Neuroscience · Meta-analysis
Exercise helps reset the body's internal clock and may prevent disease
- The body's internal clock controls sleep, hormones, and heart function, and when it falls out of sync, health problems follow.
- Exercise acts as a powerful signal that can adjust this internal clock without medication, similar to how light does.
- Researchers reviewed evidence from multiple studies showing that physical activity could help prevent circadian rhythm disorders and related diseases.
Frontiers in Pharmacology · 2023 — https://doi.org/10.3389/fphar.2023.1282357
Effects of exercise on circadian rhythms in humans
1 Introduction
Biological rhythms refer to repetitive processes that occur over specific periods of time, such as a day, a month, or a year. The circadian rhythm, which has a period of approximately 24 h, is particularly relevant to human health. Numerous behavioral, physiological, and biochemical activities demonstrate obvious circadian rhythms. For instance, the sleep-wake cycle, as well as daily changes in blood pressure, heart rate, and body temperature, are widely recognized to display discernible circadian patterns. When the internal biological clock becomes desynchronized with the external environment, it may lead to a mismatch between central and peripheral clocks, as well as between different tissues or organs, and even between different clock genes within the same organ. Long-term circadian disturbances are closely linked to the onset and progression of a variety of mental and physical diseases, including cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, and tumors.
In mammals, the central pacemaker of circadian rhythms is located in the suprachiasmatic nucleus (SCN). SCN output is relayed through the nuclei of the hypothalamus thereby transmitting circadian signals to the brain regions that regulate the sleep-wake cycles and synchronizing the peripheral circadian rhythms of other tissues through neurohormonal mechanisms. At the molecular level, the core clock genes and proteins form a set of highly conserved transcriptional-translational feedback loops (TTFL) that have both positive and negative regulatory elements. The transcription factors, BMAL1 and CLOCK form heterodimers, which bind to the E-box located in the promoter regions of the per and cry genes to promote the production of PER and CRY proteins. When they accumulate to a certain level in the cytosol, PER and CRY translocate to the nucleus to inhibit the activity of the BMAL1/CLOCK complex, thus repressing their own expressions. In addition, a second feedback pathway composed of nuclear receptors ROR and REV-ERB is involved in promoting and inhibiting the expression of BMAL1, respectively. These core clock components regulate hundreds of other genes, called clock-controlled genes (CCGs) in a circadian manner. Generally, core clockwork mechanisms exist in most tissues and cells of the body, but the expression of CCGs varies by cell type.
FIGURE 1. The mammalian clock system. The central clock is situated within the suprachiasmatic nucleus (SCN), where it governs peripheral clocks throughout the body (center). Light serves as the primary zeitgeber, while non-photic cues also have the capacity to synchronize circadian rhythms (left). At the molecular level (right), a set of core clock genes and proteins collaboratively form highly conserved transcriptional-translational feedback loops (TTFL).
While the circadian rhythm continues to function under constant conditions, such as constant darkness (DD), it can be affected by environmental changes and spontaneous activities like light exposure, diet, and exercise. These daily changes are referred to as zeitgebers and can entrain or reset the circadian rhythms. Among them, light is the most potent zeitgeber. Non-photic factors including medication, temperature, diet, and exercise can also entrain circadian rhythms. For example, consuming food during specific time affects the transcription levels of clock genes, which can aid in maintaining normal circadian rhythms, mitigating metabolic disorders caused by a high-fat diet (HFD), improving the body’s ability to cope with circadian disruption, enhancing running endurance without prior exercise, and even prolonging lifespan.
Over the past few years, exercise has garnered increasing attention as a significant non-photic zeitgeber. Physical inactivity is recognized as a risk factor for numerous common illnesses, including cardiovascular diseases, metabolic disorders, neurodegenerative disorders, and tumors. At the molecular level, exercise has been shown to modulate the expression of clock genes. Both aerobic and resistance exercise upregulate the expression of BMAL1 and PER2 in skeletal muscle. Regular exercise is a healthy lifestyle, in part because it helps keep the biological clock running properly. Similar to light exposure, the timing of exercise affects the circadian rhythm. Thus, exercise is expected to be a non-invasive, non-pharmaceutical intervention to facilitate the regulation of circadian rhythms. However, the best time of day for strength and endurance training to improve health remains unclear. This review summarizes relevant literature and discusses two aspects: 1) the impact of exercise on circadian rhythms; and 2) the association between exercise and circadian disorders and related illnesses.
