Living on borrowed time The$perils$of$messing$with$our$body$clock$ Matthew Lloyd
What are circadian rhythms? Circa$diem$=$about$a$day Rhythmic Zeitgeber E transcription of n t r clock genes a i n m e n t Virtually all living organisms display circadian rhythms, even bacteria, but I’m going to focus on how they work in humans, as I’m interested in how they a ff ect our health. Aspects of our behaviour and physiology that show circadian rhythmicity include sleep, physical activity, alertness, hormone levels, body temperature, immune function, and digestive activity. Almost every cell in our body has its own clock, controlling many cellular functions so that they occur at the right time of day. Unfortunately, left to their own devices these would “free-run”, meaning they will tick at their own rate and become desynchronised from the external signals they are supposed to anticipate. They also need to be able to adapt to environmental changes like seasonal variation in day length and travelling between time zones. So it’s crucial that they can be reset by a sort of “circadian pacemaker”. Our master clock is in the suprachiasmatic nucleus (SCN), a tiny area of the brain containing around 20,000 neurons. It’s responsible for keeping all the other, so-called “peripheral”, clocks in the body synchronised to the day/night cycle. The SCN receives information about light intensity directly from photosensitive retinal ganglion cells that fire (depolarise) in response to light, being activated particularly strongly by blue light. Even mice which have no rods or cones and are therefore completely blind are able to entrain to the light/dark cycle through these cells: only when their eyes are covered do their clocks start to free-run. In turn, the neurons of the SCN fire action potentials in a synchronised 24 hour rhythm, leading to entrainment of the peripheral clocks in the rest of the body via hormone signalling and the autonomic nervous system. However, light intensity is just one of many time-giving signals (“zeitgebers”). Others include food, temperature and exercise. The impact of exercise is very powerful: in one experiment, mice were kept in constant darkness, which caused their circadian rhythms to free-run. However, exercising at regular times (via scheduled locking and unlocking of their running wheels) reorganised their rhythms.
How does a molecular clock work? Clock genes Day Night oscillate… …because of a transcription- translation feedback loop (TTFL) Every cell in our body that has a nucleus also has a molecular clock constantly ticking away inside it. The clock is driven by ordinary cellular processes – transcription, translation and protein degradation – interacting in a special way. You can see that the amounts of the clock component proteins oscillate like a sine wave, with a period of roughly 24 h (not exactly – that’s where resetting comes in), but with Clock/Bmal1 in an opposite phase to Per/Cry. This gives us a clue to the mechanism of the clock: a negative feedback loop. Clock/Bmal1 drive production of Per/Cry protein, but as Per/Cry levels increase they start to feedback on Clock/Bmal1 and inhibit their own transcription. Hence this called a transcription-translation feedback loop. Per/Cry degradation then allows the process to start all over again. Clock is temperature-compensated: it doesn’t speed up or slow down in response to temperature. This is really important as most organisms don’t live in an unchanging environment. How can this work when it’s composed of a series of enzyme-catalysed chemical reactions, which will go faster at higher temperatures? Answer is that the changes in reaction rate cancel out – for example, if Per protein is made at a faster rate, it will also be degraded at a faster rate, so overall the clock still ‘ticks’ at the same rate.
Why do we get jet lag? 2 am 6 pm Trivia: what’s the most commonly used medication in space? The modern world presents many challenges to our chronobiology, which it has not evolved to cope with. These include air travel. Did you know that bees can experience jet lag? In one experiment, honey bees were flown from Paris to New York. On arrival, they started to forage for nectar, but most flowers had yet to open. Their clocks were still on Paris time and were therefore promoting behaviour that was inappropriate for the actual time of day. Many of the negative symptoms of jet lag and the health problems experienced by night shift workers may be due to “internal desynchrony”, in which the SCN and peripheral clocks receive conflicting signals, causing their phases to become uncoupled. The SCN takes a while to adapt to a new time zone (roughly a day per time zone crossed – so it will take 8 days to fully adjust to the new light/dark cycle following an 11 hour flight from London to San Francisco). So if, for example, you eat a large meal at 6 pm on arrival (meaning it’s 2 am in London), your liver and pancreas will soon be at a di ff erent phase to your SCN. Molecular clocks around the body will then be “confused” by a spike of glucose and insulin when it’s subjectively the middle of the night. Of course, much worse than the temporary misalignment induced by travel is the chronic circadian misalignment experienced by shift workers, who work when they should be asleep and try to sleep when they should be awake. They never become truly nocturnal unless they are exposed to very bright artificial light while working and shielded from any natural light during the day. Answer: sleeping tablets. May see 16 dawns and dusks in one day on ISS, which plays havoc with circadian rhythms.
