Clock-Enhancing Small Molecules and Potential Applications in Chronic Diseases and Aging

Abstract

Normal physiological functions require a robust biological timer called the circadian clock. When clocks are dysregulated, misaligned, or dampened, pathological consequences ensue, leading to chronic diseases and accelerated aging. An emerging research area is the development of clock-targeting compounds that may serve as drug candidates to correct dysregulated rhythms and hence mitigate disease symptoms and age-related decline. In this review, we first present a concise view of the circadian oscillator, physiological networks, and regulatory mechanisms of circadian amplitude. Given a close association of circadian amplitude dampening and disease progression, clock-enhancing small molecules (CEMs) are of particular interest as candidate chronotherapeutics. A recent proof-of-principle study illustrated that the natural polymethoxylated flavonoid nobiletin directly targets the circadian oscillator and elicits robust metabolic improvements in mice. We describe mood disorders and aging as potential therapeutic targets of CEMs. Future studies of CEMs will shed important insight into the regulation and disease relevance of circadian clocks.

Keywords: aging; amplitude; circadian clock; metabolic disease; mood disorder; small molecules.

Figure 1

The core circadian oscillator and regulatory molecules. The circadian clock oscillator is comprised of a network of transcriptional–translational feedback loops including the core loop (BMAL1/CLOCK/NPAS2 and PERs/CRYs), the stabilization loop (BMAL1/CLOCK, REV-ERBs, and RORs), and the auxiliary loop (DBP, E4BP4, REV-ERBs, and RORs). Various protein regulators (F-box-containing E3 ligases are shown as examples) and small-molecule modulators (nobiletin is shown) have been identified to target core clock components, regulating circadian periodicity and amplitude. See the main text for details.