mTOR Signaling in Growth Control and Disease

Laplante, Mathieu; Sabatini, David M.

doi:10.1016/j.cell.2012.03.017

Cited by 7,029 publications

(7,952 citation statements)

References 178 publications

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“…One of the primary regulators of mTORC1 activity is Akt, which activates mTORC1 activity through the inhibitory phosphorylation of TSC2 and PRAS40 (Laplante & Sabatini, 2012). Genetic studies in worms, flies, and mice consistently find that decreased signaling through the PI3K/Akt/mTORC1 signaling axis promotes longevity (Lamming, 2014), and calorie restriction, an intervention that promotes longevity in numerous species, decreases PI3K/Akt signaling in humans (Mercken et al ., 2013).…”

Section: Resultsmentioning

confidence: 99%

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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SummaryInhibition 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.

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Section: Resultsmentioning

confidence: 99%

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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“…Previous studies have observed that inhibition of mTOR1 prevents stem cell exhaustion and promotes stem cell function in vivo (Castilho, Squarize, Chodosh, Williams, & Gutkind, 2009), and our findings confirmed this conclusion. However, as a key regulator, the mTOR pathway plays various roles in most major cellular functions by regulating multiple pathways including S6K1, 4E‐BP1 and autophagy (Laplante & Sabatini, 2012). Thus, there also might be other mechanisms in addition to autophagy involved.…”

Section: Discussionmentioning

confidence: 99%

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

et al. 2017

Aging Cell

242

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SummaryBone marrow‐derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age‐related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3‐methyladenine (3‐MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity. Accordingly, the autophagy activator rapamycin could restore the biological properties of aged BMMSCs by increasing osteogenic differentiation and proliferation capacity and decreasing adipogenic differentiation capacity. Possible underlying mechanisms were explored, and the analysis revealed that autophagy could affect reactive oxygen species and p53 levels, thus regulating biological properties of BMMSCs. In an in vivo study, we found that activation of autophagy restored bone loss in aged mice. In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss.

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“…Its signals are complex, integrating many environmental cues (e.g., growth factors, energy/nutrients) to regulate important cellular processes (e.g., autophagy, macromolecule biosynthesis) (Laplante & Sabatini, 2012). mTOR inhibitors are approved to treat some cancers, with presumed effects on cancer cell proliferation or metabolism, and with many new mTOR inhibitors in development or in clinical trials (Wander et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

“…mTOR forms 2 complexes, mTORC1 and mTORC2. Rapamycin is considered primarily an mTORC1 inhibitor (Laplante & Sabatini, 2012) but can also inhibit mTORC2. Recent studies distinguish mTORC1 versus mTORC2 effects on lifespan (Selman et al ., 2009) in addition to effects on cell proliferation (Dowling et al ., 2010), metabolism (Sengupta et al ., 2010; Lamming et al ., 2012), protein translation (Thoreen et al ., 2012), immunity (Chi, 2012), and other processes (Yu et al ., 2010; Shimobayashi & Hall, 2014).…”

Section: Introductionmentioning

confidence: 99%

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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SummaryThe mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.

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mTOR Signaling in Growth Control and Disease

Cited by 7,029 publications

References 178 publications

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

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