What’s all this got to do with sleep? What’s the longest scientifically verified period without sleep? A. 3 days B. 7 days C. 11 days D. 15 days Why we need to sleep and why we need 8 hours sleep while other animals may sleep for as many as 19 hours a day or as few as 2 remains a mystery. Many essential processes occur during sleep, from toxin clearance and repair to memory consolidation. So much is going on that it’s hard to work out what was the original driving force for evolving this complex behaviour. However, what is clear is that it’s a fundamental process for nearly all animals (even those as simple as jellyfish!) and sleep deprivation is bad for us – really bad for us. Answer: 11 days! The 17-year-old student in question, Randy Gardner, experienced paranoia, hallucinations and problems with short-term memory. On the eleventh day, when he was asked to subtract seven repeatedly, starting with 100, he stopped at 65. When asked why he had stopped, he replied that he had forgotten what he was doing. Apparently no long-term health impacts from this one-o ff event. However, regular sleep deprivation is a di ff erent story, which we’ll come back to. The two-process model of sleep regulation: homeostatic sleep drive increases with duration of wakefulness and can only be satisfied by sleep; circadian driver ensures consistent and consolidated timing of sleep and wakefulness. Interact to produce a ‘sleep-gate’ when pressure to sleep peaks. Rats lacking the SCN alternate between short bursts of sleep and activity as homeostatic drive builds and then is reduced by sleep. So why is it a bad idea to look at your phone or computer screen just before bed? Blue light, as we have seen, acts to reset the clock. From dusk until the middle of the night, blue light will delay the clock, pushing back sleep later into the night. In contrast, exposure to blue light before dawn will advance the clock. Sleep habits tend to reinforce themselves: the bedtime of late types will tend to drift later, while early birds are happy to go to the gym before work when those with a later chronotype are still bleary-eyed and cursing their alarm clock.
Health impacts and treatment of SCRD Shift work associated with type II diabetes, obesity, heart disease, some cancers, and depression. Let’s take a look at diabetes and obesity. When sleep deprived, insulin sensitivity reduced, and when internal clock is misaligned with external signals insulin levels increase but sensitivity is reduced (pre-diabetic state). This e ff ect is compounded by increased appetite, especially for food rich in sugars and fat. Best way to ensure good sleep is to maintain regular sleeping patterns and not stay up too late (so no weekend lie ins), exercise regularly (and not late in the evening) and ensure your room is dark, quiet and not too hot or cold. But while improved ‘sleep hygiene’ is an option for some, for shift workers we need to find a pharmacological solution. Some people suggest melatonin as a treatment, but it doesn’t really deserve its reputation as “the sleep hormone” – it’s produced during darkness in nocturnal as well as diurnal animals – and it’s only likely to help significantly with genetic rather than behavioural causes of SCRD. Besides, be wary of the natural = safe assumption, although melatonin does seem to be fairly non-toxic even at high doses, just not very e ff ective. That doesn’t stop it being marketed in North America as the solution to bad sleep; one melatonin manufacturer’s website even urges parents to “prepare your child for academic success” by getting him or her to sleep. And it’s certainly not a “dietary supplement” – it’s synthesised from tryptophan… Light therapy i.e. well-timed use of a “SAD lamp” can help with SCRD. But we’re still searching for a wonder-drug that will rapidly shift the master clock to the appropriate phase and thus avoid the problems of desynchrony.
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