Intro to Circadian rhythm
Our body keeps time. The rhythms of our body roughly match that of the earth’s rotation. These rhythms are cycles the body follows within a 24 hour day and it repeats these rhythms day after day. The circadian system is a network of interacting neural and hormonal pathways that entails more than driving the sleep-wake cycle, they include hormonal activity, body temperature, digestion, and immune function. Every organ, even every cell, has its own daily timed circadian rhythms, certain proteins interact with the cells in the body, instructing them to be more active or to slow down.
Liken circadian rhythm as being like your dog or cat that expects to get fed at a certain time every day and lets you know if the regular timing isn’t met. Just like your pet, your body gets out of sorts when certain events don’t happen as expected.
Being out of sync with one’s circadian rhythms (circadian arrythmia) has been associated with obesity, cardiovascular disease, diabetes, gastrointestinal problems, neurodegenerative disorders (including dementia), skin issues and more.
How circadian rhythm works
Light enters the eyes (even through closed eyelids during sleep), stimulating a signal in the back of the retina and down a nerve tract to the circadian clock in the brain.
Circadian photoentrainment is the process by which the brain’s internal clock becomes synchronized with the daily external cycle of light and dark. This process is mediated by retinal ganglion cells (RGCs) which are a type of neuron located near the inner surface of the retina of the eye. RGCs are separate from rod and cone photoreceptors of the eyes. RGCs send signals to the region of the brain that houses the circadian pacemaker.
The body’s master clock is a structure called the suprachiasmatic nucleus (SCN). The SCN contains about 20,000 nerve cells and receives the input from the eyes.
As the eyes perceive the bright light of day or the darkness of night, the SCN tells the cells to act accordingly. Light is what keeps circadian rhythms in sync (or disrupted) within a 24-hour day.
Chemicals in the brain adjust a number of factors in the body, such as:
- arousal and awakeness
The body’s circadian rhythms control the sleep-wake cycle. As darkness sets in, the body’s biological clock instructs the cells to slow down. A key driver of the body’s circadian rhythms is melatonin, the sleepiness hormone. When the evening becomes dark, the hormone melatonin starts to rise and allows sleep to occur. Melatonin peaks around 2–4 A.M. and then reduces by morning, when the hormone cortisol starts to be released, allowing for wakefulness.
But the circadian rhythms control more than sleepiness-wakefulness, and the end result directly affects our health.
Circadian Rhythm and APOE4
APOE4 is the ancestral gene. For the vast majority of time, all humans were ApoEε4/4 as were the primates we evolved from. The other two alleles, ε3 and ε2, arose recently in evolutionary terms. As the ancestral gene, it’s been suggested that ApoE4s are ill-adapted to modern lifestyle/diet. Without electrical light, high-speed travel, constant food availability and around the clock work-life schedules, our ancestors' were in circadian harmony with their environment. Our ancestors were active during daylight hours and resting/sleeping during the darkness of night. But modern lifestyle ignores this day/night harmony and instead is filled with artificial light, ingested stimulants, environmental irritants, late night snacking, around the clock work demands and added stress.
Chronic circadian misalignment is associated with an increased risk of metabolic syndrome, cardiovascular disease, neurological conditions, and cancer. ApoE4s are particularly concerned with shortened longevity, cardiovascular issues, and Alzheimer’s Disease.
With particular emphasis on Alzheimer’s Disease, numerous studies have shown that cognitive processing is gated over the circadian cycle and memory retrieval is disrupted when the organization of body clock timing is compromised thereby contributing to cognitive deficits.
Circadian dysfunction not only contributes, but is also a symptom in Alzheimer’s Disease. Individuals with Alzheimer’s Disease often confuse morning and evening with sleep disturbances. They also often act differently in the fading light of late afternoon or early evening a condition called sundowning, or sundown syndrome.
Circadian Rhythm Disruptors
Some things that disrupt our circadian rhythms
Light, especially blue light exposure close to bedtime
Sunlight contains many shades of red, orange, yellow, green and blue light rays. Combined, the full spectrum of colored visible light rays creates what we call “white light” or sunlight.
