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.
Subject(s)
ARNTL Transcription Factors/metabolism , Aging/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , ARNTL Transcription Factors/deficiency , ARNTL Transcription Factors/genetics , Aging/genetics , Animals , Cell Proliferation , Cells, Cultured , Circadian Rhythm , Enzyme Inhibitors/pharmacology , Fibroblasts/enzymology , Genotype , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lung/enzymology , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Inbred C57BL , Multiprotein Complexes/metabolism , Phenotype , Phosphorylation , Signal Transduction/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Time FactorsABSTRACT
Deficiency of the transcription factor BMAL1, a core component of the circadian clock, results in an accelerated aging phenotype in mice. The circadian clock regulates many physiological processes and was recently implicated in control of brain-based activities, such as memory formation and the regulation of emotions. Aging is accompanied by the decline in brain physiology, particularly decline in the response and adaptation to novelty. We investigated the role of the circadian clock in exploratory behavior and habituation to novelty using the open field paradigm. We found that mice with a deficiency of the circadian transcription factor BMAL1 display hyperactivity in novel environments and impaired intra- and intersession habituation, indicative of defects in short- and long-term memory formation. In contrast, mice double-deficient for the circadian proteins CRY1 and CRY2 (repressors of the BMAL1-mediated transcription) demonstrate reduced activity and accelerated habituation when compared to wild type mice. Mice with mutation in theClock gene (encoding the BMAL1 transcription partner) show normal locomotion, but increased rearing activity and impaired intersession habituation. BMAL1 is highly expressed in the neurons of the hippocampus - a brain region associated with spatial memory formation; BMAL1 deficiency disrupts circadian oscillation in gene expression and reactive oxygen species homeostasis in the brain, which may be among the possible mechanisms involved. Thus, we suggest that the BMAL1:CLOCK activity is critical for the proper exploratory and habituation behavior, and that the circadian clock prepares organism for a new round of everyday activities through optimization of behavioral learning.
