Life Extension Magazine®
Circadian Rhythm, Sleep, and Aging
Circadian rhythms regulate all aspects of health from sleep to heart rate to lifespan. Two compounds have been identified that can help restore youthful circadian rhythm function.
Scientifically reviewed by: Dr. Heidi Yanoti, DC, in October 2024. Written by: Brian Parker.
Researchers are discovering a new role for circadian rhythm to help foster longevity.
In our body, circadian rhythm regulates all aspects of our health from sleep to heart rate, blood pressure to hormone release, neurological function, and even obesity.1
The potential of this area of research is so promising that three American researchers won the Nobel Prize in Physiology or Medicine for their work on the mechanisms of circadian rhythm!2
Lab studies from MIT show that a robust circadian rhythm is correlated with a longer lifespan. Other MIT studies propose that it may soon be possible to prevent and treat the diseases of aging by enhancing circadian function.3
The urgency of this research cannot be overstated. Disruption of our circadian rhythms is increasing in modern societies.
While aging itself is a factor, exposure to blue light from cell phones and computers, jet-lag travel, and certain medications worsen it. One of the first signs of circadian disruption is poor sleep performance.4
Changes in sleep and circadian rhythm are now linked with aging at the molecular level, as well as with disorders of aging including neurodegenerative disease.5,6 Based on a continuing flow of confirmatory data, Life Extension® scientists sought to identify a way to help restore the body’s circadian rhythm to a more youthful state.Two compounds have been found to help synchronize and restore youthful operation to our circadian rhythm. The priority is to enable older persons to regain control over this essential health and longevity function.
What is Circadian Rhythm?
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exposes users to blue
light, which suppresses
melatonin levels.
Nearly every cell in our body has an internal “clock” that responds to changes in light perception and exposure, helping create our circadian rhythm and our own inner body clocks.
There’s a central clock in the human brain that syncs with our circadian rhythm and regulates body functions such as wakefulness, sleep, body temperature, and hormone regulation according to the time of day.
In addition to the central clock in the brain, each of our cells in various organs contain a peripheral clock that takes its orders from the central clock. These peripheral clocks help regulate how our body functions, including our metabolism and myriad biochemical pathways.
Together, the central clock and the peripheral clocks regulate all physical functions in relation to circadian rhythm and the time of day.
What You Need to Know
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Synchronizing Circadian Rhythm
- Studies show that abnormal circadian rhythm correlates with obesity, type II diabetes, neurodegenerative diseases, cardiovascular disease, and even cancer.
- Aging itself also produces powerful dysregulation of circadian rhythm, increasing our risk of degenerative age-related diseases.
- Recent Nobel Prize-winning research suggests that we have not just a single, central biological clock in the brain, but a highly integrated hierarchy of peripheral biological clocks throughout the organs, tissues, and cells of our body.
- Protection from these complicated biological timekeeping disturbances is not easy to attain, but the combination of nobiletin and melatonin offers just that.
- Nobiletin has been shown to amplify timekeeping signals from the peripheral clocks, establishing a healthier circadian rhythm in cells and organs throughout the body.
- Melatonin synchronizes the central clock, helping it better coordinate with “real time,” while also acting on peripheral clocks to keep them “ticking” in rhythm with the central clock in the brain.
- This combination is ideal for anyone with trouble sleeping on a regular schedule, or who works unconventional hours or experiences jet lag from long airplane flights, but especially aging adults who tend to experience a degradation in sleep quality and difficulty maintaining healthy circadian rhythm.
Sleep and Circadian Rhythm
One of the key functions of circadian rhythm is to regulate our sleep cycle. Taking cues from our outside environment, the body begins to release increased melatonin levels as light levels fall and lower melatonin levels as light levels rise with the start of a new day.
People with sleep problems almost always have disrupted biological clocks, which puts them at increased risk for cardiovascular, neurological, and metabolic disorders (obesity, metabolic syndrome, diabetes).7-14
Nobel Prize for Research on Circadian Rhythm
In October of last year, American researchers Michael W. Young, Michael Rosbash, and Jeffrey C. Hall were awarded the 2017 Nobel Prize in Physiology or Medicine for their discoveries relating to “molecular mechanisms controlling the circadian rhythm.”2
Circadian rhythm is the term given to the internal “body clock” that determines the cycle of wakefulness and sleep in humans and other living creatures. These scientists discovered the biological basis of circadian rhythm—how organisms’ cells generate and regulate the body’s biological clock.
