Sirtuin-dependent clock control: new advances in metabolism, aging and cancer

Abstract

Purpose of review: The circadian clock is an intricate biological timekeeper that is subject to fine-tuning mechanisms in order to maintain synchrony with the surrounding environment. One such mechanism is performed by the mammalian sirtuins that provide plasticity to the circadian clock by sensing cellular metabolic state. The sirtuins modulate the circadian epigenome and subsequent transcriptional control, and alterations to this organized system manifest in metabolic consequences, aging phenotypes and possibly cancer.

Recent findings: New information regarding sirtuin-dependent control of the circadian clock has emerged. In addition to sirtuin (SIRT)1 and SIRT3, SIRT6 has been demonstrated as a critical regulator of circadian transcription that also serves as an interface with metabolic homeostasis. Also, new metabolic functions of SIRT1 have been described in the brain, which are critical to relay nutritional inputs to the central clock.

Summary: This review focuses on the link between the circadian clock and the sirtuins, with an emphasis on new findings. In addition, speculation on the possible connections at the physiological level will be made that could further link the clock to aging and cancer.

Figure 1. Sirtuin-dependent control of the circadian clock in the brain and periphery

The core clock transcriptional machinery, directed by CLOCK and BMAL1, drives transcription of circadian gene expression, including nicotinamide phosphoribosyltransferase (Nampt), which subsequently results in oscillatory levels of NAD⁺. In the brain, NAD⁺-dependent SIRT1 activity is critical for circadian function both in the SCN and VMH. In the liver, SIRT1, SIRT6 and SIRT3 are involved in circadian transcription and metabolic regulation. Suprachiasmatic nucleus, SCN; Ventromedial hypothalamus, VMH; Clock-controlled genes, CCGs.