You’ve probably heard a lot about circadian rhythms in terms of sleep/wake patterns and eating patterns. But, did you know that your circadian rhythms do much more than that? Our entire body is controlled by diurnal oscillations, which is why some activities seem easier at certain times of the day. This influence has the potential to impact the best times to take medication, eat your meals, and take your nutritional supplements.
Many complementary medicine traditions, such as Ayurveda and Traditional Chinese Medicine, incorporate circadian rhythms in their treatments. Western medicine is starting to recognize the power of these rhythms to both facilitate treatments and contribute to dysfunction when they are in disarray. Let’s learn more about the influence of these powerful rhythms.
The Power and Importance of the Circadian Rhythm
Every process in your body, including reacting to oxidative stress, the composition of your microbiome, and the levels of your intracellular proteins, all have some type of oscillating pattern that fits within a daily 24-hour rhythm. Your body upregulates certain components of metabolism and mechanisms required for self-defense during the hours it expects to need them and down-regulates them during periods of rest.
There are several circadian transcription factors that control positive and negative feedback loops in the cells to determine functions of key organs and systems, including your heart, lungs, immune system, and metabolism, as well as the intracellular processes, such as cellular respiration and DNA repair. In fact, this internal clock system regulates roughly one-third of your body’s entire gene activity! Your genetic code regulating these systems affects your body’s timing for peak performance, such as whether you are a morning person or a night owl.
The central regulator of your circadian rhythms is the suprachiasmatic nucleus, SCN, which is found in the hypothalamus in your brain. It does this largely through controlling the secretion of melatonin, which is the main circadian hormone.
Health problems associated with circadian rhythm disruption include:
– Cardiovascular disease
– Jet lag
– Metabolic disorders
– Neurological disorders
– Psychiatric disorders
– Social jet lag
Disruptions in the circadian rhythm also reduce your life expectancy. Furthermore, as you age, you become more sensitive to disruptions in the circadian rhythms—and less sensitive to synchronization techniques.
Metabolism, Dietary Enzymes, and Feeding Times
Circadian rhythms regulate your digestion and metabolism. In the proper rhythm, gastric emptying, thermogenesis, and motility rates reach their peak in the morning. During the active phase of the day, bile acids and nutrient transporters are regulated and more active, as is energy metabolism. Conversely, detoxification becomes more active during the rest phase.
Several factors involved in regulating metabolism have a close relationship with the core clock:
– AMPK: a signal of low cellular energy and one of the most important sensors of nutrient status
– PGC-1a: regulates energy metabolism
– PPARa: regulates genes involved in glucose and lipid metabolism
– REV-ERBa: involved in the differentiation of adipocytes
– RORa: regulates lipid storage in skeletal muscle and lipogenesis
– SIRT1: a histone deacetylase that helps to signal transcription and stability of genes if dependent upon NAD+
For example, CLOCK-BMAL1 and omega-3 fatty acids activate some nuclear receptors involved in energy homeostasis, including PPARs. Glycogen synthase functions during the active period and glycogen phosphorylase during the resting period. Polymorphisms and other variants in certain genes related to circadian rhythms are associated with obesity and metabolic disease, some of which are affected by certain diets, such as higher carbohydrate intake or higher fat intake.
Blood glucose and lipid regulation are dependent upon diurnal rhythms as well. Consuming a high-fat meal raises triglycerides in the blood more at night than the same meal consumed during the day. Important adipokines, including leptin and adiponectin, also have diurnal rhythms.
To break it down, during the day when you are awake, you have:
– Adiponectin production
– Decreased synthesis of cholesterol
– Glycolytic metabolism
– Increased synthesis of bile acids and glycogen
– Increased uptake of fatty acids
– Secretion of insulin
During night when you are fasting and sleeping, you have:
– Biogenesis of mitochondria
– Catabolism of lipid
– Gluconeogenesis and glycogenolysis
– Leptin and glucagon secretion
– Oxidative metabolism
It is not just the human cells in your body that have a daily rhythm; your microbiota impacts—and is impacted by—circadian rhythms as well. Melatonin exists in the gut in levels that are about 400 times the level in the pineal gland in the brain where it acts as a modulator of bowel function. One study found that melatonin might impact the microbiota in the gut as well as regulate other components of the circadian rhythm, like sleep.
