Reactivating Circadian Rhythms as a Therapeutic Strategy: Insights from Basic Research

One of the most significant conceptual changes brought about by the discovery of clock genes and development of circadian-clock mutant mice is the recognition that impaired circadian rhythmicity extends its impact far beyond sleep, driving pathogenesis of a wide variety of disorders such as cancer, obesity, and hypertension. However, despite this growing clinical evidence, chronobiology still lacks a coherent answer to the converse question: can restoration of circadian rhythms ameliorate-or even reverse-such diseases? In this review, three complementary pharmacological strategies-each still in preclinical development-are explored. First, direct modulation of the transcription-translation feedback loop (TTFL)-the core gene-regulatory circuit that generates 24-h rhythms in almost all nucleated cells-is reviewed as an approach to manipulation of cellular circadian biology. Second, the suprachiasmatic nucleus (SCN)-enriched G-protein-coupled receptor Gpr176 is highlighted as a central-clock target, given its ligand-independent, G_z-mediated control of cAMP signaling and demonstrated ability to reset the master pacemaker. Third, the concept of rhythmic enhancement of output function is introduced and exemplified by describing re-activation of circadian oxidized form of nicotinamide adenine dinucleotide (NAD⁺)-dependent 3β-hydroxy-steroid dehydrogenase (3β-HSD) activity in the meibomian gland-using nicotinamide mononucleotide (NMN)-to restore peripheral clock-driven steroidogenesis in this tissue, which leads to amelioration of meibomian gland dysfunction, a leading cause of dry eye disease. This review aims to highlight the molecular logic of each strategy; both mechanistic insights and safety/efficacy considerations are discussed.