The different colors have different energy and wavelengths. On one end of the visible light spectrum is red light which has long wavelengths and less energy. On the other end is blue light which has short wavelengths and high energy.
The sun is the main source of blue light and the reason why the sky is blue. But of late blue light exposure has increased with artificial sources: digital screens (TVs, computers, laptops, smart phones and tablets), electronic devices, and fluorescent, CFL (compact fluorescent light) and LED lighting. We are spending more time than ever before exposed to these devices and at close proximity which is concerning since our eyes aren’t designed to be good at blocking blue light.
Light exposure affects sleep-wake cycle by delaying and decreasing melatonin secretion. Melatonin is called the sleepiness hormone but it’s more, it also is the body’s first line of defense against oxidative stress, boosts the body’s immune systems and controls the output of growth and sex hormones. Melatonin levels decline gradually over the life-span anyway, aggravating this decline with blue light exposure adds fuel to the fire.
The Centers for Disease Control and Prevention (CDC) notes that the circadian clock is most sensitive around 2 hours before a person’s usual bedtime. Exposure to bright or blue light at this time can shift the need to sleep later, resulting in a person to get sleepy and fall asleep later in the evening and wake up later in the morning, out of alignment with the body’s natural circadian rhythm.
As just addressed in the above section on light, melatonin release is an important signal for the body, telling it to slow down for rest and repair.
But stress can cause the body to release counteracting hormones, such as adrenaline and cortisol. These hormones raise the heart rate to circulate blood to vital organs and muscles more efficiently, preparing the body to take immediate action if necessary, a reaction known as the flight or flight response. Chronic feelings of stress can cause the nervous system to maintain a heightened state of arousal for extended periods and result in sleep deprivation. Insufficient sleep can then cause further stress.
While melatonin is the hormone that tells the body to sleep, cortisol is the hormone that wakes us up. Melatonin and cortisol are in an opposite relationship; when melatonin is high, cortisol should be low and vice versa but when elevated, cortisol suppresses melatonin production. When either of these hormones get out of balance, our ability to sleep is affected.
Any type of stressor can raise cortisol levels including chemical, toxic, psychological and emotional stressors. Blood sugar problems, sleep disorders like sleep apnea, as well as chronic infections and allergies can also cause elevated levels. See Stress
Chronic feelings of stress can cause the nervous system to maintain a heightened state of arousal for extended periods and result in sleep deprivation. Insufficient sleep can then cause further stress.
Additionally, these studies Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy (Stefan Tholen et al, 2022) and The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell-differentiation commitment ((Zhi-Bo Zhang et al, 8 Aug 2022) suggest that stress-induced circadian clock disruptions influence weight gain disrupting metabolic health which in turn further interferes with a good night’s sleep.
Caffeine late in the day
Caffeine is a stimulant, thereby potentially interfering with sleep. Caffeine can be found in coffee, certain teas, some soft drinks, energy drinks, cocoa beans/chocolate, even over-the-counter medications that contain caffeine, such as Excedrin.
Half-life is the amount of time it takes for a quantity of a substance to be reduced to half the original amount. The mean half-life of caffeine in plasma of healthy individuals is about 5 hours. So since an 8 ounce cup of coffee has 95 mg of caffeine, if you consume one cup of coffee, after 5 hours you’ll still have 47.5 mg of caffeine in your body. However, depending on the person, caffeine's elimination half-life may range between 1.5 and 9.5 hours [Source: Pharmacology of Caffeine Additionally, the other half of caffeine that you consume can last much longer than 5 hours. People with caffeine sensitivities might feel symptoms for several hours or even a few days after consumption.