2 Effects of exercise on circadian rhythms
Establishing a correlation between exercise and circadian rhythms based on human studies is challenging due to the varying intensity, mode, and duration of exercise. Exercise can be classified as either aerobic or resistance training depending on the energy-producing systems and weight-bearing conditions, or continuous exercise and intermittent exercise based on the length of rest periods. In 2020, the World Health Organization guidelines on physical activity and sedentary behaviour underscored the pivotal role of regular physical activity in preventing and treating non-communicable diseases, recommending that adults engage in at least 150–300 min of moderate-intensity or 75–150 min of vigorous-intensity aerobic physical activity per week. Therefore, the majority of studies investigating the relationship between exercise and circadian rhythm have focused on moderate to high-intensity aerobic exercise lasting more than 30 min per day. This chapter reviews the associations of the timing of exercise with circadian rhythms under normal, constant, and disturbed light conditions.
TABLE 1. Effects of exercise on human circadian rhythm.
2.1 Normal light/dark (LD) condition
Chronotypes refer to different phenotypes that are produced by individuals entraining different exogenous and endogenous factors, which play a crucial role in health and shift work tolerance. Based on these variations, people can be classified into morning types (early birds), evening types (night owls), and those with no extreme bias. Studies have investigated the effects of morning and evening exercise on circadian rhythms in individuals with different chronotypes. Both morning and evening exercise advanced the sleep-wake cycle and dim light melatonin onset (DLMO) in night owls, while evening exercise delayed the phase of DLMO in early birds. A questionnaire survey on a large sample size (N = 909) found that evening exercise led to a delayed sleep onset time than morning exercise, and the night owls were more significantly affected.
The timing of exercise is a crucial factor to consider. For instance, under a condition of 16-h light:8-h dark (LD16:8), resistance exercise in the morning or noon can advance the circadian phase of core body temperature, whereas long-term rest in bed can delay it. Furthermore, research on the relationship between children’s physical activity and sleep found that exercise time is related to sleep duration and efficiency. Proper exercise during normal photoperiods can effectively regulate circadian rhythms, and it is recommended that the general population chooses morning exercise to improve sleep quality and advance sleep onset time.
2.2 Constant condition
In a constant environment without time cues, Miyazaki et al. found that 2 hours of moderate-intensity intermittent exercise (using a bicycle ergometer) in the afternoon (CT8, the timepoint of wake-up was defined as CT0) or night (CT17) delayed the onset of melatonin, while the timing of melatonin peak remained unchanged in the morning exercise group (CT2), when subjects were exposed to a constant dim light (<10 lux, equivalent to the indoor light intensity at dusk). Similarly, moderate-intensity intermittent aerobic exercise using a bicycle ergometer in the afternoon (CT10) or night (CT16) also delayed the onset of melatonin. However, when the exercise was replaced with 1-h high-intensity aerobic exercise, the melatonin peak levels increased without any changes in phases. In the same study, the authors found that cycling for 2 h in the morning (CT3) delayed the phase of melatonin peak by 1 h. Additionally, Buxton et al. found that high-intensity exercise in the afternoon (CT10.5) advanced the peak phase of melatonin, while exercise at CT1.5, CT5, and CT16.5 delayed the peak phase of melatonin.
These findings suggest that the impact of exercise on the circadian rhythm is influenced not only by the timing of exercise but also by other factors, such as exercise duration, intensity, and volume. However, even when studies use the same exercise protocol with the same timing, type, and intensity, the results may not be entirely consistent, which could be attributed to variations in sleep-wake schedules, small sample sizes, or significant individual differences.
2.3 Disturbed light/dark condition
In daily life, shift work, smartphone overuse, and long-haul flights across time zones may cause acute circadian disruption, suppressed melatonin production, and sleep deprivation. To mitigate circadian disruption, people often attempt to synchronize their activities with natural time, adjust their sleep patterns and diet, or take melatonin supplements. In recent years, more and more attention has been paid to the regulation of exercise on circadian rhythms. However, the impact of a single bout of exercise on circadian rhythms is relatively minor and much weaker than the effects of bright light exposure. Studies have shown that a single bout of exercise does not significantly influence the plasma melatonin. In contrast, regular exercise over a prolonged period has a considerable impact on circadian rhythms, including the expression of core clock genes.
