Several mouse lines with congenital growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the healthspan. We used a tamoxifen-inducible global GH receptor (GHR) knockout mouse model starting at 12 months and followed the mice until 24 months of age (iGHRKO_12-24 mice). We found sex- and tissue-specific effects, with some being pro-aging and others anti-aging. Measuring an array of cytokines in serum revealed that inactivation of the GH/IGF-1 axis at 12 months did not affect systemic inflammation during aging. On the other hand, hypothalamic inflammation was significantly reduced in iGHRKO_12-24 mice, evidenced by GFAP⁺ (glial fibrillary acidic protein, a marker of astrocytes) and Iba-1⁺ (a marker for microglia). Liver RNAseq analysis indicated feminization of the male transcriptome, with significant changes in the expression of monooxygenase, sulfotransferase, and solute-carrier-transporter gene clusters. Finally, we found impaired bone morphology, more pronounced in male iGHRKO_12-24 mice and correlated with GH/IGF-1 inactivation onset age. We conclude that inhibiting the GH/IGF-1 axis during aging only partially preserves the beneficial healthspan effects observed with congenital GH deficiency.

Graphical Abstract

Inactivating the GH axis during aging has sex- and tissue-specific effects on healthspan. Deleting the GH receptor (GHR) in the entire body at 12 months of age led to feminizing the male liver transcriptome, significantly altering the expression of p450 and sulfotransferase gene clusters. While GHR deletion during aging did not impact systemic inflammation, it was linked to reduced hypothalamic inflammation. Additionally, we observed impaired bone morphology, particularly in male mice, which correlated with the age at which GH/IGF-1 inactivation began. Our findings suggest that inhibiting the GH axis during aging only partially maintains the beneficial healthspan effects seen with congenital GH deficiency.

中文翻译：

---

衰老过程中 GH/IGF 轴失活对健康寿命的影响

几种先天性生长激素 （GH）/胰岛素样生长因子-1 （IGF-1） 轴断裂的小鼠品系显示出健康状况改善和寿命延长。目前的研究调查了停用这个轴，特别是在衰老过程中，如何影响健康寿命。我们从 12 个月开始使用他莫昔芬诱导型全球 GH 受体 （GHR） 敲除小鼠模型，并跟踪小鼠直至 24 个月大 （iGHRKO_12-24 小鼠）。我们发现了性别和组织特异性的影响，其中一些是促衰老，另一些是抗衰老。测量血清中的一系列细胞因子表明，12 个月时 GH/IGF-1 轴的失活不会影响衰老过程中的全身炎症。另一方面，iGHRKO_12-24 小鼠的下丘脑炎症显着减少，GFAP⁺（神经胶质纤维酸性蛋白，星形胶质细胞的标志物）和 Iba-1⁺（小胶质细胞的标志物）证明了这一点。肝脏 RNAseq 分析表明雄性转录组女性化，单加氧酶、磺基转移酶和溶质载体转运蛋白基因簇的表达发生显着变化。最后，我们发现骨骼形态受损，在雄性 iGHRKO_12-24 小鼠中更为明显，并且与 GH/IGF-1 失活发病年龄相关。我们得出结论，在衰老过程中抑制 GH/IGF-1 轴仅部分保留了先天性 GH 缺乏症观察到的有益健康寿命影响。

 图形摘要

在衰老过程中使 GH 轴失活对健康寿命具有性别和组织特异性影响。在 12 个月大时删除全身的 GH 受体 （GHR） 导致雄性肝脏转录组女性化，显着改变 p450 和 sulfotransferase 基因簇的表达。虽然衰老过程中 GHR 缺失不会影响全身炎症，但它与减少下丘脑炎症有关。此外，我们观察到骨骼形态受损，尤其是在雄性小鼠中，这与 GH/IGF-1 失活开始的年龄相关。我们的研究结果表明，在衰老过程中抑制 GH 轴只能部分维持先天性 GH 缺乏症所见的有益健康寿命效应。