In this study, colonies of a specific commensal bacterium, Enterobacter aerogenes, grew faster and experienced increased swarming and motility when exposed to melatonin in a dose-dependent relationship. The biggest response matched the levels of melatonin typically found in the human gut. This finding provides potential evidence that the microbiome might synchronize with the human host, and that this might happen through melatonin communication.
Another study found diurnal changes in 60 percent of the microbial composition of a mouse model, including Bacteroidales, Clostridiales, and Lactobacillales. There were higher numbers during the resting phase compared to the active phase. The diurnal fluctuations match the microbial functions that the microbiota perform. For example, during the active phase, the microbiota performing energy harvest, cell growth, and DNA repair are more active, while bacteria dealing with detoxification see a greater abundance during the resting phase. For these rhythms to occur, there had to be a functional circadian clock in the host. Food intake, feeding times, and sleep disturbances impacted the diurnal patterns of the microbiome. This change could contribute to dysbiosis and be one reason for the link between dysbiosis and metabolic disease.
Treating dysbiosis might help with modulating the circadian clock. One study postulated that the beneficial effects of probiotics on patients with IBS was due to the impact on melatonin. The randomized, double-blind, placebo-controlled trial gave one group of IBS patients a particular probiotic, VSL#3, while the control group had a placebo. The male treated patients experienced a significant increase in their morning melatonin levels after taking VSL#3 (5.43 pg/ml increased to 9.74 pg/ml), but females and the combined group did not have any significant changes. This increase in melatonin levels correlated with increased satisfaction in bowel habits. The group who had a normal circadian rhythm pre-treatment also experienced an increase in morning melatonin and better satisfaction of bowel habits. Thus, the researchers postulated that the efficacy of the probiotics came from the impact on melatonin metabolism and secretion.
Circadian rhythms might also impact the severity of an allergic response to food. In a study in an ovalbumin food allergy mouse model, the severity of symptoms was higher in the group that was exposed in the light period (rest phase) rather than the dark period (active phase). The light period group had a higher absorption of the allergen and a higher intestinal permeability. Timing and type of food also impacts the microbial makeup and its circadian rhythms.
Diet, Meal Times, and Circadian Rhythm Disruption
High-fat diets might interrupt the feeding and fasting cycles, which might negatively impact the circadian rhythms. For example, a high-fat diet stopped the normal oscillation of NAD+ in a mouse model. Amino acids, including lysine, did not change their oscillation patterns, while there was amplification in coenzyme A, which is involved in beta-oxidation and the syntheses of fatty acids. It also caused a phase shift. However, these changes were reversible through changing the diet. Another mouse study found that time-restricted feeding mitigates some of the negative metabolic changes that occur with eating ad libitum, even on the same high-fat diet.
Studies have found that meal timing relates to obesity and metabolic syndrome. In a systematic review on the subject, researchers found that in observational studies, participants who ate lunch after 3 PM were twice as likely to have a reduced response to bariatric surgery, regardless of the actual composition of the foods. In randomized control trials, participants lost more weight when they had the bulk of their calories in the early part of the day rather than at dinner. There was also an association between hyperglycemia and diabetes with those who ate the bulk of their calories at the end of the day. Feeding times can also lead to a shift of the peripheral circadian genes, which could disrupt the clock balance. It can also reset the phase through timed feeding.
Certain nutrients also impact your circadian rhythm. For example, adenosine, retinoic acid, and caffeine can shift circadian rhythms, and thiamine-deficiency might lead to a disruption. Alcohol alters your natural rhythms in several ways, including through changes in hormone secretion, body temperature, and the ability to sleep. High-salt diets increase the amplitude of the normal circadian rhythms. One study found oscillations in vitamin D, calcium, and calcium-phosphorus ratio. In this study, diabetic patient and healthy controls had their highest levels of vitamin D at noon, while their lowest levels were at 6 AM. Diabetic patients experienced a phase shift in these nutrients compared to the controls.