Studies investigating the impact of exercise on circadian disruption have employed various forced phase-shifted sleep-wake schedules. Under a forced schedule of 23.6-h sleep-wake cycle under dim light (<10 lux), Miyazaki et al. found that a 2-h cycling exercise at 3 and 7 h after waking advanced melatonin onset, which facilitate adaptation to the schedule, while the inactive group showed delayed phase of melatonin. A study with an 8-h advanced phase shift has shown that cycling at 3-h and 7-h after waking for 4 consecutive days delayed the onset of melatonin and minimum core body temperature, which is opposite to the direction of phase shift. In contrast, a few hours of intermittent bicycle exercise from CT7 for 3 consecutive days under a 9-hour-delayed sleep-wake schedule caused a delay in the phase of the minimum core body temperature. In addition, no difference was found between evening and morning types in the exercise groups, while the phase delay of the minimum core temperature was larger in the evening type in the control group.
Exercise during sleep time may negatively impact sleep quality due to increased body temperature and alertness. Moderate or high-intensity aerobic cycling for 7 days was thought to synchronize melatonin rhythm with a 9-h delayed jet lag. Light intensity may also play a role in the effect of exercise on circadian rhythm. When subjects were exposed to bright light (>5,000 lux), cycling exercise was found to shift both melatonin and body temperature phases to the same direction as an 8-h advanced or 9-h delayed phase shift, while the control group showed desynchronization between melatonin and sleep-wake cycle. In the study simulating advanced jet lag, the time of exercise was set in the morning and the middle of the night, which may include both advance and delayed regions of the phase-response curves (PRC). As a result, the advanced shift of circadian rhythms in bright light may be due to exercise enhancing the entrainment of light to the circadian rhythm by regulating the 5-HT (5-hydroxytryptamine) system or enhancing the light-sensing ability of the circadian system, which induced a larger advanced shift.
FIGURE 2. The entrainment of circadian rhythms by light and exercise. The central clock oscillator, which regulates rhythms of melatonin and body temperature, is located within the suprachiasmatic nucleus (SCN), while oscillators governing the sleep-wake cycle may exist in brain regions beyond the SCN (Yamanaka and Waterhouse, 2016; Yamanaka, 2020). Two potential pathways for entraining the central circadian rhythm through exercise are depicted: 1, exercise entrains the central clock directly; 2, exercise entrains oscillators in extra-SCN brain regions, which then transmit signals to the SCN. It is important to note that light serves as the most significant zeitgeber. The regulation of circadian rhythms by exercise can be influenced by the intensity of light, as exercise can impact the function of light perception or the entrainment process related to light.
In another interesting study, participants were subjected to a 90-min ultrashort sleep (60 min)-wake (30 min) cycle in a laboratory setting, with low light intensity during wakefulness (50 lux) and sleep (0.5 lux). Under such a condition, each individual conducted a 60-min moderate treadmill per day during one of eight periods of wakefulness (at 3-h intervals from 01:00) for three consecutive days. The PRC of aMT6s (6- sulphatoxymelatonin) onset to exercise was plotted. It was found that aMT6 onset was advanced by exercise at 07:00, 13:00, and 16:00 and delayed by exercise at 19:00 and 22:00. Such pattern was similar to a PRC of bright light. A study using hamster housed under DD showed that a 2-h wheel running during CT4-CT11 advanced the phase, while exercise during CT23−ΔΔCT3 and CT17−ΔΔCT20 delayed it. Comparison of the results between humans and hamsters showed that exercise during the active period often led to opposite phase shifts, possibly due to differences in habitual activity timing. Although the study on ultrashort sleep-wake cycles cannot fully predict the circadian rhythm phase shifts after exercise during normal sleep-wake schedules, it provides guidance for shift workers, who may need to avoid afternoon exercise and strong light exposure.
Regular exercise has been shown to promote synchronization between the sleep-wake cycle and the circadian clock, regardless of the direction of phase shift. The closer the exercise time was to the previous melatonin onset, the larger the phase shift in post-exercise melatonin onset. However, previous studies have been limited by the protocols of schedules and exercise, making it difficult to compare results directly and identify the optimal timing of exercise for preventing or treating circadian disorders. Furthermore, the phenomenon of internal desynchronization suggests that the circadian pacemakers regulating melatonin and body temperature may be independent of the sleep-wake cycle, and that other brain regions outside of the SCN may be involved in regulating the sleep-wake cycle. Further research is needed to investigate the interaction between different circadian pacemakers and whether exercise directly regulates the rhythm of the SCN, or indirectly by influencing the sleep-wake cycle.
