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Growth Hormone Receptor Deficiency Is Associated With a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans

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Growth Hormone Receptor Deficiency Is Associated With a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans

Jaime Guevara-Aguirre et al. Sci Transl Med.

Abstract

Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 μU/ml versus 4.4 μU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.

Figures

Fig. 1
Fig. 1
Ecuadorian cohort. (A, B) Several members of the GHRD cohort with Dr. J-G.A. in (A) 1988 and (B)2009 (C) Age distribution for 90 living GHRD subjects and the Ecuadorian (Control) population (D) Genotypes of the GHRD cohort. All GHRD subjects were identified based on short stature and very low IGF-I levels. Undetermined refers to subjects whose genotypes have not been confirmed (E) Serum IGF-I and IGF-II levels in 13 unaffected relatives and 16 GHRD subjects ***p<0.0001. (F) Survival of the GHRD cohort.
Fig. 2
Fig. 2
Diseases and mortality in the Ecuadorian cohort (A) Causes of death in unaffected relatives and GHRD subjects (B) Percentage of cancers per age group in unaffected relatives and GHRD subjects. (C) Percent distribution of cancer-deaths in the unaffected relatives (D) Percentage of cancer and type II diabetes in unaffected relatives and GHRD subjects. Data are shown as a percentage of all diagnosed/reported diseases. ^ = 1 case of cancer and # = no case of diabetes has been recorded. (E) Percent prevalence of obesity and type II diabetes in Ecuador (control) and GHRD subjects. # = no case of diabetes has been recorded in the GHRDs. Obesity prevalence in Ecuador is based on WHO reports for 2010 (79) while that for GHRD subjects was calculated based on BMI > 30 kg/m2. Prevalence of type II diabetes in Ecuador was obtained from the study by Shaw S.E. et al (47). (F) Fasting glucose (G) fasting insulin and (H) insulin resistance represented by HOMA-IR in relatives and GHRD subjects. Data represent mean ± SEM for 13 control and 16 GHRD samples. * p<0.05.
Fig. 3
Fig. 3
Reduced IGF-1 signaling protects against DNA damage and favors apoptosis of damaged cells. (A,B,C) Comet assay to analyze DNA damage in HMECs incubated in serum from relatives/GHRDs and treated with H2O2 for 1 hour or 24 hours (A) Representative micrographs of cells treated with 700 μM H2O2 (B, C) Tail olive moment in cells treated with H2O2 for (B) 1 hour or (C) 24 hours. Data represent mean ± SEM. At least 6 serum samples were tested per group and 100-200 cells were analyzed per sample. (D) LDH activity in HMECs incubated in serum from relatives/GHRDs and treated with H2O2 for 24 hours. Data represent mean ± SEM. 6 serum samples were tested per group in triplicates. (E) Activation of caspases in HMECs incubated in serum from relatives/GHRDs and treated with H2O2. Data are calculated as percentage of untreated control and represent mean ± SEM. 6 serum samples were tested per group. (F) LDH activity in MEFs incubated in serum from relatives/GHRDs and treated with H2O2 for 24 hours. Data represent mean ± SEM. 6 serum samples were tested per group in triplicates. (G) Tail olive moment to measure basal DNA damage in R+ (IGF-IR overexpression) or R-(IGF-IR deficient) mouse embryonic fibroblasts (MEFs). Data represent mean ± SEM. 100-200 cells were analyzed per sample. (H) Representative western blot showing phosphorylation status of Akt (Ser 473) and FoxO1 (Ser 256) in R+ and R-cells. (I) FoxO activity in R+ and R-cells transfected with a luciferase reporter plasmid (I) List of FoxO target genes significantly upregulated in HMECs incubated in GHRD serum versus serum from relatives, *p<0.05, **p<0.01, ***p<0.0001.
Fig. 4
Fig. 4
Protective effects of reduced pro-growth signaling in yeast and mammals (A) RT-PCR indicating upregulation of SOD2 and downregulation of N-Ras, PKA and TOR in HMECs incubated in GHRD serum compared to cells incubated in serum from relatives (B) Chronological survival of wild-type (WT) yeast cells and ras2Δsch9Δtor1Δ mutants cells (C) Mutation frequency over time in the CAN1 gene (measured as Canr mutants/106 cells). (D) Chronological survival of wild-type yeast cells and ras2Δsch9Δtor1Δ triple mutants treated with H2O2 (E) Mutation frequency over time in the CAN1 gene (measured as Canr mutants/106 cells) in H2O2 –treated yeast cells. Data represent mean ± SEM, n= 5. *p<0.05, **p<0.01 compared to untreated WT cells and ^ p<0.05, ^^p< 0.01 compared to untreated ras2Δ, sch9Δ, and tor1Δ triple mutants. (F) Conserved growth factor signaling pathways in mammals and yeast.

Comment in

  • Is Growth Hormone resistance/IGF-1 Reduction Good for You?
    EJ Gallagher et al. Cell Metab 13 (4), 355-356. PMID 21459318.
    GH, IGF-1, and insulin are emerging as important and independent mediators of tumor development and aging. Two recent studies report that humans with GH-receptor deficien …

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