Study: Caffeine before bedtime offsets your internal clock

A study shows that drinking caffeine three hours before bedtime can delay your internal clock significantly.

A double espresso three hours before bedtime can induce a 40-minute time delay in your body's internal clock, making it harder to go to sleep on time and more challenging to wake up in the morning, scientists have shown for the first time.

The study led by the University of Colorado Boulder and the Medical Research Council's Laboratory of Molecular Biology in Cambridge, shows for the first time that evening caffeine delays the internal circadian clock that tells us when to get ready for sleep and when to prepare to wake up.

The research team showed the amount of caffeine in a double espresso or its equivalent three hours before bedtime induced a 40-minute phase delay in the roughly 24-hour human biological clock.

The study also showed for the first time how caffeine affects "cellular timekeeping" in the human body, said CU-Boulder Professor Kenneth Wright, who co-led the study.

"This is the first study to show that caffeine, the mostly widely used psychoactive drug in the world, has an influence on the human circadian clock," said Wright.

"It also provides new and exciting insights into the effects of caffeine on human physiology," he said.

For the study the team recruited five human subjects, three females and two males, who went though a double-blind, placebo-controlled 49-day protocol.

The subjects were tested under four conditions: low light and a placebo pill; low light and the equivalent of a 200-milligramme caffeine pill dependent on the subject's weight; bright light and a placebo pill; and bright light and the caffeine pill.

Saliva samples of each participant were tested periodically during the study for levels of the hormone melatonin, which is produced naturally by the pineal gland when directed to do so by the brain's "master clock."

The master clock is re-set by exposure to light and coordinates cellular clocks throughout the human body.

Melatonin levels in the blood increase to signal the onset of biological nighttime during each 24-hour period and decrease at the start of biological daytime, said Wright.

Those who took the caffeine pill under low-light conditions were found to have a roughly 40-minute delay in their nightly circadian rhythm compared to those who took the placebo pill under low light conditions, said Wright.

The magnitude of delay from the caffeine dose was about half that of the delay induced in test subjects by a three-hour exposure to bright, overhead light that began at each person's normal bedtime.

The study also showed that bright light alone and bright light combined with caffeine induced circadian phase delays in the test subjects of about 85 minutes and 105 minutes respectively.

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Drinking caffeine in the evenings can cause a 40-minute delay in the circadian clock phase

A study shows that drinking caffeine in the evenings can have effects in a person's circadian clock such as a 40-minute phase delay.

It's no secret that slugging down caffeinated drinks in the evening can disrupt sleep.

But a new study led by the University of Colorado Boulder and the Medical Research Council's Laboratory of Molecular Biology in Cambridge, England shows for the first time that evening caffeine delays the internal circadian clock that tells us when to get ready for sleep and when to prepare to wake up. The research team showed the amount of caffeine in a double espresso or its equivalent three hours before bedtime induced a 40-minute phase delay in the roughly 24-hour human biological clock.

The study also showed for the first time how caffeine affects "cellular timekeeping" in the human body, said CU-Boulder Professor Kenneth Wright, who co-led the study with John O'Neill of the Medical Research Council's Laboratory of Molecular Biology (LMB) in Cambridge. While it has been known that caffeine influences circadian clocks of even primitive creatures like algae and fruit flies, the new study shows that the internal clocks in human cells can be impacted by caffeine intake.

"This is the first study to show that caffeine, the mostly widely used psychoactive drug in the world, has an influence on the human circadian clock," said Wright, a professor in CU-Boulder's Department of Integrative Physiology. "It also provides new and exciting insights into the effects of caffeine on human physiology."

A paper on the subject led by Wright and O'Neill is being published online in the Sept 16 issue of Science Translational Medicine.

For the study the team recruited five human subjects, three females and two males, who went though a double-blind, placebo-controlled 49-day protocol through CU-Boulder's Sleep and Chronobiology Laboratory, which is directed by Wright. The subjects were tested under four conditions: low light and a placebo pill; low light and the equivalent of a 200-milligram caffeine pill dependent on the subject's weight; bright light and a placebo pill; and bright light and the caffeine pill.

Saliva samples of each participant were tested periodically during the study for levels of the hormone melatonin, which is produced naturally by the pineal gland when directed to do so by the brain's "master clock." The master clock is re-set by exposure to light and coordinates cellular clocks throughout the human body. Melatonin levels in the blood increase to signal the onset of biological nighttime during each 24-hour period and decrease at the start of biological daytime, said Wright.

Those who took the caffeine pill under low-light conditions were found to have a roughly 40-minute delay in their nightly circadian rhythm compared to those who took the placebo pill under low light conditions, said Wright. The magnitude of delay from the caffeine dose was about half that of the delay induced in test subjects by a three-hour exposure to bright, overhead light that began at each person's normal bedtime.

The study also showed that bright light alone and bright light combined with caffeine induced circadian phase delays in the test subjects of about 85 minutes and 105 minutes respectively. There were no significant differences between the dim light/caffeine combination and the bright light/placebo combination. Nor were there significant differences between the bright light/placebo and bright light/caffeine combinations. The results may indicate a "ceiling" was reached in the phase delay of the human circadian clock due to the external factors, Wright said.

In addition, researchers at O'Neill's lab at the LMB in Cambridge used "reporter" genes that made cells glow when the clock genes were expressed to measure changes caused by caffeine. O'Neill's group showed that caffeine can block cell receptors of the neurotransmitter adenosine, which normally promotes sleep and suppresses arousal.

The results may help to explain why caffeine-drinking "night owls" go to bed later and wake up later and may have implications for the treatment of some circadian sleep-wake disorders, said Wright.

The new results could benefit travelers. Properly timed caffeine use could help shift the circadian clocks of those flying west over multiple time zones, said Wright.

In a 2013 study, Wright and his research team showed one week of camping in the Rocky Mountains with no artificial light, not even flashlights, synchronized the circadian clocks of the eight study subjects with the timing of sunrise and sunset.

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Study: People with autism may be more susceptible to genetic sleep issues

A study indicates that people with autism might be more susceptible to carrying genetic mutations that changes their circadian clock.

People with autism are twice as likely to carry alterations in genes that regulate the circadian clock, or the body’s sleep-wake cycle, as those without the disorder. The findings, published 6 May in Brain and Development, may help to explain why most children with autism have troubled sleep¹.

Insufficient sleep is known to exacerbate the core symptoms of autism, such as social deficits and repetitive behaviors. The new findings suggest that the relationship between sleep and autism may have genetic roots.

“Sleep disturbance seems to be a main feature of autism,” says lead researcher Takanori Yamagata, professor of pediatric developmental medicine at Jichi Medical University in Shimotsuke, Japan. “My hypothesis is that some circadian genes may be related to some of the genetics of autism.”

To investigate this potential link, Yamagata and his team sequenced 18 genes known to govern the body’s day-night rhythms in 28 children and adults with autism, half of whom have sleep disorders, as well as 23 controls.

They identified a total of 68 mutations in 15 of these genes. About half of the mutations are ‘silent,’ which means they have no effect on the proteins the genes encode. But the other half are ‘missense’ mutations that disrupt the corresponding protein sequence. Nine of the mutations had never been reported before, Yamagata says.

People in the autism group have about twice as many mutations in circadian genes as do members of the control group, regardless of whether they have a sleep disorder.

Within the autism group, the researchers found seven missense mutations among individuals who have sleep disorders and the same number in those who sleep normally. By contrast, just one person in the control group carries a missense mutation in a circadian rhythm gene.

“We detected many mutations only in patients with autism, but almost nothing in the control group,” Yamagata says. “So I think these genes relate to some pathophysiology of autism.”

The researchers then used three types of computer algorithms to predict the impact of the missense mutations on the gene’s function. They found that 25 of the 33 missense mutations are likely to be benign, but 8 appear to be damaging.

One of the analyses found more damaging mutations in the individuals with autism who have sleep disorders than in those who sleep normally.

But the algorithms did not agree on which mutations are likely to be harmful. “Some of these virtual programs may reflect real damage, but they are not perfect,” Yamagata says.

The researchers are investigating whether these eight mutations in circadian genes interfere with brain development in mice. They’re starting with a mutation in a gene called TIMELESS that they found in a 9-year-old boy with autism who sleeps all day and stays awake all night. The boy’s mother, who also struggles with sleep but does not have autism, has the same mutation.

The results of these mouse studies may help elucidate the genetic relationship between sleep and autism.

“It is not yet clear exactly what the basis of this interaction is,” says Mustafa Sahin, associate professor of neurology at Harvard Medical School, who was not involved in the study. “It will be very interesting to further investigate the effects of these sequence variations.”

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How to avoid issues from Daylight Savings Time

With Daylight Savings on March 8th, we will lose an hour of sleep. This article explains why it may be an issue for people and gives tips on how to avoid any problems.

You may find you feel a little more tired than usual next month as you adjust to the start of Daylight Saving Time, which begins at 2 a.m on Sunday, March 8.

