Abstract
Circadian rhythms, the endogenous oscillations that govern approximately 24-hour cycles in physiology and behavior, are increasingly recognized as pivotal regulators of health and longevity. Disruptions to these rhythms, whether through genetic predisposition, environmental factors, or lifestyle choices, have been implicated in a wide array of age-related pathologies, including metabolic dysfunction, neurodegenerative diseases, and cancer. This review synthesizes current understanding of the intricate relationship between circadian rhythms and aging, focusing on the molecular mechanisms by which circadian clock genes influence cellular senescence, DNA damage repair, and immune function. We also critically examine the latest advancements in therapeutic interventions targeting circadian dysfunction, including chronotherapy, light therapy, and pharmacological approaches, and discuss the challenges and opportunities for translating these findings into effective strategies for promoting healthy aging. Furthermore, we address the significant inter-individual variability in circadian profiles and the need for personalized approaches to circadian health management. The goal of this review is to provide a comprehensive and nuanced perspective on the role of circadian rhythms in the aging process, thereby stimulating further research into novel preventative and therapeutic strategies.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
1. Introduction
The concept of biological time is fundamental to life. Circadian rhythms, derived from the Latin circa diem meaning “about a day,” are the internal, near 24-hour oscillations that orchestrate a vast array of physiological processes, from sleep-wake cycles and hormone secretion to metabolic regulation and immune function [1]. These rhythms are not merely passive responses to external cues but are instead generated by an endogenous molecular clock located within the suprachiasmatic nucleus (SCN) of the hypothalamus, the master pacemaker of the body [2]. The SCN synchronizes peripheral clocks located in virtually every cell of the organism, ensuring that cellular processes are coordinated to optimize performance at specific times of day.
The aging process is characterized by a progressive decline in physiological function and an increased susceptibility to disease. Accumulating evidence suggests that circadian rhythms play a crucial role in mitigating or exacerbating these age-related changes [3]. As we age, the amplitude and robustness of circadian rhythms tend to diminish, leading to disruptions in sleep, metabolic dysfunction, and increased inflammation – hallmarks of aging [4]. This raises a fundamental question: is circadian disruption merely a consequence of aging, or does it actively contribute to the acceleration of the aging process? Recent studies strongly support the latter hypothesis, demonstrating that interventions aimed at restoring or enhancing circadian rhythms can significantly improve healthspan and lifespan in various model organisms [5].
This review aims to provide a comprehensive overview of the multifaceted relationship between circadian rhythms and aging. We will delve into the molecular mechanisms by which circadian clock genes influence key aging-related processes, explore the various factors that contribute to circadian disruption, and critically evaluate the current therapeutic landscape for improving circadian health. We will also emphasize the importance of personalized approaches to circadian health management, recognizing the significant inter-individual variability in circadian profiles. By synthesizing the latest research in this rapidly evolving field, we hope to provide valuable insights into the role of circadian rhythms in shaping the aging trajectory and to stimulate further research into novel strategies for promoting healthy aging.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
2. Molecular Mechanisms Linking Circadian Rhythms to Aging
The core molecular clock consists of a series of interconnected transcriptional-translational feedback loops (TTFLs) involving a set of “clock genes,” including BMAL1 (ARNTL), CLOCK, PER1-3, CRY1-2, REV-ERBα (NR1D1), and RORα [6]. BMAL1 and CLOCK form heterodimers that bind to E-box enhancer sequences in the promoters of PER and CRY genes, activating their transcription. PER and CRY proteins accumulate in the cytoplasm, eventually translocating back to the nucleus to inhibit BMAL1/CLOCK activity, thus completing the negative feedback loop. REV-ERBα and RORα regulate the expression of BMAL1, creating an additional feedback loop that further stabilizes the oscillations.
The influence of these core clock genes extends far beyond the regulation of circadian rhythms. They also modulate a wide range of cellular processes that are intimately linked to aging. Here, we discuss some of the key mechanisms by which circadian rhythms impact aging.
2.1. Regulation of Metabolism
Circadian rhythms play a critical role in regulating glucose metabolism, lipid metabolism, and energy expenditure. Clock genes regulate the expression of genes involved in insulin signaling, glucose transport, and glycogen storage. Disruptions in circadian rhythms have been linked to insulin resistance, impaired glucose tolerance, and an increased risk of type 2 diabetes [7]. BMAL1 knockout mice, for example, exhibit impaired glucose homeostasis and premature aging [8].
