Studies Link Circadian Rhythm, Metabolism, Longevity to One Protein

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Interestingly, CLOCK does more than bind DNA. It also functions as an enzyme that catalyzes the transfer of a small molecular mark (an acetyl group) to certain proteins, thereby changing their activities, much like flipping a switch. One of those targets is BMAL1.

Sassone-Corsi reasoned that for every enzyme that can add a molecular mark, there must be another that can remove it. "That's the way biology works; there is yin and yang to any function in the cell," he said.

His search led him to SIRT1, an enzyme that is responsive to metabolism and that requires, among other things, a molecule called nicotinamide adenine dinucleotide (NAD) to function. Because NAD levels fluctuate with the cell's metabolic state, SIRT1 is likewise responsive to metabolism.

"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."