“An hour seems like a minor change, but moving the clock ahead one hour can be very stressful or disruptive for some people, particularly for those who are already sleep deprived,” says to Jeffrey P. Barasch, M.D., FACCP, FAASM, Medical Director of The Valley Hospital Center for Sleep Medicine.

“The problem goes beyond just the loss of a single hour of sleep on the night of the clock change,” Dr. Barasch says, “The time change also plays havoc with the body’s circadian rhythm, or biological clock.”

This biological clock, located within a part of the brain behind the eyes, determines when we feel alert and when we are sleepy. The internal clock keeps our bodies synchronized with the daily light-dark cycle of the outside world. The biologic clock is ‘set’ or fixed to the time of day by two factors: the time we regularly wake up in the morning and our exposure to sunlight during the day. It can be reset, but (as anyone who has traveled by airplane across several time zones has experienced), the biological clock cannot be adjusted too quickly.

When we move the time clock one hour earlier for daylight savings time, our bodies remain partly on the prior schedule (known as ‘jetlag’ in plane travel). The result: 7 am in daylight savings time is equivalent to 6 a.m. standard time. Also, your typically sunlit mornings will now be dark, and that lack of morning light makes it even more difficult for your internal clock to adjust. So not only are we losing an hour of sleep, but since it can take some time to readjust, we’re left feeling tired for more than the one day on which the clocks change.

People who normally sleep well can usually adjust to the time shift with relatively little difficulty. However, if someone has been barely coping with an undiagnosed and untreated sleep disorder, daylight saving time can exacerbate and therefore unmask problems such as sleep apnea, insomnia or periodic limb movement disorder.

The following tips from Dr. Barasch can help you get a good night’s sleep:
• On the nights after the time change, go to bed at your usual time. You may experience some difficulty falling asleep, because your body’s clock has not yet adjusted.
• Get up at your usual time regularly. Although you may find this a bit difficult, it will help you adjust to the time change.
• Avoid sunlight or bright light in the first few evenings after the time change, as this will tend to keep you awake later and prevent adjustment of your body’s clock.
• Try to get sunlight exposure soon after awakening in the first few mornings after the time change, as this will help you adjust to the new time.
• A short nap can help make up for less sleep, but won’t help you acclimate to the new schedule. Don’t nap within a few hours of your regular bedtime to avoid disrupting nighttime sleep.
• Create a sleep-friendly environment that is dark, cool, comfortable and quiet.
• Have a relaxing routine before bedtime, such as soaking in a hot bath, reading or listening to soothing music.
• Avoid caffeine, nicotine and alcohol for several hours prior to bedtime, as they can disrupt sleep.

If you regularly experience daytime drowsiness, fatigue or disturbed sleep, speak to your doctor or consult with a sleep medicine specialist.

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Health consequences of sleep disorders

This article discusses the different health consequences of sleep disorders and issues with an internal clock.

Ulcers, hyperglycemia, diabetes, hypertension, gastric intestinal problems are not always caused by diet - they could be linked to a disrupted internal clock.

Working a job that requires shift-work or experiencing chronic jet lag disrupts your circadian rhythm. It results in countless consequences to your body that simply can’t be fixed by counting sheep.

“Stimulants such as caffeine can disrupt a patient’s circadian rhythm but also irregular sleep habits, jet lag, Delayed Sleep Phase Disorder, which is common in teenagers, Shift Work Sleep Disorder and Advanced Sleep Phase Disorder, which is common in older people,” says Dr. Baqhar Mohideen, the medical director of the Center for Sleep Medicine at Porter Regional Hospital.

“A quarter of American workers are on shift-work – 10 percent of which experience Shift Work Sleep Disorders.”

Delayed Sleep Phase Disorder is when patients fall asleep late and have difficulty waking up in the morning. Shift Work Sleep Disorder affects patients who work nights or rotating shifts. Advanced Sleep Phase Disorder is when patients go to bed early in the evening but wake up very early in the morning around 3 a.m., for example.

Our bodies work on a 24-hour cycle called circadian rhythm or internal clock. The main function of our internal clock is to determine when we sleep and when we wake. Unfortunately if a circadian rhythm is disrupted it affects many biological conditions in the body such as digestion, the release of certain hormones, body temperature, etc.

“Because your hormones are all mixed up, there are lots of consequences – ulcers, chronic fatigue, insulin resistance, glucose intolerance, diabetes, etc.” says Mohideen, who is a Diplomat of the American Board of Sleep Medicine.

Glucose intolerance is an umbrella term for metabolic conditions which result in higher blood glucose levels known as hyperglycemia.

