Chronobiology: The Dynamic Field of Rhythm and Clock Genes

Chronobiology is the study of biologic rhythms, including circadian rhythms, that follow a daily or ~24-hour cycle. Sleeping at night and being awake during the day is an example of a circadian rhythm related to light. In this instance, the daily light and dark cycle is an important zeitgeber, or natural time cue that influences the circadian pattern. Our internal biological clocks produce circadian rhythms that are regulated through clock genes and are involved in the essential functioning of both central and peripheral tissues.^1,2 Specifically, to modulate various body processes, core clock genes known as period and cryptochrome genes are believed to act as transcriptional regulators that affect the circadian expression of certain rhythmically expressed genes and proteins.³

Medical chronobiology specifically looks at the impact of circadian or other biologic temporal patterns on human diseases; the practice of circadian medicine incorporates this knowledge of diurnal biologic rhythms to help inform medical treatments. 

A Dynamic Field – Impacts of Chronobiology on Health and Disease

The field of chronobiology continues to expand and shed light on the relationship between circadian patterns and human physiology, diseases, and the optimal wellness of the individual. Discoveries in the field of chronobiology have been translated into clinically applicable interventions known as chronotherapeutics. The application of chronotherapy considers an individual patient’s temporal disruptions in relation to chronic conditions and therapeutic strategies.⁴

Research has suggested links between circadian-rhythm disruptions and health implications, from neurodegenerative risks to mood disorders to cardiometabolic dysfunctions.^5-10 Irregular rhythms have been associated with lifestyle patterns such as chronic shift work, social jetlag, and meal timing.^11-13 Studies also suggest that changes in the circadian-system regulation may be influenced by the aging process.¹⁴

CARDIOMETABOLIC CONDITIONS

Human and animal-based studies suggest circadian rhythms influence cardiometabolic function and diseases and may also offer an avenue for disease prevention and treatment.^15-17 With circadian rhythm disruption emerging as a potential risk factor for obesity and obesity-associated comorbidities such as diabetes and cardiovascular disease (CVD),¹⁸ studies show that patterned diets such as time-restricted feeding may reduce this risk.^17,19,20 Specific to cardiovascular physiology, a person’s heart rate, blood pressure, and risk of onset of adverse cardiovascular events fluctuate during a 24-hour day.⁶ A 2019 study investigated the influence of circadian patterns on health outcomes for patients with hypertension (n= 19,084).¹⁶ Researchers found that those patients who took their medication at bedtime rather than upon awakening had a better ambulatory blood pressure and lower risk of developing CVD.¹⁶

A 2020 review noted that glucose metabolism is one of many physiological processes influenced by circadian rhythms, and misalignment of those rhythms may lead to adverse health outcomes.⁵ In a small study of 28 participants with type 2 diabetes, effects of eating a three-meal diet with a carbohydrate-rich breakfast was compared to a six-meal diet; results after 12 weeks for those following the three-meal diet showed:²¹

• Increased weight loss.
• Lower fasting, daily, and nocturnal glucose levels.
• An increased expression of clock genes.

The study suggested that the upregulation of the clock genes on a patterned three-meal diet may help to improve glucose metabolism.²¹

NEURODEGENERATIVE DISORDERS

Circadian rhythm disturbances may also impact common neurodegenerative disorders such as Alzheimer’s disease (AD)²² and Parkinson’s disease.⁷ While circadian disruption has been reported in symptomatic AD, a 2018 cross-sectional study evaluated data from 189 cognitively normal adults to examine any relationships between circadian functions, aging, and preclinical AD.²² Results from the study indicated fragmentation of the sleep-wake cycle impacted preclinical AD, independent of age, suggesting that the presence of irregular circadian rhythm may be an early symptom or may contribute to early disease development.²² Circadian dysregulation in Parkinson’s disease development and symptomology is not fully understood, and studies continue to investigate how chronobiology-based personalized medicine may benefit interventions.^23,24

