强子结合蛋白 β（CEBPB）。值得注意的是，抑制 CEBPB 逆转了 IGF2 缺乏引起的衰老表型和减少了 SASPs。
总之，我们的研究结果强烈表明，IGF2 缺乏通过线粒体功能障碍和上调 CEBPB 信号促进肝脏衰老。这些结果为将 IGF2 视为减缓肝脏衰老进程的潜在干预靶点提供了有力证据。