The American Academy of Sleep Medicine recommends that you don’t consume caffeine at least six hours before bedtime. [Source: Sleep and caffeine
In addition to containing caffeine, albeit less than the levels found in drinks such as coffee or tea, chocolate also contains theobromine, a mild stimulant. Although the effects of theobromine are mild, some people are more sensitive than other and they last longer than caffeine. The compound has a half-life of 7.2 hours. [Source: Health Benefits of Methylxanthines in Cacao and Chocolate (Rafael Franco et al, 18 Oct 2013)
Sweets / too many carbohydrates
When consumed, sugar and carbohydrates produce high levels of glucose (blood sugar). In response to this, insulin is released by the pancreas. The primary function of the hormone cortisol is to balance the effect of insulin, so if insulin is chronically high, so is cortisol. That evening dessert not only spikes insulin but cortisol too. Cortisol levels should be trending down in the evening, so that late day insulin/cortisol spike makes it harder to fall asleep.
Prescription and over-the-counter drugs
Melatonin uses the same passageways as serotonin so if you are taking something that is blocking serotonin, it will block melatonin as well. Also, certain drugs can cause the depletion of melatonin, including: NSAIDS, antidepressants, betablockers and estrogen containing medications. As mentioned in the section on caffeine, some over-the-counter medications contain caffeine, such as Excedrin.
By its nature, working late shifts, split shifts, or throughout the night is disruptive to the body’s circadian rhythms. The effects appear to last after an person’s schedule has returned to working during the day.
According to David Earnest, professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M University College of Medicine. “When our internal body clocks are synchronized properly, they coordinate all our biological processes to occur at the right time of day or night. When our body clocks are misaligned, whether through shift work or other disruptions, that provides for changes in physiology, biochemical processes and various behaviors.” His research also found that the health impacts of shift work persist over time. The sleep-wake cycles of subjects on shift work schedules never truly returned to normal, even after subsequent exposure to a regular schedule. [Source: Shift Work Has Long-Term Negative Health Consequences (Texas A&M University Health Science Center, 16 Aug 2022)
Trying to catch up on sleep over the weekend
Despite the thought a person can catch up on sleep, research has shown that it can take up to four days to recover from one hour of lost sleep and up to nine days to eliminate sleep debt. [Source: Estimating individual optimal sleep duration and potential sleep debt. Scientific reports (S Kitamura et al, 2016)
While sleeping in for a morning or two may help, it’s not enough. According to this study, Ad libitum Weekend Recovery Sleep Fails to Prevent Metabolic Dysregulation during a Repeating Pattern of Insufficient Sleep and Weekend Recovery Sleep (Christopher M. Depner et al, 18 Mar 2019) weekend recovery sleep failed to prevent later timing of energy intake, weight gain, or reduced insulin sensitivity during recurrent short sleep following the weekend.
Quoting David Earnest, professor in the Department of Neuroscience and Experimental Therapeutics at the Texas A&M University College of Medicine, “Even those of us who do work regular schedules have a tendency to stay up late on the weekends, producing what is known as ‘social jet lag,’ which similarly unwinds our body clocks so they no longer keep accurate time. All this can lead to the same effects on human health as shift work.” [Source: Shift Work Has Long-Term Negative Health Consequences (Texas A&M University Health Science Center, 16 Aug 2022) Additionally, each hour of social jet lag is associated with an 11% increase in heart disease risk, and social jet lag is also linked with fatigue, poor mood, and worsened overall health.
Flying through two or more time zones can upset your body’s established circadian rhythms. This is known as jet lag.
Late night eating
Our body’s insulin sensitivity follows a circadian rhythm. We are most insulin sensitive in the morning and insulin resistant at night. Late night eating/snacking goes against our body’s natural rhythm leading to weight gain. Additionally, the muscles that digest food are working when they should be resting which can delay falling asleep and can prevent you from getting very important deep sleep which is when the brain's glymphatic system “cleans” itself of toxins.
Strategies to improve circadian synchronization
Some things help realign with our circadian rhythms.
Perhaps the best way to recalibrate your circadian rhythm is by going camping. Living to the cycles of the sun and darkness for a few days will reset your internal clock.
