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Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related
Tea Shavlakadze1, Jiang Zhu1, Sharon Wang1
1Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Abstract:
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.
Insights
Rapalogs, like RAD001, extend lifespan and delay aging by affecting gene expression, particularly in the kidney. This study highlights the potential of mTORC1 inhibitors in treating age-related diseases.
Area of Science:
- Gerontology
- Molecular Biology
- Pharmacology
Background:
- Rapalogs, inhibitors of the mammalian target of rapamycin complex 1 (mTORC1), are known to extend lifespan and delay age-related conditions across various species.
- The precise molecular mechanisms underlying these effects remain incompletely understood.
- Understanding these mechanisms is crucial for developing targeted therapies for age-related disorders.
Purpose of the Study:
- To investigate the gene expression changes associated with aging in rat kidneys, liver, and skeletal muscle.
- To determine if a short-term, low-dose rapalog (RAD001) can counteract age-related gene expression alterations.
- To explore the role of c-Myc in aging and its regulation by mTORC1 inhibition.
Main Methods:
- Comparative gene expression analysis in kidneys, liver, and skeletal muscle of young (6-month-old) and aged (24-month-old) rats.
- Treatment of aged rats with RAD001 (a rapalog) or vehicle, followed by tissue analysis.
- Histological evaluation of kidney tissues to assess chronic progressive nephropathy.
- Analysis of c-Myc protein levels and its regulation by proteasome inhibition.
Main Results:
- RAD001 demonstrated a more significant impact on kidney gene expression and histology compared to liver and skeletal muscle in aged rats.
- Histological examination showed reduced severity of chronic progressive nephropathy in RAD001-treated aged rats.
- Aging induced c-Myc expression in the kidney, an effect counter-regulated by RAD001 treatment, which also decreased c-Myc protein levels.
- The reduction in c-Myc protein by RAD001 was reversible with a proteasome inhibitor.
Conclusions:
- Short-term, low-dose RAD001 treatment effectively counteracts age-related changes in the rat kidney, reducing disease severity.
- mTORC1 inhibition, potentially through c-Myc pathway modulation, represents a promising therapeutic strategy for age-related disorders.
- Further research into the molecular targets of mTORC1 inhibitors, such as c-Myc, is warranted to optimize their clinical application in aging.
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