Dr. Muhammed Najjar, sleep specialist at the Franciscan Healthcare Sleep Disorders Center located in Munster, agrees there are consequences for a disrupted circadian rhythm caused by Shift Work Sleep Disorder.

“Daytime functions shouldn’t be at night. When there’s a misalignment between the patient’s internal clock and the outside world, it’s not good for the body,” says Najjar. “Shift work causes stress to the body so blood pressure gets elevated, which is why this disorder can cause hypertension. Treating circadian rhythm disorders can help lower blood pressure.”

Najjar says besides patients experiencing the side effects of a disrupted circadian rhythm there are side effects to sleep deprivation also.

Sleep deprivation affects hormones as well which can lead to body weight and body mass index issues. Gastrointestinal tract problems can surface and it can also cause insulin sensitivity which can lead to diabetes. A patient’s body can also become resistant to treatment.

“Many patients are sleep deprived because when they do sleep, it’s not adequate sleep. This affects their level of alertness and they can become accident-prone,” says Najjar. “If a patient’s shift work schedule rotates, or they sleep with a different pattern on their days off, it’s like having continual jet lag —the circadian system never gets the chance to fully catch up.”

The process of adjusting the internal clock with cues from the environment is called entrainment. Light is a stimulant and can effectively re-align one’s circadian rhythm.

Mohideen says some patients take medication or melatonin to assist in the readjustment process.

Melatonin is a body clock hormone that chemically causes drowsiness and lowers the body temperature in preparation for sleep.

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Study: Genes link circadian clock to eating schedule

A study found that specific genes link a person's circadian clock to their eating schedule.

For most people, the urge to eat a meal or snack comes at a few, predictable times during the waking part of the day. But for those with a rare syndrome, hunger comes at unwanted hours, interrupts sleep and causes overeating.

Now, Salk scientists have discovered a pair of genes that normally keeps eating schedules in sync with daily sleep rhythms, and, when mutated, may play a role in so-called night eating syndrome. In mice with mutations in one of the genes, eating patterns are shifted, leading to unusual mealtimes and weight gain. The results were published in this month's Cell Reports.

"We really never expected that we would be able to decouple the sleep-wake cycle and the eating cycle, especially with a simple mutation," says senior study author Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory. "It opens up a whole lot of future questions about how these cycles are regulated."

More than a decade ago, researchers discovered that individuals with an inherited sleep disorder often carry a particular mutation in a protein called PER2. The mutation is in an area of the protein that can be phosphorylated -- the ability to bond with a phosphate chemical that changes the protein's function. Humans have three PER, or period, genes, all thought to play a role in the daily circadian clock and all containing the same phosphorylation spot.

The Salk scientists joined forces with a Chinese team led by Ying Xu of Nanjing University to test whether mutations in the equivalent area of PER1 would have the same effect as those in PER2 that caused the sleep disorder. So they bred mice to lack the mouse period genes, and added in a human PER1 or PER2 with a mutation in the phosphorylation site. As expected, mice with a mutated PER2 had sleep defects, dozing off earlier than usual. The same wasn't true for PER1 mutations though.

"In the mice without PER1, there was no obvious defect in their sleep-wake cycles," says Panda. "Instead, when we looked at their metabolism, we suddenly saw drastic changes."

Mice with the PER1 phosphorylation defects ate earlier than other mice -- causing them to wake up and snack before their sleep cycle was over -- and ate more food throughout their normal waking period. When the researchers looked at the molecular details of the PER1 protein, they found that the mutated PER1 led to lower protein levels during the sleeping period, higher levels during the waking period, and a faster degradation of protein whenever it was produced by cells.

Panda and his colleagues hypothesize that normally, PER1 and PER2 are kept synchronized since they have identical phosphorylation sites -- they are turned on and off at the same times, keeping sleep and eating cycles aligned. But a mutation in one of the genes could break this link, and cause off-cycle eating or sleeping.

"For a long time, people discounted night eating syndrome as not real," says Panda. "These results in mice suggest that it could actually be a genetic basis for the syndrome." The researchers haven't yet tested, however, whether any humans with night eating syndrome have mutations in PER1.

When Panda and Xu's team restricted access to food, providing it only at the mice's normal meal times, they found that even with a genetic mutation in PER1, mice could maintain a normal weight. Over a 10-week follow-up, these mice -- with a PER1 mutation but timed access to food -- showed no differences to control animals. This tells the researchers that the weight gain caused by PER1 is entirely caused by meal mistiming, not other metabolic defects.

Next, they hope to study exactly how PER1 controls appetite and eating behavior -- whether its molecular actions work through the liver, fat cells, brain or other organs.

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