Myint Soe Maung Maung Phone, Lasher Alexander Tate, Liu Kaimao, Geurts Aron M, Austad Steven N, Sun Liou Y
Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Aging Cell. 2025 Jun 5;24(8):e70126. doi: 10.1111/acel.70126.
Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains unclear how generalizable these findings are across mammals. Evidence in rats is limited and inconsistent. These conflicting results highlight the need for further investigation into the role of GH signaling in longevity across species. To address this gap, we developed a novel GH-deficient rat model using CRISPR/Cas9 technology to introduce a 10 bp deletion in exon 3 of the gene encoding rat GH-releasing hormone (GHRH) yielding a non-functional GHRH product. Physiological characterization of GHRH knockout (KO) rats revealed that they were half the body weight of wild-type controls. Additionally, relative to controls, they displayed an increased percent body fat, enhanced insulin sensitivity, reduced circulating insulin-like growth factor I (IGF-I) concentration, and a decreased reliance on glucose oxidation for energy metabolism, as determined by indirect calorimetry. Analysis of the gut microbial community in adult GHRH-KO rats further revealed a less diverse male microbiome, but a more diverse female KO microbiome compared to controls. Collectively, these findings demonstrate that multiple aspects of the GH activity-deficient phenotype, well-documented in mice, are faithfully recapitulated in our rat model. Therefore, the GHRH-deficient rat model represents a valuable new tool for advancing our understanding of the role of GH signaling in aging processes.
多项针对生长激素（GH）信号传导基因敲除小鼠的研究表明，这种基因敲除会导致体型减小、寿命显著延长（在某些情况下延长超过50%），并改善多个健康参数。然而，这些发现对所有哺乳动物的普遍适用性仍不清楚。大鼠方面的证据有限且不一致。这些相互矛盾的结果凸显了进一步研究GH信号传导在不同物种寿命中的作用的必要性。为了填补这一空白，我们利用CRISPR/Cas9技术开发了一种新型的生长激素缺乏大鼠模型，该模型在编码大鼠生长激素释放激素（GHRH）的基因外显子3中引入了一个10bp的缺失，从而产生无功能的GHRH产物。对GHRH基因敲除（KO）大鼠的生理学特征分析表明，它们的体重只有野生型对照的一半。此外，与对照相比，它们的体脂百分比增加、胰岛素敏感性增强、循环胰岛素样生长因子I（IGF-I）浓度降低，并且通过间接量热法测定，它们在能量代谢中对葡萄糖氧化的依赖性降低。对成年GHRH-KO大鼠肠道微生物群落的分析进一步表明，与对照相比，雄性KO大鼠的微生物群落多样性较低，而雌性KO大鼠的微生物群落多样性较高。总的来说，这些发现表明，在小鼠中得到充分记录的GH活性缺乏表型的多个方面，在我们的大鼠模型中得到了忠实的再现。因此，GHRH缺乏大鼠模型是推进我们对GH信号传导在衰老过程中的作用理解的一种有价值的新工具。
