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Series GSE108978 Query DataSets for GSE108978
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
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.
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.
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
Submission date Jan 09, 2018
Last update date Oct 22, 2018
Contact name Jun Shi
Organization name Novartis Institutes for Biomedical Research
Street address 181 Massachusetts Avenue
City Cambridge
State/province MA
ZIP/Postal code 02139
Country USA
Platforms (1)
GPL18694 Illumina HiSeq 2500 (Rattus norvegicus)
Samples (84)
GSM2918178 Kidney_6M_Vehicle_1
GSM2918179 Kidney_6M_Vehicle_10
GSM2918180 Kidney_6M_Vehicle_2
BioProject PRJNA429275
SRA SRP128590

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Supplementary file Size Download File type/resource
GSE108978_RAW.tar 5.3 Gb (http)(custom) TAR (of BW, TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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