Researchers in this field, called chronobiology, have hailed the importance of this discovery, because the dysregulation of body clocks is associated with serious health conditions including cancer, metabolic syndrome, and obesity.
Researchers Young, Rosbash, and Hall were honored for isolating a gene that regulates the internal clock of fruit flies. This gene codes for the PER protein, which builds up during the night and breaks down during the day.
Regulating the Central Clock with Melatonin
The human body contains two types of clocks that respond to circadian rhythm. We function optimally when both types of clocks are harmoniously coordinated.
Life Extension scientists have found that we can keep our central clock in sync with melatonin and our peripheral clocks operating optimally with an extract from citrus peel called nobiletin. This unique nutritional approach targets both central and peripheral clocks to regulate circadian rhythm.
The central clock in the brain operates on light detected through the eyes. With the first light of day, our body turns on the systems, ready for activity. With the arrival of nightfall, our systems begin to shut down and prepare for sleep.
This activity is regulated in part through melatonin secretions from the brain’s pineal gland. This release of melatonin helps normalize hormone and neurotransmitter functions controlled by the brain and its central clock.
Science has shown that the hormone melatonin plays a critical role in keeping the central clock in sync with the environment and can restore our circadian rhythms through healthful sleep.14,15
Melatonin also increases production of the longevity-promoting protein SIRT1.16,17
MIT scientists have shown that SIRT1 helps regulate circadian rhythm and protect against the diseases of aging.3 So melatonin activates SIRT1 and SIRT1 helps regulate the central clock and potentially prevents degradation of circadian rhythm. Melatonin tunes up and regulates the central clock so that it can better communicate with the body’s peripheral clocks.
The central and peripheral clocks need to be coordinated and talking to one another to manage all of the body’s systems. As circadian rhythm becomes dysregulated through age and lifestyle, this essential communication between the clocks becomes impaired and systems begin to fail.
About Nobiletin
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Nobiletin is a polymethoxylated flavone found in relatively high concentrations in citrus peel (Citrus sinensis) and to a much lesser extent in citrus pulp (the fleshy part of the fruit).
Approximately 50 mg of nobiletin can be obtained from about 28 liters of orange juice daily. Ingesting citrus peel is typically not a regular part of most diets and ingesting 28 liters of fruit juice daily with its vast amounts of sugar is not desirable. Based upon the currently published literature on nobiletin and circadian rhythm synchronization, nutritional supplementation is the best strategy.
Life Extension scientists have carefully calculated a human dose of nobiletin for circadian clock synchronization, 50 mg/day, from animal studies that defined the concentration of nobiletin required to achieve circadian rhythm clock-regulating effects.24 Research shows that adding a carrier oil significantly increases the oral bioavailability of nobiletin itself.24-26
Regulating Peripheral Clocks with Nobiletin
In addition to the central clock in the brain, our individual cells contain a peripheral clock that regulates many critical biological functions including liver function, blood pressure, new cell growth, and the release of hormones.8,18-21
New research indicates that nobiletin, derived from citrus peels, regulates peripheral clocks, fostering natural circadian rhythm.22
Researchers at the University of Texas Health Science Center at Houston conducted a detailed animal study using nobiletin to modulate the peripheral clocks in mice.22 This study in mice with metabolic syndrome demonstrated the impact of circadian clock regulation on weight gain.
Researchers fed mice a high-fat diet that was supplemented with nobiletin for 10 weeks.
The nobiletin-supplemented mice gained significantly less weight during the study compared with mice who received no treatment. Further, these researchers found that the lack of weight-gain was related to the beneficial effect on circadian rhythm rather than to any direct biochemical action of nobiletin.22
This animal study suggests that resetting biological peripheral clocks with nobiletin may have a beneficial impact on body weight and metabolism.
More About Circadian Rhythm and Our Health
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Circadian rhythm has intrigued scientists around the world as a target for improving health and preventing disease. Recent studies highlight the effects of circadian rhythm disruptions on psychological health and cancer risk.
