TY - JOUR
T1 - The impact of inactivation of the GH/IGF axis during aging on healthspan
AU - Poudel, Sher Bahadur
AU - Ruff, Ryan R.
AU - He, Zhiming
AU - Dixit, Manisha
AU - Yildirim, Godze
AU - Jayarathne, Hashan
AU - Manchanayake, Dulmalika Herath
AU - Basta-Pljakic, Jelena
AU - Duran-Ortiz, Silvana
AU - Schaffler, Mitchell B.
AU - Kopchick, John J.
AU - Sadagurski, Marianna
AU - Yakar, Shoshana
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to American Aging Association 2024.
PY - 2025/6
Y1 - 2025/6
N2 - 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 (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/IGF-1 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, more pronounced in male iGHRKO12-24 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.
AB - 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 (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/IGF-1 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, more pronounced in male iGHRKO12-24 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.
KW - Aging
KW - Bone
KW - Growth hormone
KW - Inflammation
KW - Insulin-like growth factor-1
KW - Liver
KW - Micro-CT
UR - http://www.scopus.com/inward/record.url?scp=85208990835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85208990835&partnerID=8YFLogxK
U2 - 10.1007/s11357-024-01426-3
DO - 10.1007/s11357-024-01426-3
M3 - Article
AN - SCOPUS:85208990835
SN - 2509-2715
VL - 47
SP - 3027
EP - 3042
JO - GeroScience
JF - GeroScience
IS - 3
ER -