Early morning light therapy
Bathe yourself in morning light. Expose your eyes (but don’t stare at the sun) to sunlight first thing in the morning for 15 minutes (30 if cloudy) this will start the hormone cascade. Throw open your curtains as soon as you wake; the sunlight will help suppress melatonin production.
Can’t do that? Buy a programmable blue-light box and set it to start brightening 15 minutes before your alarm goes off. Look for a box with a rating of 3,000 to 10,000 lux which will feel about as bright as what you’d experience outside on a cloudy day.
Reduce blue light exposure
Incandescent light bulbs emit far less blue light than other alternatives but incandescent light bulbs will no longer be available for purchase after August 1, 2023. Fortunately, now there are LED light bulbs which emit less blue light than when first introduced.
Fire/candles also emit less blue light, but they come with fire hazards and breathing smoke from any source can be unhealthy. Burning candles made of paraffin releases soot. Burning scented candles can release volatile organic compounds like formaldehyde. If you plan on using candles regularly, it’s a good idea to burn them in a ventilated room to minimize the amount of smoke you breathe in.
An easier answer is to wear blue-blocking glasses under artificial lights or while working on a computer/electronic device after the sun goes down.
Another suggestion is to install an app that filters the blue/green wavelength on your computer/phone at night.
Keep it dark when sleeping
Our eyelids are translucent and studies have shown that even a small amount of light perceived through closed eyelids can disrupt circadian rhythm and your sleep quality. Keep the bedroom as dark as possible at night. Consider adding blackout (light blocking) curtains over all windows or cover your eyes with a contoured eye mask.
Turn off or cover any electronic devices that glow or put out any light. Your room should ideally be pitch black all night. Consider replacing digital clocks with analogue clocks. If you must get up during the night, don’t turn on the main lights. If you really need light to go to the bathroom, look at having a low wattage red nightlight or use a red light flashlight/headlamp.
Stick to a schedule
Staying up late on the weekends is enticing, but as discussed above it will catch up with you. It’s best to go to bed and wake up at the same time, give or take 15 minutes, seven days a week.
Restrict the use of caffeine, alcohol, and tobacco. Keep the bedroom as quiet as possible while sleeping.
Meal Timing/Time restricted eating
It has been shown that meal timing, quality, and quantity can prevent circadian disruption and even induce circadian resynchronization. Time-restricted eating is a dietary pattern that optimizes circadian elements such as daily rhythms for insulin peaks and glucose tolerance. Although more research is necessary to confirm, ideal eating hours seem to be between 8 am and 6 pm. This schedule respects eating when it makes the most sense, given the daily waxing and waning of various hormones like cortisol, insulin, and leptin. Ideally, the most energy-dense high-quality food should be consumed in the morning and an overnight fast (both food and caloric drinks) of at least 12 hours should be followed.
As discussed above, melatonin is a hormone produced by the body and we can increase melatonin production naturally by such strategies as reducing light exposure at night, avoiding caffeine, and exposing yourself to natural daylight.
But sometimes people need help, especially as they get older when melatonin production appears to decline. Supplemental melatonin is not a sleeping pill, but can be used as a as a sleep inducer and help synchronize with the circadian rhythms. Recognize that melatonin will not make up for bad habits like eating heavy meals, drinking alcohol too close to bedtime, using electronics late at night, or keeping an inconsistent bedtime.
Melatonin is best consumed in low doses (0.5 milligrams to 1 milligram) in the 30 to 60 minutes leading up to your intended bedtime.
Deeper Dive into the science
Circadian Rhythm and Alzheimer’s Disease/the Brain
Predictor of cognitive impairment: metabolic syndrome or circadian syndrome(Yang Liu et al, 4 Jul 2023) From conclusions:
- Individuals with CircS [circadian syndrome] alone or both MetS [metabolic syndrome] and CircS have a high risk of cognitive impairment. The association was even stronger in participants with CircS alone than those with both MetS and CircS, suggesting CircS probably have a stronger association with cognitive functioning than MetS and could be a better predictor for cognitive impairment.
