Studies Link Circadian Rhythm, Metabolism, Longevity to One Protein

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"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.

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"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."

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For more on understanding how sleep works, visit the National Institute of Neurological Disorders and Stroke.

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