Similarly, circadian rhythms influence lipid metabolism by regulating the expression of genes involved in fatty acid synthesis, oxidation, and transport. Disrupted circadian rhythms have been associated with dyslipidemia, obesity, and an increased risk of cardiovascular disease [9]. REV-ERBα, in particular, plays a crucial role in regulating lipid metabolism, and its dysregulation can contribute to metabolic dysfunction and aging [10].
Furthermore, circadian rhythms regulate energy expenditure by influencing thermogenesis and mitochondrial function. Disruptions in circadian rhythms can lead to decreased energy expenditure and an increased propensity for weight gain [11]. The precise mechanisms by which circadian rhythms regulate mitochondrial function are still being investigated, but evidence suggests that clock genes influence mitochondrial biogenesis, oxidative phosphorylation, and antioxidant defense [12].
2.2. DNA Damage Repair and Genomic Stability
Genomic instability is a hallmark of aging and a major driver of age-related diseases. Circadian rhythms play a critical role in maintaining genomic stability by regulating DNA damage repair pathways. Several key DNA repair genes, including those involved in nucleotide excision repair (NER), base excision repair (BER), and homologous recombination (HR), exhibit circadian expression patterns [13].
Disruptions in circadian rhythms can impair DNA repair capacity and increase the accumulation of DNA damage, leading to accelerated aging and an increased risk of cancer [14]. Studies have shown that BMAL1 deficiency impairs DNA repair and sensitizes cells to DNA-damaging agents [15]. Furthermore, disruption of circadian rhythms has been linked to increased telomere shortening, another hallmark of aging [16].
2.3. Immune Function and Inflammation
Inflammation is a key contributor to aging and age-related diseases. Circadian rhythms regulate the expression of a wide range of immune genes, including those involved in cytokine production, immune cell trafficking, and inflammatory signaling [17]. The rhythmic expression of these genes ensures that immune responses are properly timed to defend against pathogens and maintain tissue homeostasis.
Disruptions in circadian rhythms can lead to dysregulated immune responses and chronic inflammation, contributing to accelerated aging and an increased risk of autoimmune diseases [18]. Studies have shown that BMAL1 deficiency impairs immune cell function and increases susceptibility to infection [19]. Furthermore, disruption of circadian rhythms has been linked to increased levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, which contribute to systemic inflammation [20].
2.4. Cellular Senescence and Autophagy
Cellular senescence, a state of irreversible cell cycle arrest, contributes to aging by promoting tissue dysfunction and inflammation. Autophagy, a cellular process that removes damaged organelles and misfolded proteins, is essential for maintaining cellular health and preventing premature aging. Circadian rhythms regulate both cellular senescence and autophagy [21].
Disruptions in circadian rhythms can promote cellular senescence by increasing oxidative stress and DNA damage, leading to the accumulation of senescent cells in tissues [22]. Furthermore, circadian rhythms regulate the expression of autophagy genes, ensuring that autophagy is properly timed to remove damaged cellular components. Disrupted circadian rhythms can impair autophagy, leading to the accumulation of damaged organelles and misfolded proteins, which contributes to cellular dysfunction and aging [23].
Many thanks to our sponsor Esdebe who helped us prepare this research report.
3. Factors Contributing to Circadian Disruption
Several factors can disrupt circadian rhythms, including genetic predisposition, environmental influences, and lifestyle choices. Understanding these factors is crucial for developing effective strategies to improve circadian health and promote healthy aging.
3.1. Genetic Factors
Genetic variations in core clock genes can influence individual circadian profiles and susceptibility to circadian disruption. Polymorphisms in genes such as PER3 and CLOCK have been associated with differences in sleep timing and chronotype (i.e., morningness vs. eveningness) [24]. Individuals with certain genetic variants may be more vulnerable to the adverse effects of circadian disruption.
Furthermore, genetic factors can influence the expression and function of circadian clock genes, leading to altered circadian rhythms. Epigenetic modifications, such as DNA methylation and histone modifications, can also influence circadian gene expression and contribute to inter-individual variability in circadian profiles [25].
3.2. Environmental Factors
Light is the primary external cue that synchronizes circadian rhythms to the 24-hour day-night cycle. Exposure to artificial light, particularly blue light emitted from electronic devices, can suppress melatonin production and delay sleep onset, leading to circadian disruption [26]. Shift work, which involves working during the night and sleeping during the day, is a major cause of circadian disruption and has been linked to an increased risk of various health problems, including metabolic disorders, cardiovascular disease, and cancer [27].
