Circadian Rhythm, Sleep, and Aging
A Major Advance
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?
other mobile devices
exposes users to blue
light, which suppresses
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.
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
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.
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.
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.
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.
- 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.