BMAL1-dependent regulation of the mTOR signaling pathway delays aging

Aging (Albany NY). 2014 Jan;6(1):48-57. doi: 10.18632/aging.100633.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / deficiency
  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism*
  • Aging / genetics
  • Aging / metabolism*
  • 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
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • deptor protein, mouse
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus