Zachary Sheridan 10 January 2010 The Plague of the 21st Century Traveler An In-Depth Analysis of Jet Lag and the Biological Processes it Affects Abstract
Sheridan 2 In this investigation, the subject of jet lag or rapid time zone change syndrome was discussed. Jet lag is a syndrome that affects the circadian cycle of patients that rapidly change time zones by travelling in airplanes. Jet lag affects many travelers especially business travelers and this fact has led to the research question: What does Rapid Time Zone Change Syndrome or jetlag indicate about the human body and its circadian rhythm and how are the symptoms of jet lag treated? First, the process of the body s circadian cycle was analyzed. The circadian rhythm is a cycle which dictates several processes of daily life such as sleeping. The sleep-wake cycle is regulated using different genes such as clock, period, and cryptochrome which translate certain proteins which induce or inhibit sleep in a patient based on the amount of light that is captured through the eyes. Next, the disruptions which jet lag causes were analyzed and shown that they caused many symptoms including insomnia. There are several treatments available for the symptoms which fall into two main categories: non-invasive treatments such as light therapy and invasive treatments such as the controversial treatment of melatonin ingestion. After analyzing how jet lag affects the circadian rhythm and how they are treated, a conclusion was reached that jet lag can pose a serious risk for some people, especially those who have an underlying disease such as diabetes. Through the analysis of all aspects of jet lag and the circadian cycle, it was found that the disruptions which jet lag causes originates at the molecular level and may cause many physiological problems. However, these problems can be allayed using treatments such as light therapy and, if a treatment like light therapy does not work, more invasive treatments such as the intake of melatonin can be used to re-synchronize the patient s circadian cycle.
Sheridan 3 Table of Contents Introduction... 4 Analysis and Investigation... 7 The Process of the Circadian Cycle... 7 Disruption Caused by Jet Lag and Symptoms Experienced... 10 Treatments of Jet Lag... 12 Conclusion... 15 Bibliography... 17
Sheridan 4 Zachary Sheridan 2 January 2010 The Plague of the 21 st Century Traveler An In-Depth Analysis of Jet Lag and the Biological Processes Which it Affects Introduction In the 21 st century many people have felt the effects of travelling to other parts of the world in a relatively short amount of time due to the ever-growing technology of travel. Travelers, including business travelers and vacationers, have been afflicted with a syndrome called Rapid Time Zone Change Syndrome, better known as jet lag. Jet lag has been a problem ever since the commercial airplane was invented and put into use. Jet lag became a significant problem when air travel became more accessible to a wide variety of people. More importantly, in today s ever-shrinking world, more and more people are travelling to farther places and as a result, almost everyone has felt the effects of jet lag. Every person who travels far distances around the world by airplane has felt the effects time zone changes have had on their body. As I will elucidate, these effects are the result of a disruption of one s circadian rhythm the biological clock that regulates all biological processes in the body, including sleep. There has been an increase within research in the area of chronobiology (which entails the study of circadian rhythm) and as a result there have been several treatments to try to alleviate the symptoms of jet lag. However, there has not been a silver bullet cure or treatment for this common condition. The partial treatment or remedies that are used today all target the body s inherent biological clock or what has become known as the circadian clock.
Sheridan 5 Studies conducted on circadian behavior dates back to a French astronomer named Jean Jacques Ortous de Mairan. In 1729 de Mairan formulated an experiment based on the opening and closing of the leaves of a heliotrope in which he was very interested. De Mairan formulated an experiment to see if the movements were based on the light of the sun and the time of day. The procedures of de Mairan s experiment included putting a set of plants in a permanent dark place. He found out the plants leaves still opened and closed in what appeared to be a daily rhythmic motion (Bentley, Benzer and Binkley 4). He cautiously concluded the plants had some mechanism for an internal clock or cyclic regulation. This study has become a classic circadian experiment which influenced later scientists to develop a greater understanding of the process of circadian rhythm. One of the more well known scientists who was influenced by de Mairan s experiment was Charles Darwin who is known for his theory of evolution. In 1938, Nathaniel Kleitman and Bruce Richardson performed an experiment in which they tried to change their circadian cycles by living in Mammoth Cave in Kentucky for 32 days by shining artificial light on themselves. They wanted to test their hypothesis that they could change their circadian rhythm from a 24 hour cycle to a 28 hour cycle. The purpose of their experiment was to test if the normal circadian rhythms of organisms are just reactions to the environment. The results of the experiment were inconclusive but it sparked the interest of many scientists like Jurgen Aschoff who used the human isolation concept by putting people in bunkers and allowing them to turn on the lights whenever they felt like it. Aschoff concluded that the circadian rhythms of humans are not affected by light or other external variables in a pronounced way (Bentley, Benzer and Binkley pg.5 para. 1-2). In recent times, space travel has been used to study circadian rhythms in a more controlled manner. Scientists are able to test the effect of the lack of gravity on circadian rhythms. (Bentley, Benzer and Binkley pg. 5 para.3).
Sheridan 6 Studies have indicated that the lack of gravity has an effect on the circadian rhythms of organism ranging from unicellular organisms to the most complex multi-cellular organisms humans (Bentley, Benzer and Binkley pg.5 para.6). The word circadian comes from the Latin words circa and diem which means about and a day ( Definition of Circadian para.4). Circadian rhythms are approximately 24 hour cycles in which many organisms including animals and plants have that endogenously act as biological clocks. The circadian cycle is important to the life of an organism because the circadian cycle regulates biochemical, behavioral, and physiological processes within the organism. The circadian clock regulates these processes enabling the organism to function and live within the parameters of the light and dark cycles of the day which are a result of the position of the sun. Studies have shown there are factors or cues that can change or reset the circadian clock and are referred to as zeitgebers ( Definition of Zeitgeber para.2). An example of a zeitgeber is light which can reset the circadian clock. The word zeitgeber comes from the German words zeit which means time and geber which means giver. This term originated from the German scientist Jurgen Aschoff who made major contributions to the study of chronobiology ( Definition of Zeitgeber para.2). Investigations have uncovered occurrences when the circadian clock in humans is disrupted and as a result, patients can suffer from many different disorders. The factors that can cause disruptions in the circadian cycle include shift work, hormone regulation, medications, extreme time zone changes (jet lag), and certain changes in a person s routine. Some common circadian disruption disorders include Shift Work Sleep Disorder, Delayed Sleep Phase Syndrome, Non 24 Hour Sleep Wake Disorder, and probably the most common disorder, jet lag or rapid time zone change syndrome ( Circadian Rhythm Disorders para.4) The fact that jet lag
Sheridan 7 or rapid time zone change syndrome is a common occurrence especially in people who travel regularly has led me to develop the following research question: What does Rapid Time Zone Change Syndrome or jetlag indicate about the human body and its circadian rhythm and how are the symptoms of jet lag treated? Rapid Time Zone Change syndrome or jet lag indicates a disruption in the circadian rhythms of the patient, most noticeably in the sleep cycle. The rapid change of time zones from travel desynchronizes the rhythms of the body which results in a chemical imbalance in the patient. Consequently, many symptoms are expressed that can be alleviated or prevented by a variety of treatments which will be discussed. Analysis and Investigation The Process of the Circadian Cycle Before analyzing the effects and possible treatments of jetlag, the processes involved in the circadian cycle have to be discussed. The circadian cycle occurs at the genetic level in which certain genes and transcription activators are responsible for the increase or decrease of chemicals or hormones in the body. There has not been many studies with regards to the genetic processes of circadian rhythms in humans, but there has been many studies in mice and drosophila models which parallels those of humans. According to Wilma Eck, there are four main genes that have proven to be related in the regulation of the circadian cycle of drosophila and humans (para. 7). These genes are called CLOCK, PER (period), CRY (cryptochrome) and TIM (timeless). There are three PER gene homologs, two CRY homologs, and one TIM homolog. These genes code for certain messenger RNA (mrna) molecules which in turn code
Sheridan 8 or express certain proteins and hormones. These messenger RNA molecules are called mper1, mper2, mper3, mcry1, mcry2, and mtim1. In the brain, the suprachiasmatic nucleus (SCN), located in the hypothalamus, is the central pacemaker of the body which regulates all circadian rhythms including sleep (Ek para. 7). These genes interact with the SCN to regulate levels of hormones the body produces which ultimately regulate circadian activities. The CLOCK gene interacts with a transcription activator called BMAL1/MOP3 which increases certain levels of the aforementioned mrna molecules while decreasing other mrna molecules. The PER and CRY genes in turn inhibit the CLOCK/BMAL1 complex. Light is important to the circadian cycle because it acts as a regulator or timer for the cycle to reset or start the transcription/termination cycle over again. The light we see either from the sun or from artificial sources is captured through our eyes. The photosensitive ganglion cells of the retina capture the light information and the light (photons) is converted to electrical signals which are sent to the suprachiasmatic nucleus (Messersmith para. 6). Based on the amount of electrical signals the SCN receives, the SCN will activate transcription of the PER and CRY proteins. The two proteins enter the SCN and perform two different functions. The CRY proteins act as photoreceptors and regulate the Clock/BMAL1 complex based on the amount of light the person sees. On the other hand, the PER protein enters the SCN and interacts with the TIM protein to create a complex. This process occurs in a cyclic fashion with mper and mtim levels rising around midday which increase PER and TIM proteins that associate with each other forming dimers. There, dimers then enter the SCN and undergo a process of phosphorylation which continues throughout the night. Approximately four hours before dawn, the TIM/PER complex peaks, signaling the termination of the transcription of the two mrna molecules. The PER protein then
Sheridan 9 leaves the complex and the TIM protein is rapidly degraded (Ek para.5). Lastly, the whole cycle resets at about noon the next day by the master biological clock located in the suprachiasmatic nucleus (Ek para. 5). This master clock resets the cycle as a result from exposure to light with help from the interaction of the CRY and the TIM proteins (Ek para. 5). The SCN plays a major role in controlling other parts of the body (and the brain) including the cerebral cortex, in the pineal gland, and peripheral tissues such as liver, kidney and heart. (Reghunandanan and Reghunandanan 1). The SCN contains many neurotransmitters that affect the circadian rhythm in some way or affect the behavior of the person directly. These neurotransmitters include histamine, melatonin, serotonin, and nitric oxide. Histamine can reset the circadian cycle similar to that of light pulses (Reghunandanan and Reghunandanan 5) Serotonin is a neurotransmitter that regulates the pacemaker responses to light (Reghunandanan and Reghunandanan 7). Melatonin, which is secreted by the pineal gland, is mostly found in the SCN. Melatonin has several effects on the circadian rhythm which include sleep induction and shifting or amplifying the circadian cycle (Reghunandanan and Reghunandanan 7). The secretion of melatonin is controlled by the SCN but the presence of light terminates the secretion. There are other neurotransmitters in the SCN which play a role in the circadian cycle. For example, another major neurotransmitter is nitric oxide, which required in order to initiate phase changes of electrical activity (Reghunandanan and Reghunandanan 4). The SCN is the master clock which sets all circadian cycles and it is also the controller of vital organs, glands, and other part of the brain.
Sheridan 10 Disruption Caused by Jet Lag and Symptoms Experienced The body has an intricate cycle previously described in this paper that controls every circadian activity such as sleep, eating, and even movement. When a person flies across many time zones, this cycle gets desynchronized because the body is still synchronized to the previous time zone. This desynchronization has a negative effect on the SCN because it receives electrical signals that light is present but its internal clock indicates that it should be nighttime. This is where the problem of jet lag arises because the SCN is signaling to the organs and glands that it is nighttime which results in secretions of certain proteins like melatonin (a protein that induces sleep), lowers the glucose level in the blood, and lowers blood pressure. However, at the same time there are conflicting processes because it is daytime or it is earlier than the body recognizes it to be so the glands secrete nighttime hormones and proteins like melatonin. Suppression of melatonin will make the person feel fatigued but one knows it is not time to sleep. As a result, fatigue is the most common symptom of rapid time zone change syndrome (Cunha 1). Later the individual may have difficulty sleeping because the circadian clock is signaling it is daytime or early in the morning. Since the circadian clock is indicating that is time to get up, the hormones that were secreted at night have stopped being secreted and the individual has the urge to wake up. This symptom is called insomnia, and is another common symptom of jet lag simply due to the desynchronization of the circadian clock (Cunha 1). Another common symptom is anxiety (Cunha 2). Since the master clock is desynchronized, the individual will feel anxious often at nighttime because when the person wants to go to sleep, the body is raising blood pressure due to its clock indicating it is morning.
Sheridan 11 Patients suffering with jet lag also acquire other manifestations that are not directly associated with the circadian clock, but are as serious as the previously aforementioned symptoms (Cunha 1). One of these symptoms is dehydration which can result from extensive traveling. The patient will become dehydrated because oftentimes the patient will not drink as much water as they should while on the plane or they will drink an alcoholic beverage or a caffeinated beverage which can aid in dehydration. In addition, the dry atmosphere on the airplane increases the risk of dehydration especially if the person does not drink enough liquids (Cunha 3). Dehydration can lead to other secondary symptoms such as constipation, headache, or even confusion. Two other symptoms that a patient can experience from jet lag is nausea and irritability (Cunha 1). These symptoms could be caused by a variety of factors and could be a result of other symptoms. For example, the patient could be irritable or nauseous because they did not get enough sleep or no sleep at all during the flight. Another symptom which patients could experience is susceptibility to sicknesses because in some people, especially those who are not healthy, their immune system can be compromised from the lack of sleep and dehydration. There are some more serious symptoms that patients have reported after travelling through many time zones. These symptoms include irregular heartbeat, coordination problems, and memory loss (Cunha 1). These symptoms could be serious and should be treated by a physician as soon as possible. Every patient afflicted with rapid time zone change syndrome will not always experience these symptoms. There are some factors which have to be taken into account that would influence the type and severity of the symptoms the patient would experience. One factor is the direction of travel (Cunha 2). If the patient is travelling from east to west, the severity of the symptoms will be relatively low because the body is gaining hours. The more severe cases of jet
Sheridan 12 lag occur when the patient travels from west to east because the body will, in essence lose hours which will desynchronize the body s clock in a more detrimental way. Regardless of direction of travel, each person will be affected differently by jet lag. There are many factors which one must take into consideration that will influence how the patient will be affected such as age and their medical history. For example, a patient with an illness or disorder such as diabetes has a greater risk of serious complications if they travel across many time zones. Treatments of Jet Lag Since many people, especially today, have been afflicted with rapid time zone change syndrome, there has been an increase in research to try and alleviate the symptoms of jet lag and even cure the syndrome all together. There are two main categories in which all treatments of jet lag fit. There are non-intensive treatments and intensive, more dramatic treatments that are used to treat jet lag. The non-intensive treatments are those that the patient can use if they are experiencing mild symptoms of jet lag. The intensive treatments are treatments in which prescription medications or physician assisted procedures are taken if the non-invasive treatments are ineffective. These types of treatment are usually for patients who experience severe symptoms especially those related to sleep. The less intensive or non-intensive treatments of jet lag include simple steps for a patient to follow in order to reduce symptoms like fatigue or insomnia. The first step is for the patient to synchronize their body before they travel. This means that the patient should adjust their schedule to the time zone they will be travelling to a few weeks before travelling (Cunha 3). For example, if the time zone they will be travelling to is four hours ahead, the patient should go to sleep at least an hour earlier so that there will be less of a desynchronization when the patient
Sheridan 13 arrives at their destination. Another step is for the pateint to be healthy and fit before travelling (Cunha 3). When the patient is healthy and fit, they will be able to withstand more physical stress that the desynchronization will have on the body. Also if the patient is healthy, there is less of a risk of serious complications of jet lag. Another important step is to limit or cut out any consumption of caffeine or alcohol before or during the travelling period (Cunha 3). Alcohol and caffeine have the ability to modify and disrupt ones sleeping schedule which could amplify the symptoms the pateint will experince due to jet lag. Since the patient should not consume any alcohol or caffeine, the patient should drink plenty of water to avoid dehydration and constipation (Cunha 3). Getting up and walking around the airplane regularly is another way to reduce symptoms of jet lag (Cunha 3). Walking around the plane revitalizes and refreshes your body (Cunha 3) which can help to reduce fatigue by increasing physical activity. The last step a patient can take is to avoid or limit sleep medications when on an airplane (Cunha 3). Taking sleep medications can lead to the pateint becoming addicted to the medication as well as inactivity on the plane which can amplify the patient s symptoms. The patient should consult a physician before taking any sleeping medication while traveling. The second category of treatment for jet lag is invasive treatments in which the pateint takes a certain medication or undergoes a treatment process usually with the aid of a physician. There are fewer invasive treaments because some of them are deemed controversial or possibly unsafe. The two invasive treatments that will be discussed is melatonin intake, which is a chronobiotic, and light therapy. Melatonin is referred to as a chronobiotic because it relates to the treatment of the circdian clock. Melatonin has been a relatively controversial method to treat or even cure jet lag. The purpose of taking melatonin is to re-synchronize the patient s circadian rhythm by inducing sleep thus shifting the circadian cycle. The melatonin that is ingested by the
Sheridan 14 patient acts as the melatonin secreted by the pineal gland since the SCN is signaling to the pineal gland to not secrete melatonin. The body is tricked and receives the melatonin as if it was orginating from the pineal gland and sleep induction occurs. According to a 1989 study on the effects of melatonin on jet lag patients, Subjects taking melatonin reported less jet lag and took less time to recover from their shift across 12 time zones (Petrie, Conaglen, and Thompson 706). This study provided important evidence as a step towards an effective treatment of jet lag. However, there has been some controversy surrounding the subject of ingesting synthetic melatonin. First, No information has been compiled on the long-term effects of taking melatonin. (Cunha 4). The long term effects could negativley affect the health of the patient especially for people who travel often and would take melatonin frequently. Second, there are no standards for manufacturing over-the-counter melatonin pills (Cunha 4). The dosage required has not been a standard and some researchers believe that higher doses can reduce the effect of the melatonin on the circadian phase shifts as well as have a negative effect on the patient s heath. Curently in the United States, over-the-counter melatonin is considered a dietary supplement (Cunha 4). However, before a patient takes synthetic meltonin, they should consult their physician because it may have a harmful effect if combined with other prescription drugs. Melatonin is not a wide spread treatment for jet lag due to the controversy and lack of research. However a treatment that is widely used to treat jet lag is light therapy. Light therpay involves synchronizing a patient s circadian cycle by entraining the cycle using bright lights. The lights reset the circadian clock because the lights have the same effect on the body as sunlight. The patient is subjected to bright light for a specific amount of time. The time is figured out by what time zone the patient travelled from. As the patient sees the light, the light signals reach the suprachiasmatic nucleus by the process previously described and the SCN shifts the circadian
