BMAL1-dependent regulation of the mTOR signaling pathway delays aging.
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.
Center for Gene Regulation in Health and Diseases, BGES, Cleveland State University, Cleveland, OH.
Rohini V
RV
Khapre
Anna A
AA
Kondratova
Sonal
S
Patel
Yuliya
Y
Dubrovsky
Michelle
M
Wrobel
Marina P
MP
Antoch
Roman V
RV
Kondratov
D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002940:Circadian Rhythm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C570841:deptor protein, mouse; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus