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Circadian Rhythm Reset

Novel Natural Ways to Reset Your Circadian Rhythm
Your body is programmed to know the ideal time  to sleep, wake up, eat, exercise, focus on work, rest and sleep again. This is our internal body clock or what we call our Circadian Rhythm. Our circadian clock regulates almost every cell and process in our body and it turns out that disruptions in this clock by external factors such as light from our computers, phones and  TV screens,  timing of our meals, shift work and jet lag have severe consequences on human health. In fact, circadian rhythm disruption, which is so common in our society, can be linked to almost every disease state including cognitive impairment, psychiatric illness, diabetes, excess weight, heart disease and even cancer.  

Normalizing this Circadian Rhythm has  become recognized as such an important factor in halting disease and improving health that  the 2017 Nobel Prize in Physiology and Medicine was awarded to three circadian rhythm researchers who discovered a “clock” protein that, like a clock, builds up in cells at certain times of the day  and breaks down at other time periods regulating bodily functions.  

Understanding the powerful regulation of health by normalizing circadian rhythm has led to a whole new field called Chronomedicine that recognizes that there are optimal times and less than optimal or even dangerous times for taking medications and  having medical interventions. Unfortunately, our world is  no longer designed to live the way our circadian clocks are set, and although there is no substitute for good sleeping and eating habits, we have come up with some simple biohacks useful for helping to reset your clock, improve health, lose weight and fight aging. OHP put these together into one easy to use program to reset your Biologic Clock and start a new path to optimal health!
What's in the Circadian Reset Package?
Melatonin
Melatonin is a hormone secreted by the Pineal Gland and it is one of the master signals controlling circadian rhythms. Its secretion is affected by factors such as age, light, environmental and physiological factors. Melatonin is a key regulator of our internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti‐inflammatory agent. There is more and more evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications partly due to its regulation of our satiety hormones, leptin and adiponectin.These results support the concept of melatonin as a potential therapeutic agent for obesity and many other disorders. Moreover, lower levels of melatonin secretion speed aging, tumor formation, fat accumulation (especially dangerous belly fat) and heart function.Recommended dose is typically between 3 and 5mg for helping reset circadian rhythms. Interestingly, we often use very high doses to help inflammation and pain! 
References
1) Regulation of myocardial metabolism by the cardiomyocyte circadian clock.
Chatham JC, Young MEJ Mol Cell Cardiol. 2013 Feb; 55():139-46.
2) Farhud D, Aryan Z. Circadian Rhythm, Lifestyle and Health: A Narrative Review. Iran J Public Health. 2018;47(8):1068-1076.3) Mundey K et al, Phase-dependent treatment of delayed sleep phase syndrome with melatonin (2005)Kayumov L, et al, A Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effect of Exogenous Melatonin on Delayed Sleep Phase Syndrome (2001)4) Revell VL, Burgess HJ, Gazda CJ, et al, Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light (J Clin Endocrinol Metab. 2006Jan;91(1)) 5) McArthur AJ et al, Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment (1996)
6) Lemoine P, et al, Prolonged-release melatonin for insomnia - an open-label long-term study of efficacy, safety, and withdrawal (2011)
7) Brown GM, Light, Melatonin and the Sleep-Wake Cycle (1994)
Srinivasan V, Spence DW et al, Jet lag: therapeutic use of melatonin and possible application of melatonin analogs (2008)
8) Breslow ER, Phillips AJK, Huang JM, et al, A Mathematical Model of the Circadian Phase-Shifting Effects of Exogenous Melatonin (2013)
9) Nagtegaal JE, Kerkhof GA, Smits MG et al, Delayed sleep phase syndrome: A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset (J Sleep Res. 1998 Jun;7(2):135-43
10) Alexander, Scott, Melatonin: Much More Than You Wanted To Know (Slate Star Codex, July 10, 2018)
Leptin
Leptin is a hormone produced primarily by fat cells. It regulates appetite and fat storage. So, when leptin is well controlled and our body has a normal response to it, we do not feel hungry and we lose excess fat. However, overfeeding, eating at the wrong times and inadequate sleep or exposure to light during sleep force the body into what is known as “a leptin resistant state.” When this happens, the body no longer recognizes that it does not need to be fed and fat storage is increased. Recent research has shown that disruption of circadian rhythm alters the normal production of serum leptin, leading to leptin resistance  independently of changes in external food cues or physical activity. Therefore it is critically important to restore normal leptin sensitivity to prevent obesity and all its related complications! The main ingredient in leptigen is a specific type of glycosaminoglycan called Oralvisc that helps to restore leptin sensitivity. This same ingredient can also markedly reduce joint pain and stiffness. 