In general, exercise plays an important role in regulating circadian rhythms. Exercise at night usually delays the circadian phase, which means it can make it harder to fall asleep at night and wake up in the morning. However, the effect of daytime exercise on circadian rhythms is more controversial. It is important to note that the effects of exercise on circadian rhythms can vary depending on several factors such as exercise intensity, mode, duration, energy supply, and frequency. Therefore, it is essential to consider these variables when designing an exercise regimen that aims to regulate the body’s internal clock.
FIGURE 3. Melatonin rhythm and the phase changes after exercise. Melatonin is produced by the pineal gland. The onset of melatonin typically occurs 2–3 h before sleep onset and peaks in the middle of the night. Exercise at night usually delays the melatonin phase. However, the effect of daytime exercise on the melatonin rhythm is controversial.
Due to variations in detection methods and data processing, the results from studies of sleep-related circadian rhythm markers may be inconsistent. Activity accelerometers are often used for real-time detection of sleep, but only provide a rough estimate of sleep cycles as misjudgment of low-frequency activities may overvalue sleep time. While questionnaires are more convenient and suitable for large sample size research, they are relatively subjective. Additionally, the reliability of questionnaires is lower than that of activity accelerometers when investigating short-term sleep quality due to social factors influencing activity on work-free days. The most common marker of circadian rhythm detection in body fluids is DLMO, which can be detected in blood, saliva, and urine. The criteria for determining the onset of DLMO can be divided into absolute and relative thresholds. Different test samples and calculation methods used to evaluate the phase, amplitude, and period of circadian rhythm may lead to inconsistent results. Therefore, it is difficult to compare the intervention results of exercise on circadian rhythm at the same time systematically.
3 The relationship between exercise timing and diseases related to circadian disorders
Desynchronization between internal circadian rhythms and the environment can lead to various diseases. Disturbances in circadian rhythm not only affect sleep quality but also have a significant impact on energy metabolism, skeletal muscle, and vascular function in the body. Exercise can directly regulate disease-related physiological factors, or indirectly affect disease development by regulating circadian rhythm.
3.1 Sleep disorders
Sleep is mainly regulated by circadian rhythms and sleep-wake homeostasis. Sleep-wake homeostasis is determined as the driving force of sleep regulation, where the longer a person has been awake, the stronger the urge to sleep becomes. When the sleep pressure surpasses a threshold, it triggers sleep onset. The circadian wake-promoting signal interacts with the sleep-wake homeostasis to generate the sleep-wake cycle. Primate experiments have shown that the circadian system plays a stronger role in regulating arousal than sleep-wake homeostasis and SCN lesions lead to an increase in total sleep time, while exercise can interfere with sleep and wake behavior by influencing the input and output of SCN circadian signals and the expression of clock genes.
It is well known that aerobic exercise, such as running for 30 min every morning for 3 weeks, is beneficial to sleep quality, mood, and concentration. High-intensity interval exercise was shown to improve sleep quality as well. Under disrupted light/dark schedules, certain exercise could also improve sleep and facilitate adaptation. In rodent models, increased brain-derived neurotrophic factor (BDNF) is associated with increased slow wave activity during sleep, and its related pathway is activated by endurance exercise. As a nonphotic zeitgeber, regular exercise entrains the circadian rhythms at the molecular and physiological levels. On the other hand, sleep quality and the sleep-wake cycle can also affect exercise performance.
3.2 Cardiovascular diseases
Cardiovascular diseases (CVD) are the leading causes of death worldwide. Disruption of circadian rhythms increase the risk of cardiovascular diseases by increasing blood pressure and platelet aggregation. In a study involving CVD and type 2 diabetes patients who underwent 6 months of exercise, the expression of ALAS1, a CCG, increased in parallel with the diseases’ rehabilitation.. The variations in the CLOCK and BMAL1 genes have been associated with an increased risk of cardiovascular diseases (CVD). Additionally, BMAL1 plays a crucial role in vascular protection and angiogenesis, and its expression restored through exercise in aged endothelial cells.