A study from the prestigious Lancet Psychiatry in 2018 showed that disrupted circadian rhythms are associated not only with sleep disturbances, but also with an increased risk of depression and bipolar disorder.27 The study, which used specialized accelerometer data to measure the size of circadian rhythm “waves” in more than 91,000 people, also showed that circadian disturbances were associated with unstable mood and loneliness, and lower happiness and health satisfaction scores.
Use of cellphones and other mobile devices exposes users to blue light, which suppresses melatonin levels and disrupts circadian rhythms, resulting in sleep disturbances. This drop in melatonin signaling may be especially dangerous for women carrying the BRCA1 or BRCA2 mutations indicating high risk for breast cancers, because of the growing understanding of how circadian rhythm and cancer formation are interrelated.28
Other Circadian Benefits of Nobiletin
This research suggests that nobiletin controls circadian rhythms by turning on peripheral sensors that regulate circadian clock genes, helping restore natural circadian rhythms.22
Specifically, nobiletin binds to certain cellular receptors that support signaling from the peripheral clock genes.22,23 This turns up the volume of the peripheral clock signals, which enhances coordination of the mice’s circadian clock rhythms.22,23
This “louder” signal can favorably influence many genes regulated by the peripheral clock, including those responsible for:
Maintaining normal cell reproduction and growth while preventing cancer development.
Supporting cellular energy systems that help prevent insulin resistance, type II diabetes, and metabolic syndrome.
Promoting healthy immune responses that resist infections, as well as patrolling for cancers and suppressing autoimmune disorders.
Producing and metabolizing essential hormones to support normal metabolism, energy, sex drive, and other crucial functions.
Jet Lag and its Effects on the Body
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The disorienting, energy-sapping effects of jet lag are actually just a symptom of disrupted circadian rhythm. But jet lag also has little-known effects on the internal workings of the body and its organs.29
Human sleep cycles are strongly linked to the daily cycle of day and night, and light and dark. Core body temperature drops as we sleep, and the lowest temperature coincides with the point of maximum sleepiness in this cycle, about two to three hours before waking.
Our bodies don’t recognize the change when we fly into new time zones, so our core temperature during sleep continues to drop based on the day/night cycle of wherever we last were. Waking up according to a new day/night cycle but before the full internal temperature drop makes one feel groggy and not well-rested. The worst symptoms of jet lag occur at this point, when the daylight tells your brain you should be awake but your core temperature makes you feel sleepy.
These symptoms can be mitigated, experts say, by keeping your sleep environment dark—drawing curtains, etc.—until you’ve completed a full sleep cycle. Strategic napping when necessary can also be helpful.
Melatonin supplements, which can safely induce sleepiness, are also helpful for readjusting the sleep cycle when traveling.
Jet lag also affects internal organs such as the heart, pancreas, liver, and gastrointestinal tract.
Most obvious is “gut lag,” which includes symptoms such as being constipated or feeling hungry at odd times of the day. Evidence suggests gut lag can also affect the bacteria known as the intestinal microbiome, leading to diarrhea, and can impair the gut bacteria’s immune function.
Doctors say one can avoid digestive issues by keeping eating to a minimum while flying between destinations. Problems can also be mitigated by immediately adhering to the meal schedule that is appropriate for one’s new time zone. Exercise and staying hydrated are also recommended, as both contribute to keeping your bowels on a regular schedule.
Summary
Circadian rhythm is vital to all aspects of human biology, though most people think of it as simply related to sleep/wake cycles.
Aging is associated with decreased circadian rhythm and dysregulation of sleep patterns. Epidemiologic studies indicate that age-induced changes in circadian rhythm negatively affect health at the molecular level, and contribute to diseases of aging, especially neurodegenerative disease.
Life Extension scientists developed the combination of nobiletin and melatonin to support proper synchronization of both the central and peripheral clocks.
Melatonin acts on the central clock. It is a natural hormone produced at night in the brain’s pineal gland.
Nobiletin, derived from citrus peels, acts on the peripheral clocks in our organs, tissues, and cells. Nobiletin has been shown to help coordinate and enhance circadian rhythm by amplifying the signals from those clocks.
Studies suggest that dysregulation of our circadian clocks is linked to a myriad of health problems and age-induced disease including metabolic, cardiovascular, and neurodegenerative problems.
This approach to synchronizing circadian rhythm through the central and peripheral biological clocks is a novel and promising strategy to beneficially affect the health of the entire body.