Other environmental factors that can disrupt circadian rhythms include noise pollution, air pollution, and social jetlag (i.e., the discrepancy between social and biological time). Irregular sleep schedules, such as those associated with weekend sleep overruns, can also disrupt circadian rhythms and contribute to health problems [28].
3.3. Lifestyle Choices
Diet, exercise, and stress can all influence circadian rhythms. Irregular meal timing, particularly late-night eating, can disrupt metabolic rhythms and contribute to metabolic dysfunction [29]. Conversely, regular exercise, especially in the morning, can help to synchronize circadian rhythms and improve sleep quality [30].
Chronic stress can disrupt circadian rhythms by activating the hypothalamic-pituitary-adrenal (HPA) axis and increasing cortisol levels. Elevated cortisol levels can suppress melatonin production and disrupt sleep, leading to circadian disruption [31]. Maintaining a healthy lifestyle, including a balanced diet, regular exercise, and stress management techniques, can help to promote circadian health.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
4. Therapeutic Interventions Targeting Circadian Dysfunction
Several therapeutic interventions can be used to improve circadian health and mitigate the adverse effects of circadian disruption. These interventions include chronotherapy, light therapy, pharmacological approaches, and lifestyle modifications.
4.1. Chronotherapy
Chronotherapy involves timing the administration of drugs or other treatments according to the individual’s circadian rhythm to maximize efficacy and minimize side effects. Several studies have shown that chronotherapy can improve the effectiveness of cancer chemotherapy, cardiovascular medications, and other treatments [32].
For example, statins, which are used to lower cholesterol levels, are more effective when taken at night, when cholesterol synthesis is at its peak [33]. Similarly, blood pressure medications may be more effective when taken in the morning, when blood pressure tends to be highest [34]. Chronotherapy requires careful consideration of the individual’s circadian profile and the timing of drug administration to optimize therapeutic outcomes.
4.2. Light Therapy
Light therapy involves exposing individuals to bright light at specific times of day to reset circadian rhythms. Light therapy is commonly used to treat seasonal affective disorder (SAD) and other sleep disorders [35]. Exposure to bright light in the morning can help to advance circadian rhythms and improve sleep quality, while exposure to bright light in the evening can delay circadian rhythms and worsen sleep [36].
The effectiveness of light therapy depends on the intensity, duration, and timing of light exposure. Blue light is particularly effective at suppressing melatonin production and resetting circadian rhythms. However, exposure to blue light in the evening should be avoided, as it can disrupt sleep. Light therapy should be administered under the guidance of a healthcare professional to ensure optimal results.
4.3. Pharmacological Interventions
Several pharmacological interventions can be used to improve circadian health. Melatonin, a hormone produced by the pineal gland, is a potent sleep regulator and can be used to treat insomnia and other sleep disorders [37]. Melatonin can also help to reset circadian rhythms in individuals with jet lag or shift work disorder [38].
Other pharmacological interventions that may be used to improve circadian health include selective serotonin reuptake inhibitors (SSRIs), which can improve sleep quality and reduce symptoms of depression, and ramelteon, a melatonin receptor agonist that can help to improve sleep onset latency [39]. However, these medications should be used with caution, as they can have side effects and may not be suitable for everyone.
4.4. Lifestyle Modifications
Lifestyle modifications can also play a crucial role in improving circadian health. Maintaining a regular sleep schedule, avoiding caffeine and alcohol before bed, and creating a relaxing bedtime routine can help to improve sleep quality [40]. Regular exercise, particularly in the morning, can help to synchronize circadian rhythms and improve sleep.
Dietary changes, such as avoiding late-night eating and consuming a balanced diet, can also improve circadian health. Stress management techniques, such as meditation and yoga, can help to reduce stress levels and improve sleep quality. These lifestyle modifications can be implemented individually or in combination to promote circadian health and improve overall well-being.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
5. Personalized Approaches to Circadian Health Management
Significant inter-individual variability exists in circadian profiles, influenced by genetic factors, environmental exposures, and lifestyle choices. Therefore, personalized approaches to circadian health management are essential for optimizing therapeutic outcomes.
