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BMAL1-dependent regulation of the mTOR signaling pathway delays aging.

Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV - Aging (Albany NY) (2014)

Bottom Line: Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%.Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling.We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.

View Article: PubMed Central - PubMed

Affiliation: Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, Cleveland, OH.

ABSTRACT
The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.

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Expression of mtor and deptor is deregulated in the liver of Bmal1−/− miceThe expressions of several components of TORC1 and upstream regulator of TORC1 in the liver of wild type and Bmal1−/− mice were analyzed across the daily cycle on mRNAs level by real-time RT PCR. All expression data were normalized to 18S ribosomal RNA expression. (a-c) Expression of mRNAs for tor(a), deptor(b), rheb(c) in the liver of TRF WT (black diamonds) or Bmal1−/− (grey squares) mice. Results represent average for 4 animals of each genotype for each time point.* - statistically significant difference between the genotypes. Bars on the top of the figure represent light (open bars) and dark (black bars) parts of the day.
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Figure 5: Expression of mtor and deptor is deregulated in the liver of Bmal1−/− miceThe expressions of several components of TORC1 and upstream regulator of TORC1 in the liver of wild type and Bmal1−/− mice were analyzed across the daily cycle on mRNAs level by real-time RT PCR. All expression data were normalized to 18S ribosomal RNA expression. (a-c) Expression of mRNAs for tor(a), deptor(b), rheb(c) in the liver of TRF WT (black diamonds) or Bmal1−/− (grey squares) mice. Results represent average for 4 animals of each genotype for each time point.* - statistically significant difference between the genotypes. Bars on the top of the figure represent light (open bars) and dark (black bars) parts of the day.

Mentions: In order to get an insight into possible molecular mechanisms of the BMAL1-dependent regulation of mTOR signaling, we investigated expression of some components of the mTORC1 complex and its upstream regulators. Expression of tor and deptor mRNA was highly affected by BMAL1 deficiency. Expression of tor was significantly upregulated at several time points (Figure 5a), while expression of deptor was significantly downregulated (Figure 5b) in the liver of Bmal1−/− mice in agreement with the increased mTORC1 signaling in these animals. At the same time, we did not detect any significant effect of BMAL1 deficiency on the expression of the mTORC1 upstream regulator rheb (Figure 5c), suggesting that the regulation of tor and deptor expressions is specific. Thus, the BMAL1-dependent regulation may occur at least partially at the transcriptional level, although the existence of other mechanisms cannot be excluded at this point.


BMAL1-dependent regulation of the mTOR signaling pathway delays aging.

Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV - Aging (Albany NY) (2014)

Expression of mtor and deptor is deregulated in the liver of Bmal1−/− miceThe expressions of several components of TORC1 and upstream regulator of TORC1 in the liver of wild type and Bmal1−/− mice were analyzed across the daily cycle on mRNAs level by real-time RT PCR. All expression data were normalized to 18S ribosomal RNA expression. (a-c) Expression of mRNAs for tor(a), deptor(b), rheb(c) in the liver of TRF WT (black diamonds) or Bmal1−/− (grey squares) mice. Results represent average for 4 animals of each genotype for each time point.* - statistically significant difference between the genotypes. Bars on the top of the figure represent light (open bars) and dark (black bars) parts of the day.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927809&req=5

Figure 5: Expression of mtor and deptor is deregulated in the liver of Bmal1−/− miceThe expressions of several components of TORC1 and upstream regulator of TORC1 in the liver of wild type and Bmal1−/− mice were analyzed across the daily cycle on mRNAs level by real-time RT PCR. All expression data were normalized to 18S ribosomal RNA expression. (a-c) Expression of mRNAs for tor(a), deptor(b), rheb(c) in the liver of TRF WT (black diamonds) or Bmal1−/− (grey squares) mice. Results represent average for 4 animals of each genotype for each time point.* - statistically significant difference between the genotypes. Bars on the top of the figure represent light (open bars) and dark (black bars) parts of the day.
Mentions: In order to get an insight into possible molecular mechanisms of the BMAL1-dependent regulation of mTOR signaling, we investigated expression of some components of the mTORC1 complex and its upstream regulators. Expression of tor and deptor mRNA was highly affected by BMAL1 deficiency. Expression of tor was significantly upregulated at several time points (Figure 5a), while expression of deptor was significantly downregulated (Figure 5b) in the liver of Bmal1−/− mice in agreement with the increased mTORC1 signaling in these animals. At the same time, we did not detect any significant effect of BMAL1 deficiency on the expression of the mTORC1 upstream regulator rheb (Figure 5c), suggesting that the regulation of tor and deptor expressions is specific. Thus, the BMAL1-dependent regulation may occur at least partially at the transcriptional level, although the existence of other mechanisms cannot be excluded at this point.

Bottom Line: Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%.Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling.We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.

View Article: PubMed Central - PubMed

Affiliation: Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, Cleveland, OH.

ABSTRACT
The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.

Show MeSH
Related in: MedlinePlus