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| Status |
Public on Dec 25, 2010 |
| Title |
Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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
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| Overall design |
Primary Human Mammalian Epithelial Cells (HMECs), were cultured in HMEC medium (ScienCell) at 37oC and 5% CO2 in Poly-L-Lysine coated culture dishes (Sigma). Treatment consisted of cells being stimulated with HMEC basal medium containing either 15% GHRD serum or 15% control serum for 6 hours. Cells were then harvested and processed for RNA extraction.
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| Contributor(s) |
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng C, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo V |
| Citation(s) |
21325617 |
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| Submission date |
May 24, 2010 |
| Last update date |
Jun 22, 2020 |
| Contact name |
Supriyo De |
| Organization name |
NIA-IRP, NIH
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| Department |
Laboratory of Genetics and Genomics
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| Lab |
Computational Biology & Genomics Core
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| Street address |
251 Bayview Blvd
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| City |
Baltimore |
| State/province |
Maryland |
| ZIP/Postal code |
21224 |
| Country |
USA |
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| Platforms (1) |
| GPL6947 |
Illumina HumanHT-12 V3.0 expression beadchip |
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| Samples (11)
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| Relations |
| BioProject |
PRJNA127189 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE21980_RAW.tar |
6.2 Mb |
(http)(custom) |
TAR |
| GSE21980_non-normalized.txt.gz |
11.3 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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