References
1. Jéquier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002 Jun;967:379-88. [PMID: 12079865]
2. Fukuda M, Williams KW, Gautron L, et al. Induction of leptin resistance by activation of cAMP-Epac signaling. Cell Metab. 2011 Mar 2;13(3):331-39. [PMID: 21356522]
3. Lin L, Martin R, Schaffhauser AO, et al. Acute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol Regul Integr Comp Physiol. 2001 Feb;280(2):R504-09. [PMID: 11208581]
4. Wang J, Obici S, Morgan K, et al. Overfeeding rapidly induces leptin and insulin resistance. Diabetes. 2001 Dec;50(12):2786-91. [PMID: 11723062]
5. Shapiro A, Mu W, Roncal C, et al. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1370-75. [PMID: 18703413]
6. Vasselli JR, Scarpace PJ, Harris RB, et al. Dietary components in the development of leptin resistance. Adv Nutr. 2013 Mar 1;4(2):164-75. [PMID: 23493533]
7. Leon-Cabrera S, Solís-Lozano L, Suárez-Álvarez K, et al. Hyperleptinemia is associated with parameters of low-grade systemic inflammation and metabolic dysfunction in obese human beings. Front Integr Neurosci. 2013 Aug 23;7:62. [PMID: 23986664] helps to restore leptin sensitivity. 
Relora
Relora is a  patented and proprietary blend of Magnolia officinalis and Phellodendron amurense bark extract standardized to honokiol and berberine, respectively. Relora works by balancing the hypothalamus in the brain, which regulates important functions such as hormone levels, temperature, weight, and sleep cycles. Relora also helps to balance the entire HPA axis (hypothalamic-pituitary-adrenal axis), which is a central pathway to restoring circadian rhythm. These herbs have a history of traditional use in treating stress and occasional feelings of anxiousness. In modern times, they and their actives (honokiol and berberine) are used to support relaxation and reduce the perception of stress and stress-related eating. Rodent stress studies demonstrate a reduction in induced feelings of anxiousness.[1,2] Human studies demonstrate positive changes in DHEA (dehydroepiandrosterone) and cortisol levels, less weight gain (compared to controls), and reductions in perceived stress and transitory feelings of anxiousness in subjects taking Relora 
References
1. Sufka KJ, Roach JT, Chambliss WG Jr, et al. Anxiolytic properties of botanical extracts in the chick social separation-stress procedure. Psychopharmacology (Berl). 2001 Jan 1;153(2):219-24. [PMID: 11205422]
 2. LaValle JB, Hawkins EB. Botanicals in dietary supplements: Stress and anxiety: the potential benefit of a proprietary combination of magnolia and phellodendron extracts. Dana Point, CA: Integrative Health Resources; 2013:1-15. http://www. nextpharmaceuticals.com/stage/pdfs/Relora%20Article-2013-LaValle.pdf. Accessed February 22, 2015.
 3. Talbott SM, Talbott JA, Pugh M. Effect of Magnolia officinalis and Phellodendron amurense (Relora®) on cortisol and psychological mood state in moderately stressed subjects. J Int Soc Sports Nutr. 2013 Aug 7;10(1):37. [PMID: 23924268] 
4. Garrison R, Chambliss WG. Effect of a proprietary Magnolia and Phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial. Altern Ther Health Med. 2006 Jan-Feb;12(1):50-54. [PMID: 16454147]
 5. Kalman DS, Feldman S, Feldman R, et al. Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo controlled clinical trial. Nutr J. 2008 Apr 21;7:11. [PMID: 18426577] 
Sensoril
Sensoril is an optimized type of ashwagandha (Withania somnifera) that represents a major advancement in ashwagandha preparations. Sensoril’s proprietary and patented extraction process produces very high, powerful levels of stress-fighting, cognition-enhancing ashwagandha bioactive constituents. Sensoril’s excellent safety record is one of the most comprehensive of any ashwagandha ingredient sold. Ashwagandha has been revered as an adaptogen for thousands of years. It is used to balance, energize, and revitalize the body and for its value as a cognition enhancer. Sensoril possesses multiple health benefits, and its superior efficacy has been demonstrated in randomized, double-blind, placebo-controlled human clinical trials. Recently, however, its powerful effects on restoring core clock transcript expression rhythms in the phase of Per1, Cry1, and Bmal1 genes in the Suprachiasmatic nucleus (the master regulator) of the brain have been recognized. Thus, this herb has powerful benefits on circadian rhythm restoration and the associated health gains!
