Chronotherapeutic and Epigenetic Regulation of Circadian Rhythms: Nicotinamide Adenine Dinucleotide-Sirtuin Axis

Circadian rhythms are endogenous oscillations coordinating the physiological and behavioral activities with the daily light-dark cycle and are controlled by molecular mechanisms. Nicotinamide adenine dinucleotide (NAD+), a critical cofactor in redox processes and a substrate for many enzymes, is an important metabolite in circadian rhythms. NAD+ levels show strong circadian oscillations, which are caused by the rhythmic production of biosynthetic enzymes such as nicotinamide phosphoribosyl transferase. In contrast, the circadian clock system regulates the expression of NAD+ biosynthetic enzymes, resulting in a bidirectional regulatory loop. Sirtuins, a class of NAD+-dependent protein deacetylases, regulate the circadian clock by interacting with the core clock components and transcriptional regulators. Sirtuin (SIRT) 1 deacetylates and modulates the activity of key circadian transcription factors such as brain and muscle arnt-like 1 and period circadian regulator 2, while SIRT6 regulates the expression of circadian-controlled metabolic genes. This review explored the complex relationships among NAD+, sirtuins, and the circadian clock machinery, emphasizing their roles in sustaining metabolic homeostasis and coordinating cellular processes with daily environmental cycles. Moreover, circadian disruptions are strongly associated with aging, which results in the dysregulation of NAD+ homeostasis and sirtuin activity and contributes to the development of various age-related pathologies. Strategies to restore NAD+ levels or modify the sirtuin activity have emerged as promising treatment options for circadian rhythm disturbances and age-related disorders. This review also aimed to cover new horizons in this subject, such as the development of NAD+ boosters and sirtuin modulators, chrono-pharmacological methods, and the study of epigenetic mechanisms underlying sirtuin-mediated circadian regulation.