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.