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| Status |
Public on Jun 26, 2018 |
| Title |
Short-term low-dose mTORC1 inhibition in aged rats counter-regulates age-related gene changes and blocks age-related kidney pathology |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes.
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| Overall design |
Transcriptional profiling was performed in kidney, liver and gastrocnemius muscles from three experimental groups of male Sprague Dawley rats. Rats aged 4.5 month (m) and 22.5 m were treated with vehicle and rats aged 22.5 m were treated with RAD001 for 6 weeks, with a read-out at 6 and 24 months.
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| Contributor(s) |
Shavlakadze T, Zhu J, Wang S, Zhou W, Morin B, Egerman MA, Fan L, Wang Y, Iartchouk O, Meyer A, Valdez R, Mannick JB, Glass DJ, Lloyd KB |
| Citation(s) |
29304191 |
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| Submission date |
Jan 09, 2018 |
| Last update date |
Oct 22, 2018 |
| Contact name |
Jun Shi |
| E-mail(s) |
[email protected]
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| Organization name |
Novartis Institutes for Biomedical Research
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| Street address |
181 Massachusetts Avenue
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02139 |
| Country |
USA |
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| Platforms (1) |
| GPL18694 |
Illumina HiSeq 2500 (Rattus norvegicus) |
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| Samples (84)
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| Relations |
| BioProject |
PRJNA429275 |
| SRA |
SRP128590 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE108978_RAW.tar |
5.3 Gb |
(http)(custom) |
TAR (of BW, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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