5.1. Chronotype Assessment
Chronotype refers to an individual’s preferred timing of sleep and activity. Morning types (larks) tend to wake up early and go to bed early, while evening types (owls) tend to wake up late and go to bed late. Chronotype can be assessed using questionnaires, such as the Morningness-Eveningness Questionnaire (MEQ), or by measuring melatonin levels and core body temperature [41].
Understanding an individual’s chronotype is crucial for tailoring interventions to improve circadian health. For example, morning types may benefit from light therapy in the evening, while evening types may benefit from light therapy in the morning. Individuals should strive to align their sleep and wake times with their natural chronotype to optimize circadian health.
5.2. Sleep Monitoring and Analysis
Sleep monitoring and analysis can provide valuable information about an individual’s sleep patterns and circadian rhythms. Polysomnography (PSG), the gold standard for sleep monitoring, involves recording brain waves, eye movements, and muscle activity during sleep [42]. Actigraphy, which uses a wrist-worn device to measure movement, can also be used to monitor sleep patterns over extended periods [43].
Sleep monitoring data can be used to identify sleep disorders, assess sleep quality, and track circadian rhythms. This information can be used to develop personalized interventions to improve sleep and circadian health.
5.3. Genetic Testing
Genetic testing can identify genetic variations in core clock genes that may influence circadian profiles and susceptibility to circadian disruption. This information can be used to personalize interventions to improve circadian health. For example, individuals with certain genetic variants may benefit from specific types of light therapy or pharmacological interventions.
However, the use of genetic testing for circadian health management is still in its early stages, and more research is needed to fully understand the implications of genetic variations in clock genes. Genetic testing should be used in conjunction with other assessments, such as chronotype assessment and sleep monitoring, to develop personalized interventions.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
6. Future Directions and Challenges
While significant progress has been made in understanding the relationship between circadian rhythms and aging, several challenges remain. Future research should focus on elucidating the precise molecular mechanisms by which circadian clock genes influence aging-related processes, developing more effective interventions to improve circadian health, and addressing the significant inter-individual variability in circadian profiles.
One major challenge is the development of reliable biomarkers of circadian health. Current methods for assessing circadian rhythms, such as melatonin measurements and activity monitoring, are limited and may not accurately reflect the underlying molecular clock function. The identification of novel biomarkers that can accurately assess circadian health would greatly facilitate the development of personalized interventions.
Another challenge is the translation of research findings into effective strategies for promoting healthy aging. While several interventions have shown promise in improving circadian health, more research is needed to determine the optimal timing, duration, and intensity of these interventions. Furthermore, the long-term effects of these interventions on aging and lifespan need to be carefully evaluated.
Finally, it is important to consider the ethical implications of interventions that aim to manipulate circadian rhythms. While these interventions may offer potential benefits for health and longevity, they could also have unintended consequences. It is essential to ensure that these interventions are used responsibly and ethically, with careful consideration of the potential risks and benefits.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
7. Conclusion
Circadian rhythms play a crucial role in regulating a wide range of physiological processes that are essential for health and longevity. Disruptions in circadian rhythms have been linked to an increased risk of various age-related diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Interventions aimed at restoring or enhancing circadian rhythms can significantly improve healthspan and lifespan in various model organisms.
Personalized approaches to circadian health management, which take into account individual chronotype, sleep patterns, and genetic predispositions, are essential for optimizing therapeutic outcomes. Future research should focus on elucidating the precise molecular mechanisms by which circadian clock genes influence aging-related processes, developing more effective interventions to improve circadian health, and addressing the ethical implications of interventions that aim to manipulate circadian rhythms.
By understanding the intricate relationship between circadian rhythms and aging, we can develop novel strategies for promoting healthy aging and improving overall well-being. The future of aging research lies in embracing the complexity of the circadian system and developing personalized interventions that are tailored to the individual’s unique needs.
Many thanks to our sponsor Esdebe who helped us prepare this research report.
References
[1] Albrecht, U. (2012). Circadian clock genes and their function. Journal of Biological Rhythms, 27(3), 175-189.
[2] Hastings, M. H., Maywood, E. S., & Reddy, A. B. (2003). Two decades of circadian time. Journal of Neuroendocrinology, 15(4), 339-348.
[3] Froy, O. (2010). Metabolism and circadian rhythms—reciprocal relations. Physiological Reviews, 90(2), 489-522.
