Have you ever wondered what makes you feel sleepy at night, and hopefully wakes you up again in the morning? Or, why you get jet-lagged when you travel to a different time zone? Why are some people night owls and others are larks? And, how do blind people know when to go to sleep and when to wake up? The answers to all these questions are based on a fascinating mechanism that we share with all living creatures, known as the circadian (about the day) rhythm or biologic clock.

Yes, I meant it. We share this biologic clock with other animals and plants, and even with bacteria. Obviously, this implies that it is probably essential to life itself. And you might guess that problems with its function can have serious consequences to your health.

So where is this biologic clock located in our body? And, what makes it tick?

 

The eyes have it

In the back of the eyes, there is a layer of cells, called the retina, populated by light-sensitive cells, called photoreceptors. There are two types of cells, rods, and cones, based on their shape. These cells are actually neurons, and when stimulated by light, they send an electric pulse to the optic nerve.

One of the curiosities of how we perceive the real world is the optic nerve from the left eye and the one from the right cross inside the brain. What we see on the left goes to the right hemisphere of the brain, and what we see on the right goes to the left. The crossing point is called the chiasma (from the Greek letter chi whose symbol is ?). Right above this crossing point there is a group of neurons called, for obvious reasons, the suprachiasmatic nucleus (SCN). Herein lies your biological clock!

One of the major ways the SCN tells us its time to go to bed or to wake up is by sending axons to a tiny pine cone-shaped gland sitting above it, appropriately named the pineal gland. This rice-sized gland, in response to stimuli from the SCN, secretes the hormone melatonin, which induces sleepiness. But that’s not all it does. Anybody who ever traveled across time zones knows that not only do you get jet-lagged, but your digestive system (yes, I mean bowel movement) is out of whack as well, and so is your alertness, reaction time, body temperature, blood pressure—in short, your whole physiology.

 

What’s your circadian cycle?

On average, melatonin secretion starts at about 9 PM and stops about 7:30 AM. But none of us like to think of ourselves as average. Indeed, most of us would classify ourselves as “morning person” or “evening person.” So what makes one a lark or a night owl?

Morning people have their melatonin secretion start early, around 7 PM. These are the people that cannot last past the first 15 minutes of the evening news. But they are sprightly and irritatingly cheerful at the ungodly hour of 5-5:30 AM.

Evening people are at the opposite extreme. Their melatonin secretion starts at around 11 PM and wanes at about 9 AM.

Anybody who has had a teenager son or daughter has experienced the painful ordeal of waking them up in time for school. Are they lazy, or is this some kind of a teenage rebelliousness? None of the above.

During adolescence the circadian rhythm changes and because of this most teens experience a sleep phase delay. This shift in teens’ circadian rhythm causes them to naturally feel alert later at night, making it difficult for them to fall asleep before 11:00 pm. Since most teens have early school start times along with other commitments, this sleep phase delay can make it difficult to get the sleep teens need—an average of 9 1/4 hours, but at least 8 hours.

 

Watching over many watches

How does melatonin influence the functions of such diverse tissues as brain, lungs, adrenal glands, esophagus, pancreas, spleen, liver, even skin? If melatonin had to wake up every single cell in the morning and put it to sleep at night, it would probably fail miserably. After all, a skin cell and a pancreas cell are very different both structurally and metabolically.

As a solution to this dilemma, evolution came up with sort of a Federal System. The cells in each of the tissues have their own “molecular oscillators”. The basic genetic influence is the same in all of them, but each is influenced by local epigenetic modifications, cell metabolism, oxidative stress, and many other local conditions. The remarkable thing is that all these local tissue cycles have a 24-hour period. Melatonin, “the Feds” so to speak, synchronizes them so they all work together as one system.

Is it that surprising that all cells in the body have their own molecular 24-hour clock? Not really. Remember that a circadian cycle is as ancient as life itself. It is vital to survival because of the living organisms dependence on light/darkness cycles.

However, the utility of the circadian cycle varies by tissue. Consider the liver, for example. Its dependence on a light/dark cycle is secondary at best. This is because it needs to react to hormonal cycles that regulate feeding and blood protein synthesis. So we find that the liver, compared to some other tissues, is only weakly regulated by melatonin, and is, in fact, much more responsive to feeding cycles.

 

What about the blind?

Of the 200,000 totally blind people in the U.S., up to 70% suffer from severe sleep disorder. They may experience bouts of sleepiness in the middle of day and be wide awake during the night. Many of them notice that the periods of sleepiness actually shift forward by half an hour to an hour every day. What’s happening?

The neurons of the biological clock, like any other cell in the body, have their own metabolic oscillator, free of any input from the light/dark cycle. But this free-running cycle is slightly longer; it runs at about 12.2 hours. Among sighted people, the clock is reset each day by the light-sensing retinal cells in the eyes that signal to the brain that it is daytime. But a blind person will accumulate a delay of about 0.4 hours, or 24 minutes, every day or about an hour every 3 days. You can see how this can cause severe sleep disorder over time.

 

Synthetic melatonin

Problems with wake/sleep cycle are not restricted to the blind. Sighted people may suffer from the same problem. These people, sighted and blind, grouped together as “non-24 hour”, have something in common: their circadian cycle is out of kilter, usually longer than the normal.

Fortunately, synthetic melatonin works for people with sleep disorders, including the blind. A daily dose of 10 mg restores people to the light/dark circadian cycle. This restoration to normal is called entrainment and is not restricted to blind people only. It works for sighted people, whose circadian rhythms are altered by jet lag or shift work.

Researchers still know little about the effective doses of melatonin. One of the reasons is that people with wake/sleep cycle problems react differently to the hormone. So right now, dosing is a matter of trial and error. The hormone is sold over the counter as a nutritional supplement, usually in 3-milligram tablets. Taken in the afternoon, it shifts the body’s clock earlier, tricking it into thinking dusk has already fallen. Taken in the morning, however, it delays the clock, as if dawn had not yet arrived.

For people who cannot tolerate melatonin, the synthetic drugs ramelteon (Rozerem), agomelatin (Melitor), and tasimelteon (Hetlioz), have been approved by the FDA. These drugs have structures that mimic that of melatonin, and work by occupying the melatonin receptors.

 

That’s not all…

Our daily life is regulated by the circadian cycle of dark/light. But here is a teaser. There is another biological clock that governs our lives. In fact, this clock determines how long we live. Who amongst us is not dying to know this secret to life? The good news is that the story of this super-clock is the subject of my next post.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

5 COMMENTS

  1. Very interesting article! I have insomnia for 3 years now. When it started, I used to wake up at 4 am, getting earlier thru the years till now, when I wake up at 1am. From thereon, I’m half asleep. My brain is awake altho my body want wants to lie fown and try to sleep. How should I take melatonin?

  2. It’s a coincidence, IMO.
    Most people have no idea what time they were born (and many don’t have their birth certificates), so to study it scientifically would be impossible. Not to mention, no one would pay for such a study.

    If you believe in astrology, however, you may believe whatever you like!

  3. Fascinating, but is there any co-relation between the time of the day that you were born, and the time of the day that your melatonin secretion starts? My mother tells me that I was born at about 06.30 hrs and I am definitely a morning person. My son on the other hand was born at 0100 hrs and is definitely a night owl.
    Is this just coincidence?

LEAVE A REPLY

Please enter your comment!
Please enter your name here

This site uses Akismet to reduce spam. Learn how your comment data is processed.