Circadian Rhythm

Circadian rhythms integrate a finely tuned network of biological processes recurring every 24 hours, coordinating physiological and behavioral responses to ensure an adaptive metabolism within the environmental milieu. ^[1] The circadian rhythm regulates biological functions including sleep-wake preference, body temperature, hormonal secretion, food intake, and cognitive and physical performance. ^[2] The suprachiasmatic nucleus of the hypothalamus, numbering only about 10,000 neurons on each side of the third ventricle, is the principal circadian clock that directs the daily cycles of behaviour and physiology. ^[3]

The discovery of the cell-autonomous transcriptional and post-translational feedback loops that drive circadian activity in the suprachiasmatic nucleus provided a powerful exemplar of the genetic specification of complex mammalian behaviours. ^[3] The clock genes period and timeless were first discovered in large-scale Drosophila genetic screens, and feedback of period and timeless on their own transcription forms the core of the molecular clock. ^[4] Core clock genes regulate the sleep-wake cycle via transcription-translation feedback loops, and genetic polymorphisms and epigenetic modifications that disrupt this circadian rhythmicity can predispose individuals to insomnia. ^[5] The central clock in the hypothalamus is synchronized with peripheral clocks in the organs and is influenced by cues such as light, sleep, and eating times to adjust cellular and organ function. ^[6] Visible light synchronizes the human biological clock in the suprachiasmatic nuclei to the solar 24-hour cycle, with short blue wavelengths being the strongest synchronizing agent, in part by suppressing melatonin secretion. ^[7]

Endogenous circadian rhythms dampen with age, compromising the temporal coordination of cellular function, tissue function and behavior. ^[8] The circadian system and sleep homeostatic mechanisms become less robust with normal aging, and the amount and pattern of sleep-related hormone secretion change as well. ^[9] Dysfunction in 24-hour circadian rhythms is a common occurrence in ageing adults and is more severe in people with age-related neurodegenerative diseases including Alzheimer's disease, related dementias and Parkinson's disease. ^[10] Accumulating evidence indicates that circadian and sleep disturbances, long considered symptoms of neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. ^[11] NAD+ biosynthesis and SIRT1 function together to regulate metabolism and circadian rhythm, linking the age-related decline in NAD+ to circadian regulation. ^[12]

When circadian rhythms are perturbed or misaligned as a result of jet lag, shift work or other lifestyle factors, adverse health consequences arise and the risks of diseases such as cancer, cardiovascular disease or metabolic disorders increase. ^[13] Clock-based therapeutic strategies include chronotherapy, in which dosing time is deliberately optimized for maximum therapeutic index, and pharmacological agents that target core clock components and proximal regulators. ^[13] Sustaining a robust feeding-fasting cycle, even without altering nutrition quality or quantity, can prevent or reverse chronic diseases characteristic of aging in experimental models by optimizing the timing of external cues to sustain a robust circadian clock. ^[8] Some therapies such as light therapy and chronobiotics have been developed to correct circadian misalignment, though published work still has limitations. ^[14]