References
1)Jagota, A., Kukkemane, K., & Thummadi, N. B. (2020). Biological Rhythms and Aging. Models, Molecules and Mechanisms in Biogerontology, 443–463. doi:10.1007/978-981-32-9005-1_20 
2)Jagota, A., & Kowshik, K. (2017). Therapeutic Effects of Ashwagandha in Brain Aging and Clock Dysfunction. Science of Ashwagandha: Preventive and Therapeutic Potentials, 437–456. doi:10.1007/978-3-319-59192-6_21 
3). Pingali U, Pilli R, Fatima N. Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy Res. 2014 Jan;6(1):12-18. [PMID: 24497737] 
4) Chengappa KN, Bowie CR, Schlicht PJ, et al. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013 Nov;74(11):1076-83. [PMID: 24330893] 
Suntheanine
Suntheanine is a pure form of L-theanine that is produced via a patented fermentation process, resulting in a 100% pure L-isomer theanine. Clinical research suggests that 50 to 200 mg/d of Suntheanine naturally stimulates activity in the brain known as alpha waves, which are associated with a relaxed but alert mental state. L-theanine had significant anti-stress effects on experimental animals under psychosocial stress. In humans, similar results were observed wherein L-theanine helped the body resist biochemical changes associated with stress.The disruption of the circadian rhythm has been shown to be involved in the development of coronary artery disease. This is one of the reasons many heart attacks and strokes happen early in the morning. L-Theanine treatment enhances the expression of clock genes, including Bmal1, Cry1, Rev-erbα, and Per2. and is able to help regulate the vascular circadian gene rhythm involved in the process of vascular smooth muscle structure to offer cardiovascular support
References
1)Wang R, Xiao M, Zhang Y, et al. RNA-Sequencing Analysis Reveals l-Theanine Regulating Transcriptional Rhythm Alteration in Vascular Smooth 
2)Tian X, Sun L, Gou L, et al. Protective effect of l-theanine on chronic restraint stress induced cognitive impairments in mice. Brain Res. 2013 Mar 29;1503:24-32. [PMID: 23395732] 
 3)Unno K, Tanida N, Ishii N, et al. Anti-stress effect of theanine on students during pharmacy practice: positive correlation among salivary α-amylase activity, trait anxiety and subjective stress. Pharmacol Biochem Behav. 2013 Oct;111:128-35. [PMID: 24051231] 
4) Yoto A, Motoki M, Murao S, et al. Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses. J Physiol Anthropol. 2012 Oct 29;31:28. [PMID: 23107346]
Banaba Leaf
We know that disturbed sleep patterns predispose people to obesity and diabetes. New research now shows that daily fluctuations in powerful hormones called glucocorticoids directly synchronize the biological clock as an integral part of our mechanism for regulating blood sugar.  Researchers from Stanford University School of Medicine have presented new research showing a direct link between glucocorticoid hormones and genes that regulate our biological clock.  The work could help diabetics control their blood sugar levels and may shed light on why night-shift workers are at risk for obesity and diabetes. Banaba leaf has a long history of use in folk medicine, particularly in Southeast Asia, as a glucose modulator. More recently, animal and human research on banaba leaf and its actives, including corosolic acid, suggest multiple mechanisms that influence glucose and lipid metabolism. Furthermore, corosolic acid inhibits the enzyme that facilitates the conversion of cortisone to cortisol. In light of this new research, these qualities make Banaba leaf the perfect adjunct to help restore the biologic clock!
