The impact of inactivation of the GH/IGF axis during aging on healthspan

Several mouse lines with congenital growth hormone (GH) / insulin-like growth factor-1 (IGF1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the health span. 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 (iGHRKO12-24 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/IGF1 axis at 12 months did not affect systemic inflammation during aging. On the other hand, hypothalamic inflammation was significantly reduced in iGHRKO12-24 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, which was more pronounced in male iGHRKO12-24 mice and correlated with the onset age of GH/IGF1 inactivation. We conclude that inhibiting the GH/IGF1 axis during aging only partially preserves the beneficial health span effects observed with congenital GH deficiency. Comparative gene expression profiling analysis and GO analyis of floxed GHR mouse liver samples with RNA-seq