Gut microbiota and circadian rhythm in Alzheimer’s disease pathophysiology: a review and hypothesis on their association (Mohammad Rafi Khezri et al, 2 May 2023)
- Although amyloid-β (Aβ) deposition and tau hyperphosphorylation and aggregation are mainly considered the main characterizations of AD, several other processes are involved. In recent years, several other changes, including alterations in gut microbiota proportion and circadian rhythms, have been noticed due to their role in AD progression. However, the exact mechanism indicating the association between circadian rhythms and gut microbiota abundance has not been investigated yet. This paper aims to review the role of gut microbiota and circadian rhythm in AD pathophysiology and introduces a hypothesis to explain their association.
Circadian dysregulation and Alzheimer’s disease: A comprehensive review(Peter Iacobelli, 20 Nov 2022)
- ...it appears that there is a physiologic association between circadian rhythm dysregulation and AD. This review will explore the physiology of circadian dysregulation in the AD brain, and will propose a basic model for its role in AD‐typical pathology, derived from the literature compiled and referenced throughout.
Research advances in the study of sleep disorders, circadian rhythm disturbances and Alzheimer’s disease (Xiangyang Xiong et al, 17 Aug 2022)
- Sleep disorders are very common in neurodegenerative diseases and are a key factor in the quality of life of patients and their families. Alzheimer’s disease (AD) is an insidious and irreversible neurodegenerative disease. Along with progressive cognitive impairment, sleep disorders and disturbances in circadian rhythms play a key role in the progression of AD. Sleep and circadian rhythm disturbances are more common in patients with AD than in the general population and can appear early in the course of the disease. Therefore, this review discusses the bidirectional relationships among circadian rhythm disturbances, sleep disorders, and AD. In addition, pharmacological and non-pharmacological treatment options for patients with AD and sleep disorders are outlined.”
Circadian clocks, cognition, and Alzheimer’s disease: synaptic mechanisms, signaling effectors, and chronotherapeutics (Kari R. Hoyt & Karl Obrietan, 7 May 2022)
- In this review we describe recent findings regarding the complex set of cellular signaling events, including kinase pathways, gene networks, and synaptic circuits that are under the influence of the clock timing system and how this, in turn, shapes cognitive capacity over the circadian cycle. Further, we discuss the functional roles of the master circadian clock located in the suprachiasmatic nucleus, and peripheral oscillator populations within cortical and limbic circuits, in the gating of synaptic plasticity and memory over the circadian cycle. These findings are then used as the basis to discuss the connection between clock dysregulation and cognitive impairments resulting from Alzheimer’s disease (AD). In addition, we discuss the conceptually novel idea that in AD, there is a selective disruption of circadian timing within cortical and limbic circuits, and that it is the disruption/desynchronization of these regions from the phase-entraining effects of the SCN that underlies aspects of the early- and mid-stage cognitive deficits in AD. Further, we discuss the prospect that the disruption of circadian timing in AD could produce a self-reinforcing feedback loop, where disruption of timing accelerates AD pathogenesis (e.g., amyloid deposition, oxidative stress and cell death) that in turn leads to a further disruption of the circadian timing system. Lastly, we address potential therapeutic approaches that could be used to strengthen cellular timing networks and, in turn, how these approaches could be used to improve cognitive capacity in Alzheimer’s patients.
Circadian control of heparan sulfate levels times phagocytosis of amyloid beta aggregates (Gretchen T. Clark et al, 10 Feb 2022) According to this research, the brain’s ability to clear a protein closely linked to Alzheimer’s disease is tied to our circadian cycle. The research underscores the importance of healthy sleep habits in preventing the protein Amyloid-Beta 42 (AB42) from forming clumps in the brain.
