Although we sometimes lose track of time and are surprised to discover the hour, our bodies have usually already reminded us that it’s way past bedtime, or that we should have eaten lunch an hour ago. Actually, our bodies are very good at keeping time and can count not just in minutes or months but in years too. The biological clocks we have on board help keep our bodies running on schedule, because we are complicated machines and our efficient running depends not on pell-mell, anything-goes activity, but on a carefully timetabled programme. Hormones, for example, are not released any old how, but in a carefully controlled way. Growth hormone at night, testosterone in the early morning, gonadotrophin releasing hormone every ninety minutes and so on.
Although we may think that we are agents of free will, much of what we do, and more pertinently, when we do it, is dictated by our body clock. Here again we find hormones in the thick of it. Not only is the messenger slave of the body clock a hormone, melatonin, but many of our other hormones can also have a time-warping effect, making time appear to run either more quickly or more slowly. The truth about hormones and time is the subject of this chapter.
Hormones and Stopwatches
If something interests you – reading this chapter, for instance – time will seem to pass quickly. But if – and I hope this is unlikely – you are already bored by the end of this paragraph, time will appear to drag. This effect – think of it as the ‘watched kettle’ syndrome – is not just an artefact of our mind but the hallmark of a ‘stopwatch’ in the brain, the so-called interval timer that marks spans of up to two hours. The onset of an event lasting a familiar amount of time – say a traffic light at the bottom of your road changing to red – activates the start button of the interval timer which is located in the brain. Hitting ‘start’ gets a particular sub-set of nerves that normally fire at will to sing from the same songsheet, as it were, and to fire in a coordinated way. Meanwhile, a whoosh of the nerve transmitter dopamine is released. Both of these things together wake up a particular set of brain cells, which proceed to monitor this unusual phenomenon until the nerves return to their random pattern of yore.
So, your red-light watching creates a unique pattern and when, once again, you are sitting in front of that light, and the pattern begins once more, the monitor in the brain (actually spiny cells in the striatum, if you want the science) recognizes and tracks it. When the monitor reckons (from past experience) the red light should turn to amber, it sends a ‘time’s up’ signal to the decision-making centres of the brain. For people with diseases that affect dopamine release – like Parkinson’s – time runs slow, and they consistently underestimate the length of intervals of time. Marijuana has the same effect. On the other hand, recreational stimulants like cocaine and amphetamine, which increase the availability of dopamine, expand time. Stress hormones, such as cortisol or adrenaline, can also slow down the sense of time passing as they too increase dopamine. This is why, during stressful, nasty experiences, every second feels like an hour. It’s also why, when you are late, and freaked out by traffic, with your child still waiting on the school’s doorstep to be collected, red lights cruelly seem to stay red for ever. It’s your hormones tinkering with your interval timer.
Down Memory Lane with Your Hormones
Now let me digress a moment, to think about times past. Many people are able to recall where they were when they heard a particular piece of news – 9/11 for instance, or the assassination of President Kennedy. Here, the emotions of an event that we perceive to be highly consequential to our lives seem to burnish memory. It is very clear that stress hormones affect memory formation, as memories recorded at the time of a traumatic or very emotional event appear to be ‘burnt in’, remaining vivid for decades. There is an odd flashbulb effect to these memories, with some aspects (not always the most important) being recorded in minute detail, while others are hazy. For instance, someone might remember a brooch on a dress of woman involved in an accident, but not the style or length of the dress or what she was carrying, or another detail altogether – the noise made by rain falling, or a smell – yet not who was standing next to them at the time.
One of the most miserable days of my life took place on a quiet sunny day in September 1997. For fifteen years, I ran a mother and baby research charity, and for twelve of them worked closely with Diana, the Princess of Wales, who was the charity’s patron. She was not only very dear to me, but had been a hugely important part of my working life. As I stood in Westminster Abbey, waiting for the arrival of the coffin, I was struggling to stay in control. Then, amid unbearable silence, came a creak, creak sound. It was the noise made by the boots of the guardsmen bearing the coffin. I remember every moment of the next hour and the way, as the coffin left, that overwhelming grief forced its way from somewhere visceral to emerge in a choking soundless howl. To this day I have no idea of who was next to me or how I got home. About two months later I was making a programme on hypnosis for the BBC. I did not considered myself suggestible, but the hypnotist Paul McKenna still managed to hypnotize me. The producers told me that I had sat there for twenty-five minutes with tears rolling down my face. When Paul asked me what I had been thinking of, the words simply fell out of my mouth unbidden. The creak of the guardsmen’s boots. Such is the power of memory burnt into the brain’s circuits by hormones.