Proanthocyanidins, which are one of the biggest classes of polyphenols, have the potential to regulate the peripheral components of the circadian rhythms. Polyphenols are found in a variety of plant-based foods, including fruits, cocoa, nuts, vegetables, red wine, and tea. In a mouse model study, both healthy and obese rats were given chow supplemented with different doses of grape seed proanthocyanidin extract (GSPE). The obese group was fed a diet comprised of higher-fat diet (comprised of 23.4 percent fat, 35.2 percent carbohydrates, and 11.7 percent protein), and one group was given 25 mg of the GSPE per kg body weight.
The rats given GSPE had an increased expression of two important circadian genes in the liver: Clock and Per2 in a dose-dependent fashion. The increase became significant at 25 and 50 mg GSPE/kg/body weight. In the mWAT, all of the circadian genes studied were modulated by GSPE, with Clock, BMal1, and Per2 increased at 50 mg, while the genes that Clock and Bmal1 regulate, such as Rora, Rev-erba, and Nampt, were repressed. HmgCoAR were not modulated. In the intestines, Bmal1 and HmgCoAR were modulated, with all doses increased Bmal1 and 25 mg/kg body weight increased HmgCoAR. They found that these modulations in the main and periphery circadian genes occurred in the obese mice as well, demonstrating that the polyphenols were able to counteract disruption in the rhythm that occurs with obesity. Another study confirmed this, but that the timing of administration might impact the efficacy. This is just another reason why eating a colorful diet rich in a variety of phytochemicals is so important.
Liver, Metabolism, Detox Capabilities, and Diurnal Oscillation
There are three PARbZip transcription factors controlled by Clock and Bmal1 in the liver that regulate detoxification: D-site binding protein, thyrotrophic embryonic factor, and hepatic leukemia factor. Studies have found that knockout mice without these genes are unable to metabolize xenobiotics. This is because these genes activate cytochrome P450 oxidoreductase. They also power the daily oscillations of these pathways, especially those controlled by the CYP systems.
Enzymes affected in the liver by the circadian master control include:
– Metabolism of carbohydrates: PEPCK, PKLR, KLF10
– Metabolism of lipids: PPAR, PGC1, LXR
– Metabolism of amino acids: KLF15, OCD
– Detoxification: TEF, HLF, DBD
– Plasma protein synthesis: TFPI
– Metabolism of bile acids: SREBP, INSIG
Diet and expected function determines some of this effect. For example, some enzymes used to metabolize cholesterol, such as HMG-CoA reductase peaks at times where the body does not expect to consume cholesterol.
Bile acids play an important role in the digestion and absorption of dietary fat, fat-soluble vitamins, steroids, and certain drugs. They also play an important role as signaling molecules for metabolism and immune modulation. Bile acids also follow a circadian rhythm, controlled by the central clock. CYP7A1, the gene that regulates the synthesis of bile acids, peaks in the middle of the active period and sees its minimum in the middle of the rest period. In humans, there are two peaks: 1:00 PM and 9:00 PM. Most bile acid synthesis occurs right after you eat.
There are three phases of detox, and each one has its own regular schedule. Phase I of detoxification requires the CYP genes, of which there are 18 different families. Humans have a total of 57 CYP genes, with different families responsible for the metabolism of different molecules. CYP1 genes handle the majority of xenobiotics and drugs. CYP enzymes increase their activity during the active phase. Conversely, phase II and III enzymes reach their peak during the rest phase. This impacts the ability to metabolize drugs, and it also might impact your ability to detoxify other xenobiotics. For many drugs, morning consumption makes it easier to absorb the drug, since it is the time at which bile acid synthesis hits a peak, which helps to facilitate the absorption and transportation of the drug.
Matching medication usage with the natural circadian rhythms has a major impact on its efficacy and safety. A meta-analysis found that taking medications on a schedule that matches circadian cycles led to a 5-fold enhanced tolerance of the drug, as well as twice the efficacy of the drug, compared to the same treatment not on a schedule. Similar instances occur with metabolism and the detoxification of other xenobiotics.