Circadian Clock Regulates Inflammation and the Development of Neurodegeneration (Xiao-Lan Wang & Lianjian Li 14 Sep 2021)
- Disruption of circadian clock machinery influences key activities involved in immune response and brain function. Moreover, Immune activation has been closely linked to neurodegeneration. Here, we review the molecular clock machinery and the diurnal variation of immune activity. We summarize the circadian control of immunity in both central and peripheral immune cells, as well as the circadian regulation of brain cells that are implicated in neurodegeneration. We explore the important role of systemic inflammation on neurodegeneration. The circadian clock modulates cellular metabolism, which could be a mechanism underlying circadian control. We also discuss the circadian interventions implicated in inflammation and neurodegeneration. Targeting circadian clocks could be a potential strategy for the prevention and treatment of inflammation and neurodegenerative diseases.
MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases (Chisato Kinoshita et al, 23 Jul 2020)
- Circadian misalignment not only disturbs the sleep/wake cycle and rhythmic physiological activity but also contributes to the development of various diseases, such as sleep disorders and neurodegenerative diseases. The patient with neurodegenerative diseases often experiences profound disruptions in their circadian rhythms and/or sleep/wake cycles. In addition, a growing body of recent evidence implicates sleep disorders as an early symptom of neurodegenerative diseases, and also suggests that abnormalities in the circadian system lead to the onset and expression of neurodegenerative diseases. The genetic mutations which cause the pathogenesis of familial neurodegenerative diseases have been well studied; however, with the exception of Huntington’s disease, the majority of neurodegenerative diseases are sporadic. Interestingly, the dysfunction of microRNA is increasingly recognized as a cause of sporadic neurodegenerative diseases through the deregulated genes related to the pathogenesis of neurodegenerative disease, some of which are the causative genes of familial neurodegenerative diseases. Here we review the interplay of circadian rhythm disruption, sleep disorders and neurodegenerative disease, and its relation to microRNA, a key regulator of cellular processes.
Aging Disrupts the Circadian Patterns of Protein Expression in the Murine Hippocampus (Paula Adler et al, Jan 2020)
- In this study, we profiled the hippocampal proteomes of young and middle-aged mice across two circadian cycles using quantitative mass spectrometry in order to explore aging-associated changes in the temporal orchestration of biological pathways. Of the ∼1,420 proteins that were accurately quantified, 15% (214 proteins) displayed circadian rhythms in abundance in the hippocampus of young mice, while only 1.6% (23 proteins) were rhythmic in middle-aged mice. Remarkably, aging disrupted the circadian regulation of proteins involved in cellular functions critical for hippocampal function and memory, including dozens of proteins participating in pathways of energy metabolism, neurotransmission, and synaptic plasticity. ... These insights into aging-induced changes in the hippocampal proteome provide a framework for understanding how the age-dependent circadian decline may contribute to cognitive impairment and the development of neurodegenerative diseases during aging.
The role of sleep deprivation and circadian rhythm disruption as risk factors of Alzheimer’s disease (Hao Wu et al, Jul 2019)
- Emerging evidence suggests that sleep deprivation (SD) and circadian rhythm disruption (CRD) may interact and increase the risk for the development of Alzheimer’s disease (AD). This review inspects different pathophysiological aspects of SD and CRD, and shows that the two may impair the glymphatic-vascular-lymphatic clearance of brain macromolecules (e.g., β-amyloid and microtubule associated protein tau), increase local brain oxidative stress and diminish circulatory melatonin levels. Lastly, this review looks into the potential association between sleep and circadian rhythm with stress granule formation, which might be a new mechanism along the AD pathogenic pathway. In summary, SD and CRD is likely to be associated with a positive risk in developing Alzheimer’s disease in humans.