The hippocampus, which plays a critical role in memory tasks and spatial learning, is the area of the brain which is richest in stress hormone receptors. Sudden acute elevations of the stress hormone cortisol enhance memory formation, while chronic long-term exposure can cause black holes in the memory. Typically memory is a problem for those with depression, in whom cortisol levels are elevated.
Why should such memory-enhancing occur? With traumatic events, it is about survival. The stress hormone rush that accompanies a near-death moment and the subsequent laying down of memory ensures that you learn from it, and don’t make the same mistake twice. Unfortunately for those with post traumatic stress disorder, this survival tactic has become so overwhelming as to be severely disabling, with vivid memories being a constant intrusion.
The Hormone of Sleep and Time – Melatonin
The circadian clock (from circa – about, and diem – a day) tunes our bodies to the cycles of light and dark caused by the earth’s rotation. The clock synchronizes our activity so that we are at our most active when food, sunlight and prey are available (or, in our modern age, when Sainsbury’s is open). It also prioritizes certain types of behaviour with the seasons – nesting in spring, hibernating in autumn – which ensures that young are produced when food is at its most plentiful.
The clock doesn’t just control cycles of sleep and wakefulness but also rigorously schedules our physiology. Under its influence, the activity of almost every system in the body varies predictably across a twenty-four-hour period. For instance, our body temperature peaks in the early evening (as those of you with fretful children with fevers will know) and drops to its nadir at about 4.30 in the morning, as does concentration and cognitive processing. Urine collection is suppressed overnight, with bowel movements similarly hobbled from about about 10.30 p.m. The most likely time for your bowel to evacuate the remains of yesterday’s lunch and supper is 8.30 a.m. Blood pressure rises very sharply at about 6.45 a.m., reaching a peak at 6.30 p.m. You are at your perkiest and most alert at 10 a.m., with best coordination at 2.30 p.m. Maximal sports performance is in the early evening – which is when most world records are broken – perhaps not surprising since this time is when cardiovascular efficiency, muscle strength and flexibility are all at their daily peak.
Hormones, too, are under the clock’s domain. For instance, twenty times as much cortisol is produced in the morning (between 4 and 8 a.m.), growth hormone and prolactin, the hormone of milk production, are secreted in greatest quantity an hour after sleep, and testosterone drives libido hardest, as it were, first thing in the morning. It’s not just daily rhythm of hormone production that is set by the clock. Hormones change with the seasons, in animals at least, and with passing time, from puberty, when the hormones that prompt action within testis and ovary are pumped out, mostly at night, in industrial quantities, to adulthood, when these are secreted in pulsed doses throughout a twenty-four-hour period.
The clock is set by light, which is just as well, because away from light the clock lacks the precision we expect of the finest timepieces. Tucked deep in a cave, our true rhythms would show themselves – and although they are close to twenty-four hours, they’re consistently out – 24.2-hour days to be exact, or, for some blind people, twenty-five hour days. So what, you might say, an extra twelve minutes a day – does it matter? Actually it matters a great deal. Over a period of time we would drift out of phase with the sun, and do inappropriate things, like (if we were mice) emerge from burrows at inadvisable times, or (as humans), sleep through Sunday lunch or want to shop at 3 a.m. Every day, the clock is reset through our exposure to light, and has a preference for natural light. We think, particularly in the dead of winter, that it is brighter inside than outside. Actually, we are deceived: soon after dawn, natural light is fifty times brighter than normal office lighting. At noon, natural light is up to a thousand times brighter. Even in winter. Even in Britain.
So where is this clock and how does it work? Is there a hormone in it somewhere? You bet.
