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Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice
Emma L Baar1,2, Kathryn A Carbajal1,2, Irene M Ong3,4
1Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Abstract:
Inhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age-associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate-specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.
Insights
Rapamycin extends lifespan by inhibiting the mechanistic Target Of Rapamycin (mTOR) pathway. This study found aging does not increase mTOR signaling, suggesting rapamycin
Area of Science:
- Gerontology
- Molecular Biology
- Signaling Pathways
Background:
- The mechanistic Target Of Rapamycin (mTOR) pathway is crucial for cell growth and metabolism.
- Inhibiting mTOR with rapamycin extends lifespan in various model organisms, including mice.
- The effect of aging on mTOR signaling has not been thoroughly investigated, despite its role in lifespan extension.
Purpose of the Study:
- To comprehensively assess age-associated changes in mTORC1 and mTORC2 signaling.
- To investigate these changes across multiple tissues (liver, muscle, adipose, heart) and sexes.
- To determine if rapamycin extends lifespan by counteracting age-related increases in mTOR signaling.
Main Methods:
- Analysis of mTORC1 and mTORC2 signaling activity in C57BL/6J.Nia mice of different ages and sexes.
- Examination of age-associated mTOR signaling in liver tissues of HET3 and DBA/2 mouse strains.
- Assessment in liver, muscle, and adipose tissues of F344 rats.
Main Results:
- Age-associated changes in mTORC1 and mTORC2 signaling varied significantly by tissue and sex.
- Young female mice exhibited higher mTORC1 activity in liver and heart compared to young males.
- Aging did not consistently increase mTOR signaling across most tissues examined.
Conclusions:
- Aging does not generally lead to increased mTOR signaling in most tissues.
- Rapamycin's lifespan-extending effects are unlikely to be mediated by reversing or blunting age-related mTOR increases.
- Tissue- and sex-specific variations in mTOR signaling are important considerations in aging research.
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