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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors / deficiency
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ARNTL Transcription Factors / genetics
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ARNTL Transcription Factors / metabolism*
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Aging / genetics
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Aging / metabolism*
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Animals
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Cell Proliferation
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Cells, Cultured
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Circadian Rhythm
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Enzyme Inhibitors / pharmacology
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Fibroblasts / enzymology
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Genotype
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lung / enzymology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Inbred C57BL
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Multiprotein Complexes / metabolism
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Phenotype
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Phosphorylation
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Signal Transduction* / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Time Factors
Substances
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ARNTL Transcription Factors
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Bmal1 protein, mouse
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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deptor protein, mouse
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mTOR protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Sirolimus