If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.
References
- Available at: https://www.nigms.nih.gov/education/pages/factsheet_circadianrhythms.aspx. Accessed July 31, 2018.
- Available at: https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html. Accessed July 31, 2018.
- Available at: http://news.mit.edu/2013/the-link-between-circadian-rhythms-and-aging-0620. Accessed August 2, 2018.
- Baron KG, Reid KJ. Circadian misalignment and health. Int Rev Psychiatry. 2014;26(2):139-54.
- Musiek ES, Holtzman DM. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science. 2016;354(6315):1004-8.
- Hood S, Amir S. Neurodegeneration and the Circadian Clock. Front Aging Neurosci. 2017;9(170):170.
- Scheer FA, Hilton MF, Mantzoros CS, et al. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106(11):4453-8.
- Nohara K, Yoo SH, Chen ZJ. Manipulating the circadian and sleep cycles to protect against metabolic disease. Front Endocrinol (Lausanne). 2015;6:35.
- Zelinski EL, Deibel SH, McDonald RJ. The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body. Neurosci Biobehav Rev. 2014;40:80-101.
- Yu EA, Weaver DR. Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging (Albany NY). 2011;3(5):479-93.
- Roenneberg T, Merrow M. The Circadian Clock and Human Health. Curr Biol. 2016;26(10):R432-43.
- Manoogian ENC, Panda S. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res Rev. 2017;39:59-67.
- Froy O. Circadian rhythms and obesity in mammals. ISRN Obes. 2012;2012:437198.
- Albrecht U. Timing to perfection: the biology of central and peripheral circadian clocks. Neuron. 2012;74(2):246-60.
- Pevet P. The internal time-giver role of melatonin. A key for our health. Rev Neurol (Paris). 2014;170(11):646-52.
- Tajes M, Gutierrez-Cuesta J, Ortuno-Sahagun D, et al. Anti-aging properties of melatonin in an in vitro murine senescence model: involvement of the sirtuin 1 pathway. J Pineal Res. 2009;47(3):228-37.
- Rodella LF, Favero G, Rossini C, et al. Aging and vascular dysfunction: beneficial melatonin effects. Age (Dordr). 2013;35(1):103-15.
- Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445-62.
- Andreani TS, Itoh TQ, Yildirim E, et al. Genetics of Circadian Rhythms. Sleep Med Clin. 2015;10(4):413-21.
- Buhr ED, Takahashi JS. Molecular components of the Mammalian circadian clock. Handb Exp Pharmacol. 2013(217):3-27.
- Li JZ, Bunney BG, Meng F, et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci U S A. 2013;110(24):9950-5.
- He B, Nohara K, Park N, et al. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metab. 2016;23(4):610-21.
- Chen Z, Yoo SH, Park YS, et al. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc Natl Acad Sci U S A. 2012;109(1):101-6.
- Manthey JA, Cesar TB, Jackson E, et al. Pharmacokinetic study of nobiletin and tangeretin in rat serum by high-performance liquid chromatography-electrospray ionization-mass spectrometry. J Agric Food Chem. 2011;59(1):145-51.
- Evans M, Judy WV, Wilson D, et al. Randomized, double-blind, placebo-controlled, clinical study on the effect of Diabetinol((R)) on glycemic control of subjects with impaired fasting glucose. Diabetes Metab Syndr Obes. 2015;8:275-86.
- Evans M. Bioavailability of citrus polymethoxylated flavones and their biological role in metabolic syndrome and hyperlipidemia. 2012.
- Lyall LM, Wyse CA, Graham N, et al. Association of disrupted circadian rhythmicity with mood disorders, subjective wellbeing, and cognitive function: a cross-sectional study of 91 105 participants from the UK Biobank. Lancet Psychiatry. 2018;5(6):507-14.
- Mortazavi SAR, Mortazavi SMJ. Women with hereditary breast cancer predispositions should avoid using their smartphones, tablets, and laptops at night. Iran J Basic Med Sci. 2018;21(2):112-5.
- Available at: https://www.washingtonpost.com/national/health-science/why-crossing-time-zones-makes-you-feel-bad-and-what-you-can-do-about-it/2018/07/20/39417254-6a88-11e8-9e38-24e693b38637_story.html. Accessed August 3, 2018.
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