Drugging the Circadian Clock: Nobiletin, Nicotinamide Mononucleotide, and Resveratrol as Candidate Circadian Amplifiers

Strengthening the core circadian oscillator, here operationally described as “circadian amplification,” has been proposed as a novel therapeutic concept. This mini-review examines the preclinical and limited clinical evidence regarding three naturally derived compounds, nicotinamide mononucleotide (NMN), resveratrol, and nobiletin, as potential candidate circadian amplifiers. NMN and resveratrol are proposed to influence the NAD+/SIRT1 axis, which may affect circadian clock function. Nobiletin appears to act through a distinct pathway, including ROR-related clock modulation within the auxiliary feedback loop, and has shown circadian-enhancing effects in preclinical models. Preclinical studies suggest that these compounds may restore circadian gene expression and improve metabolic parameters, while human studies remain nascent. NMN, resveratrol, and nobiletin are promising compounds of chronobiological interest that may modulate circadian clock-related pathways. However, direct evidence supporting true “circadian amplification” in humans remains insufficient at present.