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Thursday, April 6, 2017

Chronic diseases and aging: potential applications of circadian clock-enhancing small molecules

Abstract (as presented by the authors of the scientific work):

"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."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Future directions and concluding remarks (as presented by the authors of the scientific work):

"Circadian amplitude regulation and pharmacological modifiers are exciting research topics with promising translational potential. The list of CEMs will likely continue to grow, either from phenotypic screening, as in the case of NOB, or from targeted ligand development (14). On the other hand, pharmacological agents shown to target or mimic clock-enhancing pathways such as CR, TRF, and exercise are a rich venue for discovery of additional clock-targeting agents (63, 130, 161, 170). For example, a growing number of small molecules or drugs have been shown to extend life span and health span, including those deliberately designed to mimic CR and other manipulations (170, 171). Future studies should characterize their circadian clock effects and delineate molecular mechanisms.

Besides metabolic diseases, mood disorders, and aging, other chronic diseases such as neurodegenerative diseases (172, 173) have also been shown to correlate with dampened circadian amplitude or clock dysregulation and may represent new venues for studies of clock modifiers. In addition to antidepressive effects, several studies have shown neurological efficacies of NOB using transgenic disease models (Table ​(Table2).2). For example, 11-day oral administration of NOB resulted in an overall memory improvement in olfactory-bulbectomized (OBX) mice based on the step-through passive-avoidance task and the Y-maze test (111). OBX mice share clinical features with both human neurodegenerative diseases and major depression (174). The depression-like phenotype is thought to derive from pathological or compensatory mechanisms within the cortical–hippocampal–amygdala circuit, which typically involve deterioration of spine density and/or synaptic strength changes (175). Future studies are required to determine the specific role of circadian clocks and RORs in disease models.

Significant gaps of knowledge remain regarding circadian amplitude regulation, especially the mechanisms employed by CEMs. At the intracellular level, questions of particular interest include gene expression regulation, such as cofactor recruitment, epigenetic mechanisms, and chromosome dynamics (1). At the intercellular and system levels, other coupling molecules in addition to VIP and the communication between peripheral and central clocks are outstanding questions (50). It is conceivable that CEMs execute distinct mechanistic schemes to restore a robust overall output under disease or aging conditions. Exemplified by the complex and divergent ROR mechanisms when bound by distinct ligands (74, 90, 91), a detailed mechanistic understanding is important to fully exploit the therapeutic potential of individual CEMs.

In conclusion, circadian clocks safeguard physiological health, and dysregulated and dampened clocks can serve as therapeutic targets to mitigate disease symptoms. Exciting functional and mechanistic studies await to develop CEMs as novel preventive and therapeutic agents."

Full-text access of the referenced scientific work:

Gloston GF, Yoo SH, Chen ZJ. Clock-Enhancing Small Molecules and Potential
Applications in Chronic Diseases and Aging. Front Neurol. 2017 Mar 15;8:100. doi:
10.3389/fneur.2017.00100. eCollection 2017. Review. PubMed PMID: 28360884; PubMed
Central PMCID: PMC5350099.


Prof. Atanas G. Atanasov (Dr. habil., PhD)

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