Circadian Rhythm and Alzheimer’s Disease (Jan Homolak et al, 21 Jun 2018)
- To conclude, a growing body of evidence (both from clinical studies and animal research) supports a complex and meaningful relationship between circadian rhythms and Alzheimer’s disease. Although numerous hypotheses have been generated in order to explain the etiology of AD, it still remains to be fully elucidated. However, circadian rhythm interacts with most if not all systems and risk factors known to be responsible for AD development and progression. Therefore, it represents an interesting target for possible disease prevention and treatment. The relationship between AD and circadian rhythm seems to be bi-directional and the optimum goal would be to meaningfully influence disease progression by circadian intervention, or at least provide valuable symptomatic relief and greatly reduce socioeconomic costs and suffering. In the era of precision medicine, which strives toward fully personalized care, a deeper understanding of the circadian rhythm–AD relationship should help provide a successful evidence-based comprehensive approach and more effective treatments.
Circadian Rhythm and Heart/Cardiovascular Disease
Myocardial Rev-erb–Mediated Diurnal Metabolic Rhythm and Obesity Paradox (Shiyang Song et al, 17 Jan 2022)
- The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.
Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart (Sandrine Lecour et al, 10 Sep 2021)
- In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.
Circadian rhythms influence cardiovascular disease differently in males and females: role of sex and gender (W Glen Pyle & Tami AMartino, October 2018)
- The circadian mechanism underlies our daily physiology; humans are adapted to be awake in the day and sleep at night. A new frontier is translation of circadian biology to benefit patients with cardiovascular disease. This review provides an overview of circadian rhythms in cardiovascular physiology, pathophysiology and what happens when we disturb rhythms. Intriguingly, recent studies reveal that biological sex and gender influence cardiovascular disease. Moreover, the circadian mechanism influences heart disease a sexually dimorphic manner, underlying the pathophysiology of myocardial infarction, cardiac hypertrophy, cardiac aging, renal sodium handling and blood pressure regulation. This leads to new understanding about how men and women exhibit differences in resilience to cardiovascular diseases, how myocardium remodels, and are important for developing circadian therapies to benefit both male and female patients.
Implications of disturbances in circadian rhythms for cardiovascular health: A new frontier in free radical biology (Neelam Khaper et al, 1 May 2018)
- This review summarizes the current knowledge on circadian rhythms in the cardiovascular system, and the implications of rhythm disturbances for cardiovascular health. Furthermore, we highlight how free radical biology coincides with the pathogenesis of myocardial repair and remodelling after MI, and indicate a role for the circadian system in the oxidative stress pathways in the heart and brain after MI. This fusion of circadian biology with cardiac oxidative stress pathways is novel, and offers enormous potential for improving our understanding and treatment of heart disease.
Influence of the Cardiomyocyte Circadian Clock on Cardiac Physiology and Pathophysiology (Tami A. Martino & Martin E. Young, 22 Mar 2015)
- Cardiac function and dysfunction exhibit striking time-of-day-dependent oscillations. Disturbances in both daily rhythms and sleep are associated with increased risk of heart disease, adverse cardiovascular events, and worsening outcomes. For example, the importance of maintaining normal daily rhythms is highlighted by epidemiologic observations that night shift workers present with increased incidence of cardiovascular disease. Rhythmicity in cardiac processes is mediated by a complex interaction between extracardiac (e.g., behaviors and associated neural and humoral fluctuations) and intracardiac influences. Over the course of the day, the intrinsic properties of the myocardium vary at the levels of gene and protein expression, metabolism, responsiveness to extracellular stimuli/stresses, and ion homeostasis, all of which affect contractility (e.g., heart rate and force generation). Over the past decade, the circadian clock within the cardiomyocyte has emerged as an essential mechanism responsible for modulating the intrinsic properties of the heart. Moreover, the critical role of this mechanism is underscored by reports that disruption, through genetic manipulation, results in development of cardiac disease and premature mortality in mice. These findings, in combination with reports that numerous cardiovascular risk factors (e.g., diet, diabetes, aging) distinctly affect the clock in the heart, have led to the hypothesis that aberrant regulation of this mechanism contributes to the etiology of cardiac dysfunction and disease. Here, we provide a comprehensive review on current knowledge regarding known roles of the heart clock and discuss the potential for using these insights for the future development of innovative strategies for the treatment of cardiovascular disease.