Furthermore, timed exercise can appropriately reset the circadian system after circadian disruption to preserve cardiovascular health and exercise at evening is good for lowering blood pressure and heart rate. For instance, a 45-min aerobic exercise session in the evening, as opposed to the morning, led to a reduction in blood pressure by decreasing vasomotor sympathetic modulation and systemic vascular resistance in hypertensive individuals. In the case of patients with coronary artery disease, a 12-week regimen of evening walking produced more favorable outcomes than morning walking, resulting in lower levels of low-density lipoprotein cholesterol, fibrinogen, and white blood cell count. The risk of all-cause and CVD mortality was significantly reduced in the midday-afternoon and mixed moderate-to-vigorous intensity physical activity (MVPA) timing groups. Although one study linked morning exercise to a lower risk of CVD and stroke, the mid-afternoon exercise subgroup was not included in this study. Overall, midday -afternoon and evening exercise is more commonly recognized as beneficial to cardiovascular health.
3.3 Cancer
The International Agency on Cancer (IARC) published an assessment in 2019 that classified shift work involving circadian disruption as “possibly carcinogenic to humans”. It is well known that long-term circadian disorders can affect the expression and activity of tumor suppressors and oncogenes, which disrupt homeostasis and increase the likelihood of tumors. The transcription, stability, and activity of p53, one of the most important tumor suppressor proteins, are regulated by BMAL1 and PER2. Additionally, overexpression of Per1 has been demonstrated to block the cell cycle in human cancer cells. Exercise has been found to have a positive impact on cancer prevention and treatment. For example, one study found that people who exercised in the morning had a lower risk of prostate and breast cancer. Patients with rectal cancer who engage in exercise during and after neoadjuvant chemoradiation demonstrate an elevated rate of pathologic complete response. Exercise inhibited the growth of tumors and improved anti-cancer treatment efficacy. The pathway that prevents metastasis can be elicited through exercise-induced increase in cell damage, intratumoral metabolic stress, tumor perfusion and oxygen delivery. In addition, daily exercise at a fixed time was more beneficial for improving fatigue and quality of life in cancer survivors than irregular exercise. The expression of core clock genes is regulated by exercise, but further research is needed to determine whether the effect of core clock genes on tumors is mainly attributed to their function of regulating circadian rhythm. Taking exercise as a non-drug approach to cancer will be an important direction in the development of sports medicine. It is necessary to explore exercise programs to maximize the prevention and treatment of cancer and its complications.
3.4 Metabolic diseases
In recent years, metabolic diseases such as diabetes and cardio- and cerebrovascular diseases are the leading causes of death worldwide. Circadian disruption is a risk factor for metabolic syndrome. Exercise has been shown to improve glucose and lipid metabolism, increase insulin sensitivity, and prevent or even reverse hyperglycemia, hyperlipidemia and hypercholesterolemia, which can reduce the risk of metabolic diseases and related complications partly by regulating circadian rhythms. A study found that 6-week moderate-intensity cycling before breakfast was three times more beneficial for lipid utilization than exercise after breakfast, and had greater benefits for improved insulin sensitivity and blood glucose. This may be related to lower insulin levels during fasting exercise and the body’s tendency to use fat for the need of energy. Moreover, exercise can lead to higher irisin levels, which can promote the browning of adipocytes. This process increases the interaction between fat and muscle tissue, which can lead to improved metabolic function. Extensive changes in the expression of core clock genes including Bmal1, Clock, Cry1/2, Per1/2/3, Rev-Erbα, and Rorα have been observed after acute endurance exercise in mice. After early daytime exercise, but not early nighttime exercise, circadian associated repressor of transcription (Ciart) and Per1 transcript were induced and involved in the regulation of skeletal muscle and liver metabolism. Transcriptome and metabolome analysis in mice showed that exercise during the early active period resulted in immediate changes to carbohydrate and adipose tissue metabolism, increased expression of genes associated with angiogenesis and glycolysis, and increased expression of genes associated with fatty acid oxidation, branched amino acid catabolism, and ketone metabolism.
The above evidence suggests that exercise during the early active period may be more effective in treating metabolic disorders in both mice and humans. Nevertheless, it is important to acknowledge that several studies have indicated potential advantages of afternoon exercise in individuals with metabolic challenges. For example, in individuals with type 1 diabetes, post-exercise blood glucose levels were notably lower following afternoon resistance exercise (RE) compared to fasting morning RE. In men with type 2 diabetes, a 2-week regimen of afternoon high-intensity interval training (HIIT) not only led to more substantial improvements in blood glucose levels than morning HIIT but also resulted in an increase in thyroid-stimulating hormone (TSH) levels, accompanied by enhancements in mitochondrial content and skeletal muscle lipid profiles. Additionally, in overweight/obese men, evening exercise was associated with improved glycemic control and a partial reversal of metabolic changes induced by a high-fat diet (HFD), whereas morning exercise did not yield the same outcomes. These conflicting results indicate that the relationship between the timing of exercise and its effects on metabolism is complex and may vary depending on the exercise protocols, the population being studied and the specific metabolic outcome being measured. To gain a more comprehensive understanding of the relationship between exercise timing and metabolism, additional studies with more diverse experimental populations and time nodes are required.