Ten years ago, little was known about biological clocks. Today clock-watching is a major theme in biology and biological ‘clocks’ have been found everywhere, even in the simplest organisms, like blue-green algae. All our tissues also seem to have their own little clocks, which beat to a drum-beat set by the master clock, which in mammals is located in the suprachiasmatic nucleus (SCN). The brain tracks fluctuations in light with the help of cells in the retina, at the back of the eye. A pigment in the cells detects light and sends information about its brightness and duration to the SCN, which dispatches information to all the bits of the brain that control daily rhythms, including, via a relay station, the pineal gland, which secretes the hormone melatonin.
Now let me introduce you properly to the pineal gland, known to the ancients as the third eye. A little dangle of glandular tissue protruding from the mid-brain, somewhere behind the eyes, it was known primarily as a photo receptor in animals like frogs and salamanders. If you’re thinking, how could it detect light inside the skull, remember back to when you were a child and reading under the bedclothes with a torch. Putting a hand over the torch still lets light through. This is certainly the case in amphibian and reptile skulls, although not in human skulls.
This titchy gland has always provoked heated debate, not least amongst physiologists. Some were convinced that it had an important role in sexual activities and reproduction, while other physiologists claimed it was nothing but sexual delusion on their part. In 1954 a review of pineal tumours in humans showed that those that destroyed the pineal were associated with advanced sexual development while those that originated from it were linked to delayed sexual development. By 1958, the pineal hormone had been isolated. It was called melatonin, because in amphibians this hormone moves the granules that contain melanin (the pigment of moles and freckles) to the centre of the cell thereby lightening the skin. It is also related as well as to the brain transmitter serotonin. By 1973, it had been noted that the levels of melatonin in the blood varied and that although scarcely detectable during the day, they soared during the hours of darkness. Now we know that melatonin is not only the hormone of sleep, but also the hormone slave of the body clock – relentlessly coordinating our activity so that it is in step with our environment, night or day, summer or winter, spring or fall.
The pineal is an unusual gland, in that it is like the middle bit of the adrenal gland, the part that secretes fight or flight adrenaline, producing its hormone not in response to something circulating in the blood, but rather in response to nervous stimulation. The suprachiasmatic nucleus (SCN) receives information from cells at the back of the eye. The SCN tells the pineal when it is daytime, not by a direct signal but by sending a message to another brain region, the paraventricular nucleus. The effect of SCN’s message is to stop it telling the pineal gland to release melatonin. After dark, the SCN releases the brake, allowing the paraventricular nucleus to carry on relaying its ‘secrete melatonin now’ message.
If mammals lose their eyes, they are both visually blind and circadian blind, having no synchronisation of their twenty-four-hour patterns to the light dark cycle. If birds, reptiles of fish lose their eyes, they are blind but still maintain synchronisation of their daily rhythms because they have several light-sensing receptors elsewhere in their bodies. So there was huge excitement when it was suggested that humans might also have light receptors elsewhere – in the back of their knees.
In 1998, Scott Campbell and Pat Murphy of Cornell University Medical College in White Plains, New York, published research in Science showing that shining strong light on the backs of a person’s knees could reset their body clock. To say that this was a bombshell was an understatement. It opened up the prospect that, perhaps, as groggy shiftworkers, January depressives and jet-lagged executives slept, they could be treated with blasts of light aimed kneewards. Excitement turned to dismay as group after group of researchers failed to replicate the experiment. Finally, in 2002, the idea was firmly nailed following work from Harvard. Only light reaching the eyes can reset the clock. All a torch behind your knees will do is warm the skin.
Here’s a peculiarity. It was assumed that rods and cones, which are the specialized cells of vision that sit at the back of the eye, must be crucial to clock-setting. In mice that lack rods and cones in their eyes there is still a synchroised circardian rhythm. In humans too, some of those people who are blind through loss of sight may still have a synchronised circadian rhythm, while those who are blind because they have no eyes, do not, which has always been a puzzle. It seems that at the back of the eye there’s a tangle of nerves, a bit like the tangle of wire behind the back of the TV, and here, there are photo-receptors, which contain a pigment called melanopsin, which reacts to light in the blue part of the spectrum. For humans, light at the blue end of the spectrum is twice as biologically effective in setting our clock as any other sort.