Sheridan 15 cycle according to the amount of light and the length of time the patient is subjected to it (Wilder para. 4-8). There are three types of light therapy that are currently used on patients. The first type of light therapy is a light box (Wilder para. 9). A light box is a box that contains several bright lights that are placed on a table or desk. The therapy involves the patient to face the box a certain distance away while doing a leisure activity like reading a book (Wilder para. 10-14). Another type of light therpay is a light visor (Wilder para 18). A light visor is similar to a regular visor that the patient would wear. The visor has lights on it that hang over your eyes (Wilder para. 19). This is a more mobile version of a light box and has the same purpose as a light box. The last type of light therapy is a dawn simulator (Wilder para. 20). A dawn simulator is a room that the patient enters in which the lights in the room simulate the rising of the sun (Wilder para. 20). This last method is different from the light box or light visor in that it does not involve bright lights but rather a gradual increase of intensity and amount of light. Conclusion Jet lag or rapid time zone change syndrome is widespread among many people especially in today s society where many people travel far distances. Jet lag is more oftentimes than not, deemed by many as just an annoying side effect of long plane rides. However, jet lag can pose a serious risk to a person s health because it relates to a desynchronization or disruption of the human body s biological clock or circadian cycle. Through this discussion, the process of this cycle has shown that a disruption could cause many physiological problems which start at the molecular level in a patient with jet lag. These problems can arise either as a direct result of the disruption of the circadian rhythm or as a secondary complication of the disruption. However, there are several treatments to alleviate the symptoms of jet lag. Some treatments involve simple
Sheridan 16 procedures or tips the patient could follow before, during, and after travel. In addition, if those simple steps do not work for them there are more dramatic treatments such as light therapy or an intake of a chronobiotic like melatonin. The molecular process of the circadian cycle is a relatively new discovery and it is still not fully understood. There could be more genes or RNA molecules involved in the process that were not known before. The process described in this discussion may very well be outdated in a few years due to new prevalent discoveries. There has also been an increased push in research in order to possibly find a cure for jet lag all together. In the process of that research, new and more effective treatments could be identified making light therapy a thing of the past. However, compared to the time when commercial airplanes were first built and the first signs of jet lag were seen, chronobiology has come a long way to make people s lives more comfortable and healthy when they travel long distances.
Sheridan 17 Bibliography Bentley, William, Seymour Benzer and Sue Binkley. Time Matters: Biological Clockworks. Howard Hughes Medical Institute. <http://www.hhmi.org/biointeractive/museum/exhibit00/index.html>. Bierman, Andrew, et al. A new approach to understanding the impact of circadian disruption on human health. Journal of Circadian Rhythms 6.7 (2008): 14. Circadian Rhythm Disorders. 2008 14-September. WebMD. 2009 йил 3-October <http://www.webmd.com/sleep-disorders/guide/circadian-rhythm-disorders-cause>. Cunha, John P. Jet Lag. MedicineNet. Ed. Melissa Conrad Stoppler. 2009 4-December <http://www.medicinenet.com/jet_lag/article.htm>. Definition of Circadian. 1998 23-July. MedicineNet.com. 2009 2-October <http://www.medterms.com/script/main/art.asp?articlekey=6766>. Definition of Zeitgeber. 2004 5-September. MedicineNet.com. 2009 3-October <http://www.medterms.com/script/main/art.asp?articlekey=11607 >. Ek, Wilma. The Molecular Genetics of Circadian Clocks. 1999 August. Pro Quest. 2009 14- November <http://www.csa.com/discoveryguides/archives/circad.php#g15>. Herxheimer, Andrew and Jim Waterhouse. The prevention and treatment of jet lag. British Medical Journal 326 (2003): 296-297. Messersmith, Donna. Clockwork Genes: Discoveries in Biological Time. Howard Hughes Medical Institute. 2009 12-November <http://www.hhmi.org/biointeractive/clocks/scn.html>.
Sheridan 18 Petrie, Keith, et al. Effect of Melatonin on Jet Lag After Long Haul Flights. British Medical Journal 298 (1989): 705-707. Reghunandanan, Vallath and Rajalaxmy Reghunandanan. Neurotransmitters of the suprachiasmatic nuclei. Journal of Circadian Rhythms 4.2 (2006): 20. Scientists identify DNA that regulates antibody production. 2009 19-November. 2009 26- December <http://newswire.rockefeller.edu/?page=engine&id=1000>. Wilder, Norman J. Bright Light Therapy. 2006 11-May. SleepEducation.com. 2009 21- November <http://www.sleepeducation.com/treatment.aspx?id=4>.