3.5 Other diseases
Circadian disruption has been linked to diseases of all systems in the body, such as the musculoskeletal system, nervous system, and digestive system. Skeletal muscle is highly susceptible to aging, which leads to a loss of both mass and strength over time in elderly people. This condition, known as sarcopenia, often results in falls, fractures, physical disabilities, and other harmful consequences. Besides aging, several other factors, including inadequate nutrition, inflammation, and disrupted circadian rhythms, may contribute to sarcopenia. Inflammation and circadian rhythms are well known to interact with each other, with proinflammatory factors impairing the function of clock genes that regulate muscle function and phenotype. Specifically, TNF-α upregulates the expression of core clock genes Bmal1 and Rorα while decreasing Rev-erbα, leading to disrupted circadian rhythms in skeletal muscle. Disruption of circadian rhythms can also intensify the oxidative stress and damage of neurons by compromising the neuroprotective effect of melatonin. Long-term circadian disruption can lead to cognitive impairment or dementia, and increase the risk of neurodegenerative diseases such as Alzheimer’s disease. It can also cause inflammation in the digestive system, leading to inflammatory bowel disease.
As a non-photic factor regulating circadian rhythm, exercise can affect human health by regulating skeletal muscle and cardiopulmonary functions. Disruption of circadian rhythms in skeletal muscles is associated with an increased risk of chronic diseases, and the regulation of circadian rhythm-involved diseases by exercise is partly achieved by the regulation of skeletal muscle. Maintaining a normal circadian rhythm is important for promoting skeletal muscle regeneration and repair, which can help prevent or alleviate muscular atrophy. Both acute and long-term exercise can regulate the expression of clock genes in skeletal muscle and may improve circadian rhythms. Even low-intensity aerobic exercise can entrain the circadian rhythm of skeletal muscle. Exercise can also improve vascular health, whose deficiency is a potential risk factor for sarcopenia, by increasing the wall shear stress of arteries, stimulating endothelial cells to release nitric oxide (NO), and promoting vasodilation to improve nutrient supply to skeletal muscle. In addition, the timing of exercise has an impact on physical performance, as peak performance of aerobic exercise has been reported to occur later in the day, which is partly contributed by the diurnal fluctuations in mitochondrial function. Engaging in combined strength and endurance training during the evening may lead to greater gains in muscle mass compared to morning sessions. This suggests that exercise can be an effective strategy for preventing and managing sarcopenia by improving skeletal muscle function partly via maintaining circadian rhythms. However, further research is needed to fully understand the molecular mechanisms underlying the relationship between circadian rhythms, inflammation, and skeletal muscle function, and to identify optimal exercise interventions for preventing or treating sarcopenia.
The time of day is an important factor in maximizing the health benefits of exercise for disease prevention and treatment. In summary, regular physical exercise plays a crucial role in preventing loss of muscle mass and strength by improving the immune system and vascular endothelial function, as well as synchronizing circadian rhythms of blood vessels and muscles. Further research is needed to better understand the mechanisms underlying the relationship between circadian rhythms, exercise, and diseases.
4 Conclusion
Exercise has garnered increasing attention as a significant non-photic zeitgeber. Summarized findings from this review of human data suggest that regular exercise can regulate the expression of clock genes, synchronize the circadian rhythm, and improve sleep health, metabolic and immune functions, thereby preventing and treating various diseases related to circadian disorder. Exercise at night usually delays the circadian phase, and the effect of daytime exercise on circadian rhythms is controversial. Midday-afternoon physical activity is associated with a lower all-cause and cardiovascular disease mortality, while morning exercise is connected to a decreased risk of cancer and improved lipid metabolism. The mechanism by which exercise affects the circadian rhythm needs to be further studied. In conclusion, determining the best timing and intensity of exercise for different populations is crucial to maximize the health benefits. Exercise holds great promise as a non-pharmacological intervention for preventing and treating circadian rhythm disorders and related diseases.
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