The strong effect of light on our biological clock presents many problems for night-shift workers. Even after twenty years of night shifts, individuals will still not have shifted their circadian rhythm in response to the demands of working at night. That’s a big problem because night-shift workers do many important jobs in which safety is critical – from cab drivers to doctors to power station workers. All of them will experience that same dip of concentration and body temperature that the rest of us do around 4–5 am. Taking account of the amount of traffic on the roads, the risk of a road traffic accident occurring at 6 a.m. is twenty times that at 10 a.m. It is no coincidence that 6 a.m. is just when night-shift workers are going home. It is also noticeable that many of the major industrial accidents occur at night: Three Mile Island at 4 a.m., Union Carbide plant, Bhopal, at 12.15 a.m., and Chernobyl at 1.23 a.m.
There also appears to be a significant effect on health of night-shift working. For instance, there is an increased cardiovascular mortality compared to the normal population, higher rates of substance abuse, difficulty in sleeping, greater levels of depression, and also, significantly, more infertility, particularly in women. This is not surprising. Reproductive processes in animals must be closely matched to the environment’s clock, or else young would be produced at the wrong time. Disruption of the pineal or of the clock genes causes disruption of the reproductive cycles and mid-pregnancy loss in mice. Tumours affecting the pineal gland in human advance or delay puberty and play havoc with fertility. Although we might like to think of ourselves as non-seasonal animals, there is in fact a sharp jump in births in spring, which indicates that seasonality has not been entirely wiped from our systems. This effect is even more marked in the Scandinavian countries. Although there may be a seasonal variation in sexual activity – summer holidays leading to spring-time births – the fact that there is a direct effect on fertility is shown by seasonal variations in the quality of embryos and fertilization rates in women undergoing IVF procedures.
There are some interesting studies of female flight attendants, who show increased rates of breast cancer, that are greater than would be expected simply from the extra exposure to radiation that flight crews experience. It is put down to disruption of circadian rhythm. We’ll come to using circadian rhythm for treatment in a moment.
So why don’t night-shift workers adjust in the same way that we adjust to local time when we travel across multiple time zones? Their problem is that they have to go home. And in doing so, almost invariably, they are exposed to natural light while travelling, which as we’ve said, even shortly after dawn, is very bright. Thus their clocks are reset. As a result, night-workers show an abnormal phasing of their melatonin rhythm. Levels are often high when they are awake (but should be asleep) and low when they are trying to rest.
Timed light is the obvious treatment for jet lag but that presents many practical difficulties, which is why melatonin is the treatment of choice for many. It can be bought over the counter in any drugstore in the US, where, astonishingly, it is classified as a food supplement.
Today we live in a 24/7 society. My local supermarket is open twenty-four hours a day, and if I wanted to I could play all night on e-Bay, or go out clubbing until dawn. Our parents couldn’t do any of these things, because shops shut at 6 p.m, or much earlier if you lived outside London. So potentially we can live life constantly exposed to light, when in theory it should be dark. Our bodies are pretty confused by this degree of light pollution and it has been suggested that inappropriate light signals may be affecting our sleep patterns.
All animals sleep. Birds do it, bees do it and yes, pretty certainly, educated fleas do it too. Certainly Drosophila, those tiny flies that cluster around rotting fruit, do. Fish too. Dolphins slumber with one half of their brain awake and the other half asleep. We all need to sleep, for without sleep, we sicken and die remarkably quickly. In fact, almost as quickly as if we had been deprived of water. Sleep is one of the great enigmas of science, because although clearly physical recovery is an important aspect of it – both for body and mind – there’s far more to it than that. There are four stages of sleep, with the body cycling between two quite different types: REM (rapid eye movement) sleep, and a deep sleep in which we are both blind and paralysed. Each has a different function – but what? There are many theories: consolidation of memory is one, switching the brain ‘offline’ for repairs is another. But it could be several of these things – or quite possibly none of them.
Over each twenty-four-hour period, we are pushed and pulled by two opposing forces. Our circadian rhythm pushes us to be alert during day. There is also a strong biological drive for sleep, which increases the longer you have been awake. By 10 p.m., we are still surprisingly perky, despite having had many hours without sleep. This is the circadian wakefulness drive at work. When we do sleep, we have probably satisfied our sleep debt by about 4 a.m., yet we tend to sleep on for a few hours – that’s the other bit of the push-me pull-you. We see the true extent of the battle between these opposing forces in people who are allowed to sleep one hour in every three over several days, and yet, despite severe sleep deprivation, are still unable to sleep during afternoon and early evening peaks of the circadian cycle. A win on points for our circadian rhythms?