References
1)Glucocorticoid regulation of the circadian clock modulates glucose homeostasis
Alex Y.-L. So, Teresita U. Bernal, Marlisa L. Pillsbury, Keith R. Yamamoto, Brian J. Feldman Proceedings of the National Academy of Sciences Oct 2009, 106 (41) 17582-17587; DOI: 10.1073/pnas.0909733106
2)Miura T, Takagi S, Ishida T. Management of diabetes and its complications with banaba (lagerstroemia speciosa l.) and corosolic acid. Evid Based Complement Alternat Med. 2012;2012:871495. [PMID: 23082086] 
3) Miura T, Itoh Y, Kaneko T, et al. Corosolic acid induces GLUT4 translocation in genetically type 2 diabetic mice. Biol Pharm Bull. 2004 Jul;27(7):1103-05. [PMID: 15256748]
4) Rollinger JM, Kratschmar DV, Schuster D, et al. 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches. Bioorg Med Chem. 2010 Feb 15;18(4):1507- 15. [PMID: 20100662] 
5) Dushkin M, Khrapova M, Kovshik G, et al. Effects of rhaponticum carthamoides versus glycyrrhiza glabra and punica granatum extracts on metabolic syndrome signs in rats. BMC Complement Altern Med. 2014 Jan 20;14:33. [PMID: 24444255]
Intermittent Fasting
Paolo Sassone-Corsi, Ph.D., the director of UC Irvine’s Center for Epigenetics and Metabolism showed that the central circadian clock in our brain isn’t the only clock but part of a whole network of internal clocks in the body. When these clocks get out of sync from our typical behaviors like sleeping and eating at odd hours, the result is weight gain, cognitive impairments and a host of other disease states. Fasting can reorganize the way genes are expressed in each cell and “prime the genome”.  Then, when feeding starts again, the clocks in each tissue are back in sync. Basically, fasting is like hitting the factory reset button to get all the systems back in order and restore an internal clock that might have gone rogue.BUT..for many the thought of fasting is simply inconceivable. So Over 20 years of extensive preclinical and clinical research sponsored by the National Institutes of Health and conducted at the Longevity Institute and Diabetes and Obesity Research Institute of the University of Southern California resulted in the development of the first Fasting Mimicking DIet (ProLon®) . This 5-day meal program provides scientifically researched micro- and macro-nutrients in precise quantities and combinations that nourish you, but are not recognized as food by your body and therefore mimics a fasting state! The ProLon Fasting Mimicking Diet is your secret to fasting – with real and delicious food.
References
De Cabo R and Mattson MP. Effects of intermittent fasting on health, aging, and disease. New England Journal of Medicine. 2019;381(26):2541-2551. doi: 10.1056/NEJMra1905136.
What else can I do?
There is also support that Deep (or Delta) Sleep Inducing Peptides (DSIP), a well-known neuromodulator and natural sleep-promoting  peptide naturally found in our brains, helps to reset the circadian rhythm. It has been extensively studied for over 40 years and has been used for the treatment of poor sleep, pain conditions, stress-related symptoms, low testosterone (via stimulation of LH), and even sometimes as an antioxidant and anti-cancer protein. It exhibits a pronounced stress protective action and decreases stress-induced metabolic and functional disorders in human and animal organisms. It has also been shown in research to improve hormone levels and physical performance.DSIP promotes sleep at night and improves alertness and performance during waking hours by targeting various areas of the brain. DSIP has been described as a sleep-correcting substance rather than a sedative. It appears to exert its effect by restoring circadian rhythms. When single and multiple injections of DSIP were given in a controlled double-blind study, disturbed sleep was normalized and better performance and increased alertness was seen during awake cycles together with improved stress tolerance and coping behaviour. Low concentrations of this peptide are seen in patients with schizophrenia and depression.

If you want to learn more about DSIP and peptides in general, feel free to contact our clinical partner Boulder Longevity Institute at 303-443-0848 to schedule your 15 minute free consult with our Peptide Specialist!
References
Gimble JM, Ptitsyn AA, Goh BC, Hebert T, Yu G, Wu X, Zvonic S, Shi X-M and Floyd ZE (2009). "Delta sleep-inducing peptide and glucocorticoid-induced leucine zipper: potential links between circadian mechanisms and obesity?". Obesity reviews 10: 46–51Kovalzon VM (1994). "DSIP: a sleep peptide or unknown hypothalamic hormone?". J. Evol. Biochem. Physiol. 30: 195–199.Pollard BJ and Pomfrett CJD (2001). "Delta sleep-inducing peptide".  Eur. J. Anaesthesiol. 18: 419–422.