Maximizing Supplement Use Through Circadian Rhythms
Certain medications have been shown to be more effective and less toxic when given at different times of the day, such as iummunomodulators, glucocorticoid steroids, insulin for type-1 diabetics, cancer drugs, and more. For example, P-glycoprotein or P-gp mRNA expression in the liver and intestines, which plays a role in the detoxification of a certain cancer medication known as irinotecan, was found to have changes dependent upon time of day. The efficacy and tolerance of the drug related to the diurnal changes, with the timing of highest expression of the mRNA corresponding to the best tolerability and effectiveness of the drug. This finding has led to the development of chronopharmacology, or taking medication at appropriate times in the circadian rhythm. Chronopharmacology takes into account the daily timing of important components of drug metabolism like:
– Absorption: timing of blood flow, gut motility, emptying of the gut, transporters of the medication, and pH
– Metabolism: cytochrome P450 enzyme activity, conjugating enzyme activity, ATP-binding cassette transporters
– Genes targeted by drugs: neural receptors, HMG-CoA reductase
– Distribution: lipophilicity, affinity for binding with albumin, concentration
– Excretion: glomerular filtration rate, renal blood flow, function of the kidneys
These known body timings might also impact at what times you should take certain nutritional supplementation. For example, the timing of a calcium supplement might impact its effect on bone resorption. In one study on 18 premenopausal women, the patients took calcium supplements at either 8:00 AM or 11:00 PM. After 14 days, urine collections were studied to review markers of bone resorption. They found that the time of day had a significant effect, with evening calcium intake suppressing the usual nightly increase in parathyroid hormone and markers of the bone resorption. Morning supplementation had no impact. Therefore, they found that taking calcium in the evening could suppress bone resorption.
Although research into timing of supplement dosage is not as rich as that reviewing the impact on medication, the diurnal rhythms of your digestion, metabolism, and detoxification systems will impact the efficacy of any substances you take, including your nutritional supplements. As such, it is beneficial to bear this in mind, and ensure you maintain a balanced and functional circadian rhythm.
What You Can Do
The most important action to take is to ensure you take care to keep your circadian rhythms functional. You can test for markers, such as cortisol, melatonin, and body temperature, to determine if you are out of balance.
A few simple actions to take to maintain a balanced rhythm include:
- Avoid exercising late in the day
- Avoid foods that can induce a phase shift (i.e. soybean oil and cornstarch)
- Consume lots of antioxidant-rich fruits and vegetables, especially those rich in polyphenols
- Do not eat late at night
- Eat your biggest meals early in the day
- Follow a regular meal schedule within a restricted period of time (around 8 hours), as timed restricted feeding of the same high-fat meal was shown to produce better metabolic outcomes than eating throughout the day and a 5-hour shift in meal timing has led to a similar shift in circadian rhythms
- Get a good night’s sleep and avoid night shift work when possible
- Limit caffeine, which has been shown to shift circadian rhythms
- Make sure to expose yourself to sunlight during the day
- Minimize your light exposure at night
Certain foods can influence your melatonin levels, which in turn might help to regulate your circadian rhythms. For example, tart cherry juice, which contains melatonin, may lead to better sleep quality. In a double-blind, placebo-controlled study, 20 subjects drank two servings of either tart cherry juice concentrate or a placebo for a week, served within 30 minutes of waking and prior to their evening meal. Those who consumed the cherry juice had a significantly higher melatonin level, as well as significant increase in sleep efficiency, total sleep time, and time in bed. The timing of the melatonin circadian rhythm did not show a difference, but there were a higher mesor and amplitude. Although the researchers found the cherries did not regulate the circadian rhythms in the healthy population, they do postulate that it might help others, such as those with disturbed sleep, and that it deserves further study.
In addition to generally maintaining a functional circadian rhythm, you can also consider the impact of your enzymes, digestion and absorption, and metabolism when deciding at what time to take certain supplements (and medication if you take any). For example, you most likely want to take your calcium supplements in the evening, based on the study above. As always, discuss with a doctor before proceeding with any changes.
Rainbow Foods & Supplement Course
Did this pique your interest to learn more about the best timing for food and supplements? If so, please join me this January for the Rainbow Foods & Supplements Course, where I’ll teach you even more the emerging, trending health findings and scientific research in the food, eating, and supplement fields!