# A Novel GH Deficient Rat Model Reveals Cross‐Species Insights Into Aging

## TL;DR

A new rat model with disrupted growth hormone signaling shows similar health and longevity benefits seen in mice, offering insights into aging.

## Contribution

A novel CRISPR/Cas9-generated GH-deficient rat model was developed to clarify inconsistent findings in rats.

## Key findings

- GH-deficient rats had half the body weight of controls and increased body fat.
- They showed enhanced insulin sensitivity and reduced IGF-I levels.
- Gut microbiome diversity differed between male and female GH-deficient rats.

## Abstract

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.

Mouse studies show disrupted GH signaling reduces body size, increases longevity, and improves health. We developed a CRISPR/Cas9 GH‐deficient rat model to address inconsistent rat evidence. GH‐deficient rats mirrored these findings, showing reduced body weight, increased body fat, enhanced insulin sensitivity, and altered gut microbiomes.