The duration of sleep is very accurately regulated and it becomes increasingly easy to wake in the morning with age. We tend to be either larks or owls, something that is genetically determined. If your mother drives you mad by getting up at 5 a.m., chances are that you are going there too as you age.
Early to bed and early to rise, makes a man healthy, wealthy and wise is something our parents have all parroted at us. Benjamin Franklin said it first and he was wrong. A 1998 research study from two researchers at Southampton University showed no association between getting up and going to bed early and health, socioeconomic or cognitive advantage. If anything, owls were wealthier than larks.
About 3 per cent of people in the UK suffer from seasonal affective disorder (SAD). They become depressed as winter draws on, cutting down their activity. They crave carbohydrates and often put on lots of weight, only beginning to feel better in the spring, when they become active again. Since melatonin release is suppressed by light, the onset of shorter days means fewer hours of daylight so that the blood is carrying more melatonin than it would in summer when the days are long. It is said that SAD is a leftover of our past, the way that cavemen became semi-hibernating creatures during the winter months. The problem seems to be that while healthy people can take light cues from artificial light as well as from natural light, those with SAD respond only to the natural form. Carefully timed bright light in the blue spectrum can be a very successful treatment.
There’s an element here of another effect of melatonin – energy balance. Melatonin is a key factor in seasonal behaviours, like hibernation. One of the things that animals do before they hibernate is tuck away fat stores and then, during hibernation, their metabolism slows to a crawl. Melatonin will have an influence on humans too. You may well have found your excuse for the accumulation of post-Christmas blubber: my melatonin made me do it.
Jet lag is a phenomenon of our age. When your internal clock is telling a different time to that of your wristwatch, your body is in deep confusion. It can take anything up to a week to recover and you tend to feel worse, not the day after, but the one after that. Mental alertness disappears, your stomach is somewhere in California still and you don’t know what time of day it is. Jet lag’s effects are far more noticeable flying from west to east, than the other way around, so much so that analysis of the records of American West coast baseball teams playing away games on the East coast showed that the home team consistently scored more runs when their opponents had just flown across time zones for the match. Why should travelling west to east be worse? East to west means going with your clock’s flow. By inclination, it wants longer days. Going in the other direction means a transitional period of shorter days.
Taking melatonin can prevent jet lag, but it doesn’t work for everybody and it must be taken by your destination’s clock to be successful. It is not worth using for time zone changes of less than five hours. If travelling west, you need to delay the onset of sleep, so you should take a dose of melatonin (about 5 mg) at your destination’s bedtime (say 11 p.m.) for four nights. If travelling east, you need to advance the onset of sleep. Take a pill on the flight when it would be your destination’s bedtime. When you arrive, take a dose at the destination bedtime for four nights. Melatonin is not available in Europe except on prescription.
Melatonin is also very useful in treating the sleep problems of the blind: nearly 60 per cent report problems with sleeping and this proportion increases with increasing degree of loss of light perception.
Body Rhythms as Medicine
Using the body’s rhythms to help in treatment – so-called chronotherapeutics – is not that new an idea, but it is one that has still to take off. For instance, the risk of relapse in children with acute lymphoblastic leukaemia is two and a half times higher in children who receive their chemotherapy in the morning than those having the same treatment in the evening. This is because genes that regulate cell proliferation (in other words, the ones that are especially active in cancers) are under clock control. Disruption of the clock genes seems to accelerate tumour growth in rats, so it is not surprising perhaps that night-shift workers show an increase in cancer rates.
Melatonin – hormone of darkness and slave to the body clock – coordinates physiology on a grand scale, as we can see, not only through the day and night but through the seasons too. By affecting the release of other hormones, it also influences mood, reproduction and energy balance. It has a powerful anti-oxidant effect, which could be why low levels are associated with cancers. Since levels fall with age, you may already have guessed that melatonin is one of the most popular of all hormones with the rejuvenators de nos jours. In the next chapter, I’ll tell you how immortality is but a hormone away.