Chronotype – Health Impact for the Individual

Biological rhythms influence sleep-wake cycles, eating habits and digestion, body temperature, and other biochemical and metabolic processes.^1,2 Genetic variations in clock genes, which regulate these rhythms of the body, and environmental factors contribute to potential rhythmic differences between people within a population. Chronotype, for example, describes at what time of day a person is naturally inclined to sleep and to be awake, ranging from early types to late types (i.e., “early birds” and “night-owls”) and those in between the two extremes. In addition, chronotype may also influence appetite and physical activity,^25,26 and studies continue to investigate the impact of chronotype on disease development and treatment.²⁷ For example, chrononutrition trials are beginning to explore chronotype influences on interventions for improved metabolic health.²⁸

Shift Work and Social Jetlag

Studies have suggested that chronic shift work, or employment on a schedule outside of the 9 am to 5 pm workday, increases the risk of cardiometabolic diseases²⁹ and impaired immunity.³⁰ In addition, “social jetlag” is a term used to describe a misalignment between a person’s biological rhythm and the rhythm of their social life, including school, work, and family schedules, and it may be associated with increased risk of chronic diseases such as obesity and metabolic disorders.¹²

Social jetlag may influence meal schedules and prompt food consumption that follows irregular patterns or occurs late at night, conflicting with circadian rhythms and impacting chronic diseases.¹² To evaluate the relationship between social jetlag and late-timed meals, researchers conducted a cross-sectional study of 792 participants with obesity-related chronic diseases and found that participants with social jetlag had higher intake of calories, total fat, cholesterol, and sweets and had longer reported eating durations and overall later meal times compared to participants without social jetlag.¹² The results suggested that within this tested group, social jetlag was associated with a poorer diet and later meal times, which are not optimal conditions for individuals with obesity-related chronic diseases.¹²

Clinical Applications of Chronobiology

Circadian medicine has the potential to further personalize treatments, and additional human research studies will help clarify the applicability of chronotherapies in health interventions and their impact on patient outcomes. The evolving knowledge of medical chronobiology and circadian rhythms provides great potential for furthering the functional medicine model’s personalized, root-cause approach to optimal health and wellness.

As an example, the focused field of chrononutrition investigates food as a circadian time cue, or zeitgeber, and continues to clarify the relationship between food, metabolism, meal timing, and the circadian system. Aligning meal timing with the body’s circadian cycle for optimal glucose and insulin responsiveness, as well as with hormones such as cortisol and leptin that are also affected by circadian oscillations,³¹may be effective for improving metabolic health. As a form of circadian fasting, time-restricted eating is a dietary pattern that optimizes circadian elements^20,32 by consuming food and beverage within a shortened window of time during the day, extending a person’s nightly fast to 12 hours or more. 

Treatment interventions based on circadian rhythms have also been seen in light therapy, which is used to help alleviate symptoms of seasonal affective disorder and even of non-seasonal depression.^33,34 A recent review called for a better understanding of circadian impact on neuroinflammation and control of pain to provide new, more effective chronic pain treatments.³⁵ And most recently, researchers have also taken a closer look at maximizing the benefits of exercise by considering diurnal timing.^36-38 The picture of optimal exercise times is not entirely clear, yet clinical studies suggest that coordinating exercise timing with a patient’s chronotype may optimize the health benefits of exercise routines.^36,37,39,40 A small 2020 randomized study investigated a timed exercise intervention that focused on sedentary adults.³⁷ Researchers concluded that late chronotypes may have circadian benefit from exercise in the morning or evening while evening exercise may promote circadian misalignment for early chronotypes.³⁷

Helping patients live in line with their chronotype by exercising, sleeping, or eating at optimal times and on optimal schedules may be an important consideration for the most effective and sustainable health treatment strategy. Overall, considering the influence of circadian rhythms may help address underlying causes of chronic conditions and assist in the optimization of personalized treatments. Learn more about personalizing and implementing clinical treatments and therapeutic strategies with IFM’s Applying Functional Medicine in Clinical Practice (AFMCP) course.