Circadian Rhythm and Longevity
Inputs and Outputs of the Mammalian Circadian Clock(Ashley N. Starnes and Jeff R. Jones, 28 Mar 2023). This article is a deep dive into the mammalian circadian clock and the inputs/outputs to the suprachiasmatic nucleus (SCN), the body’s master clock. From the conclusions:
- Clearly, the SCN “connectome” or “wiring diagram” is extremely complex. The SCN does not solely process environmental light cues from the retina as is typically depicted in a simplified eskinogram. Instead, it encodes synaptic inputs from dozens of discrete brain areas and hormonal cues from the periphery. Perhaps uniquely among brain circuits, the SCN also communicates with the rest of the brain and body via both (poly)synaptic projections throughout the nervous system and non-synaptic signals to distant cells, organs, and tissues. The SCN thus exists as a central nexus within a complex, dynamic circadian network that integrates information about the outside world (light intensity) with information about an animal’s internal state (arousal, motivation, hormone levels, etc.). This integrated circadian timing signal is propagated onward to synchronize and coordinate daily rhythms in behavior and physiology. Critically, these SCN target regions each have their own molecular clocks and, within the brain, “neuronal clocks”, or daily rhythms in action potential frequency . In some cases, these local clocks are not endogenous or self-sustaining: when isolated from the SCN, these rhythms immediately or rapidly dampen. But in other cases, local clocks remain rhythmic for several days or even indefinitely without SCN input . While ablating some of these local clocks disrupts behavioral and/or physiological rhythms (despite an intact SCN), ablating other local clocks has essentially no effect on rhythmicity [144,213,214]. Consequently, clocks within different SCN target regions have different strategies by which they encode circadian time to regulate their rhythmic outputs. The SCN connectome must therefore incorporate not only inputs to and outputs from the SCN, but also how these inputs and outputs influence, and are influenced by, local clocks. This holistic understanding of circadian rhythm generation in mammals is essential to determine how the disruption of these circuits can negatively affect human health. (Bold font added for emphasis).
The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β (George A. Timmons et al, 9 Nov 2021) Research discussed in this paper demonstrates the significant role that an irregular body clock plays in driving inflammation in the body's immune cells, with implications for the most serious and prevalent diseases in humans.
Importance of circadian timing for aging and longevity (Victoria A. Acosta-Rodríguez et al, 17 May 2021)
- Here, we discuss how dietary and pharmacological interventions promote a healthy lifespan by influencing energy intake and circadian rhythms.
Changes in Circadian Rhythms Dysregulate Inflammation in Ageing: Focus on Leukocyte Trafficking (Poppy Nathan et al, 14 May 2021)
- Here, we review the core mammalian circadian clock machinery and discuss the changes that occur in this biological system in ageing. In particular, we focus on the changes that occur to leukocyte trafficking rhythmicity with increasing age and consider how this impacts inflammation and the development of immune-mediated inflammatory disorders (IMIDs). We aim to encourage future ageing biology research to include a circadian approach in order to fully elucidate whether age-related circadian changes occur as a by-product of healthy ageing, or if they play a significant role in the development of IMIDs.
Does Insufficient Sleep Increase the Risk of Developing Insulin Resistance: A Systematic Review (Trisha Singh et al, 26 Mar 2022)
- The primary purpose of this study was to investigate the effects of reduced sleep on the development of insulin resistance and explore the possible mechanisms linking the two. .... Short sleep duration was significantly associated with insulin resistance. Inflammatory markers such as C-reactive protein (CRP) and serum amyloid A (SAA), biomarkers such as glucagon-like peptide-1 (GLP-1), and circadian misalignment may play a significant role in the pathogenesis of this association. To prevent metabolic complications such as type- 2 diabetes, adequate sleep (more than seven hours per night) is required in the adult population. The causal relationship between sleep deprivation and insulin resistance is multifactorial, and further studies are warranted to understand these mechanisms better.