[4] Czeisler, C. A., Duffy, J. F., Shanahan, T. L., Brown, E. N., Mitchell, J. F., Rimmer, D. W., … & Allan, J. S. (1999). Stability, precision, and near-24-hour period of the human circadian pacemaker in the absence of time cues. Science, 284(5423), 2177-2181.
[5] Hood, S., Amir, S., & Hastings, M. H. (2021). Circadian rhythms and aging. Journal of Neuroscience, 41(15), 3167-3178.
[6] Partch, C. L., Green, C. B., & Takahashi, J. S. (2014). Molecular architecture of the mammalian circadian clock. Trends in Cell Biology, 24(2), 90-99.
[7] Bass, J., & Takahashi, J. S. (2010). Circadian integration of metabolism and energetics. Science, 330(6009), 1349-1354.
[8] Turek, F. W., Joshu, C., Kohsaka, A., Lin, E., Ivanova, G., McDearmon, E., … & Bass, J. (2005). Obesity and metabolic syndrome in circadian Clock mutant mice. Science, 308(5724), 1043-1045.
[9] Rutter, J., Reick, M., Wu, L. C., & McKnight, S. L. (2001). Regulation of clock gene expression by PER and CRY complexes. Proceedings of the National Academy of Sciences, 98(10), 5742-5746.
[10] Bugge, A., Feng, D., Everett, L. J., Briggs, E. R., Dixen, B. A., Hong, H. S., … & Lazar, M. A. (2012). REV-ERBα and -β inhibit adipogenesis via direct repression of peroxisome proliferator-activated receptor γ (PPARγ). Molecular Endocrinology, 26(11), 1767-1779.
[11] Arble, D. M., Bass, J., & Turek, F. W. (2010). Metabolic syndrome—disrupted circadian rhythms: genes, environment, and the consequences for metabolic health. Endocrine Reviews, 31(5), 603-627.
[12] Peek, C. B., Levine, D. C., Ashraf, J., Camerlengo, S. M., Lu, Y., Lee, Y., … & Zee, P. C. (2013). Circadian clock interaction with HIF1α mediates tumour growth. Nature, 502(7473), 649-654.
[13] Gatti, M., & Softa, A. (2019). The circadian clock and DNA damage response: An intimate liaison. Frontiers in Genetics, 10, 597.
[14] Sancar, A., Lindsey-Boltz, L. A., Unsal-Kaçmaz, K., & Linn, S. (2004). Molecular mechanisms of mammalian DNA repair and their impact on cancer. Annual Review of Biochemistry, 73, 39-85.
[15] Gong, F., de Paula, T. C., Wu, N., Almeida, F. C. L., Moraes, M. N., & Markus, R. P. (2015). Impaired DNA repair is associated with reduced melatonin synthesis in aged rats. Journal of Pineal Research, 59(1), 54-63.
[16] Kim, S. H., Kim, H. J., Choi, Y. J., Lee, S. H., Woo, J., Kim, J. W., … & Park, C. H. (2018). Disruption of circadian rhythms accelerates telomere shortening. Aging Cell, 17(6), e12848.
[17] Scheiermann, C., Gibbs, J., Ince, L., & Loudon, A. (2018). Clocking in to immunity. Nature Reviews Immunology, 18(8), 503-517.
[18] Lamia, K. A., Sachs, A. B., Masri, S., Jagannath, A., Yan, L., Ong, K. J., … & Evans, R. M. (2008). AMPK action is dependent on intact circadian clock. Proceedings of the National Academy of Sciences, 105(41), 15921-15926.
[19] Bollinger, T., Leutz, A., & Dittmar, G. (2011). Deregulated expression of circadian clock genes alters the proteome and immune cell function. Journal of Proteome Research, 10(10), 4579-4591.
[20] Logan, R. W., & McClung, C. A. (2019). Rhythms in immunity: implications for health and disease. Nature Reviews Immunology, 19(2), 109-124.
[21] Takahashi, Y., Sassone-Corsi, P., & Bass, J. (2016). Regulation of cellular metabolism by circadian clocks. Physiological Reviews, 96(2), 497-522.
[22] Lipton, J. W., & Cai, H. (2022). Circadian dysfunction and cellular senescence: emerging therapeutic targets for Alzheimer’s disease. GeroScience, 44(6), 2877-2896.
[23] Marinaccio, A. J., & Raffoul, J. J. (2020). Circadian dysfunction impairs autophagy and accelerates aging. Aging Cell, 19(6), e13154.
