Studies Link Circadian Rhythm, Metabolism, Longevity to One Protein

"The key finding [for both papers is] that SIRT1 is a deacetylase involved in regulating circadian biology," said Sassone-Corsi. "And because SIRT1 is regulated by NAD, it links metabolism with circadian rhythms."

Schibler's team arrived at the same conclusion from a completely different angle. Recognizing that feeding cycles are critical to synchronizing the molecular clock, Schibler reasoned there must be a clock component capable of sensing metabolic state. As NAD seemed a good candidate for such a sensor, he looked specifically at NAD-binding proteins.

"You need something that senses feeding and metabolism, and there are many [candidates]," Schibler said. "The one we report on in this paper is SIRT1. We believe we have a very good candidate with this SIRT1."

Together, the two reports demonstrate that SIRT1 activity operates in a circadian manner; that SIRT1 binds directly to CLOCK/BMAL1 in a circadian manner; that SIRT1 deacetylates both BMAL1 and PER2, leading to their degradation and/or loss of activity; and (4) that loss of SIRT1 activity dampens circadian rhythms.

Takahashi noted several interesting aspects to this study. First is the fact that SIRT1 is regulated by NAD.

"There are many deacetylases," he said. "So, it certainly didn't have to be SIRT1. The fact that the deacetylase is also regulated by a metabolic indicator is exciting."

Indeed, Schibler said he suspects, but does not yet know for certain, that NAD levels also fluctuate in a circadian manner.

Also surprising, Takahashi said, is the fact that SIRT1 is an integral component of the clock itself, like a cog in the machinery, rather than some downstream player.

"And then," he added, "because the SIRT1 pathway itself is so interesting, because of its role in longevity, that suggests a new direct link between the longevity/metabolism pathway and the circadian clock, a direct molecular link that wasn't known before."

Takahashi noted this study has potential, albeit very long-term, therapeutic implications.

"If you screw up circadian rhythm enough, you can end up with metabolic disorders," he said, citing CLOCK-mutant mice which, in addition to having disrupted circadian cycles, are also obese and predisposed to diabetes.

Said Sassone-Corsi, "SIRT1 or CLOCK might make useful drug targets. Not today or tomorrow, but in the future. I have a feeling there will be a lot of interest in these studies once they come out."

More information

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SOURCES: Paolo Sassone-Corsi, Ph.D., chairman, Department of Pharmacology, University of California, Irvine; Ueli Schibler, Ph.D., professor, Molecular Biology, and investigator, National Center of Competence in Research "Frontiers in Genetics," University of Geneva, Switzerland; Joseph Takahashi, Ph.D., professor, neurobiology and physiology, and investigator, Howard Hughes Medical Institute, Northwestern University, Evanston, Ill.; July 25, 2008,Cell