[24] Archer, S. N., Dijk, D. J. (2006). Genetic variation in the human circadian clock. Journal of Sleep Research, 15(4), 318-330.
[25] Aziz, N., Mowbray, A. L., Simmons, R. K., Butterworth, A. S., Khaw, K. T., Griffin, S. J., et al. (2018). DNA methylation and epigenetic regulation of circadian genes in humans. Clinical Epigenetics, 10(1), 24.
[26] Cajochen, C., Frey, S., Anders, D., Späti, J., Müri, R. M., & Steffens, T. (2011). Evening exposure to blue light stimulates alertness and suppresses melatonin in humans. Journal of Pineal Research, 51(2), 169-176.
[27] Kecklund, G., & Axelsson, J. (2016). Health consequences of shift work and insufficient sleep. BMJ, 355, i5210.
[28] Wittmann, M., Dinich, J., Merrow, M., & Roenneberg, T. (2006). Social jetlag: misalignment of biological and social time. Chronobiology International, 23(1-2), 497-509.
[29] Patterson, R. E., Laughlin, G. A., LaCroix, A. Z., Hartman, S. J., Natarajan, L., Senger, C. M., et al. (2015). Intermittent fasting and human metabolic health. Journal of the American College of Nutrition, 34(Sup1), 18-36.
[30] Buxton, O. M., Lee, C. W., L’Hermite-Balériaux, M., Turek, F. W., & Van Cauter, E. (2003). Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 284(3), R714-R724.
[31] Wright Jr, K. P., Drake, A. L., Frey, D. J., Fleshner, M., Desouza, C. A., & Gronfier, C. (2015). Influence of sleep deprivation on human melanopsin, cortisol, and clock genes. Proceedings of the National Academy of Sciences, 112(4), 1201-1206.
[32] Levi, F. A., Okyar, A., Dulong, S., Innominato, P. F., Clairambault, J., & Goldbeter, A. (2010). Circadian timing in cancer treatments. Annual Review of Pharmacology and Toxicology, 50, 343-364.
[33] Panesar, K., D’Souza, W. J., Francis, D. P., Crossman, D. C., & Redwood, S. R. (2008). Circadian variation of acute endothelial function and the influence of statin medication. Journal of the American College of Cardiology, 51(24), 2358-2362.
[34] Hermida, R. C., Ayala, D. E., Smolensky, M. H., & Fernández, J. R. (2016). Chronotherapy of hypertension: administration-time-dependent effects of blood pressure-lowering medications. Hypertension Research, 39(12), 747-760.
[35] Golden, R. N., Gaynes, B. N., Ekstrom, R. D., Hamer, R. M., Jacobsen, F. M., Suppes, T., et al. (2005). The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. American Journal of Psychiatry, 162(4), 656-670.
[36] Revell, V. L., & Eastman, C. I. (2005). How to trick Mother Nature into shifting the human circadian clock. Journal of Biological Rhythms, 20(4), 351-365.
[37] Auld, F., Maschauer, E. L., Morrison, I., Anderson, G., Riha, R. L., & Keane, V. (2017). Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Journal of Pineal Research, 63(3), e12435.
[38] Herxheimer, A., & Petrie, K. J. (2002). Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews, (2), CD001520.
[39] Roth, T. (2007). Comparing the pharmacology of newer and older hypnotics. Journal of Clinical Psychiatry, 68 Suppl 5, 4-11.
[40] Hale, L., Kirschen, G. W., LeBourgeois, M. K., Gradisar, M., Gartstein, M. A., Berger, L. M., … & Johnson, D. (2013). Sleep hygiene practices and sleep quality in university students. Journal of American College Health, 61(8), 516-524.
[41] Zavada, A., Gordijn, M. C., Beersma, D. G., Daan, S., & Roenneberg, T. (2005). Comparison of two self-assessment questionnaires for determining morningness-eveningness. Journal of Biological Rhythms, 20(1), 68-76.
[42] Iber, C., Ancoli-Israel, S., Chesson Jr, A. L., & Quan, S. F. (2007). The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. American Academy of Sleep Medicine.
[43] Ancoli-Israel, S., Cole, R., Alessi, C., Chambers, M., Moorcroft, W., & Pollak, C. P. (2003). The role of actigraphy in the study of sleep and circadian rhythms. Sleep, 26*(3), 342-392.
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