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The science behind our body clock and how research at MRC LMB in Cambridge reveals the impact of mealtimes

Remarkably, our body clock exists in every cell.

John O'Neill, at the MRC Laboratory of Molecular Biology, who has been researching how meal times impact on the body clock. Picture: Keith Heppell
John O'Neill, at the MRC Laboratory of Molecular Biology, who has been researching how meal times impact on the body clock. Picture: Keith Heppell

Controlling the rhythm of biological processes in our body, it is influenced by factors including exposure to light and the timing of our meals.

Disruption to this ‘circadian rhythm’ is known to be detrimental to our health, leaving shift workers, for example, at greater risk of certain diseases.

Researchers at the MRC Laboratory of Molecular Biology in Cambridge and their colleagues have now discovered the mechanism by which our mealtimes are communicated to our body clock.

The findings could help devise strategies for those working nights or suffering jet lag to minimise the disruption to their systems.

“We use the word body clock as a metaphor to describe how human biology – and in fact that of pretty much every organism on the planet – changes with a 24-hour rhythm,” Dr John O’Neill, a research leader who led the Cambridge team, tells the Cambridge Independent.

“It’s not simply because of the 24-hour day length, it’s something we have evolved to be an endogenous oscillator that allows us to anticipate the way our environment changes over time.

“If you look at humans, plants, fruit flies, fungi, they all have this intrinsic approximately 24-hour rhythm in their biology.

“I could lock you in a dark room for the next week or so and you’d probably be quite irritated, but you would continue to wake up at about the same time each day and continue to feel hungry at about the same time, and sleep at about the same time.

“It’s the result of there being a daily time-keeping mechanism in every cell, which is amazing.

Our body clock exists in every cell of the body
Our body clock exists in every cell of the body

“I could take a scraping of your skin cells and grow them in a petri dish and they would continue to have an approximately 24-hour rhythm outside of your body.

“The body clock is the co-ordination of all of these individual clock mechanisms in every cell of the body – all working together and all synchronised.”

For some years, we have understood that light is an important part of this process.

Conveyed as electrical impulses down the optic nerve, light information reaches a structure in the brain called the suprachiasmatic nucleus.

The master circadian pacemaker, it controls the timing of our sleep-wake pattern by encoding external light and dark cycles.

“This tiny part of the brain knows what time dawn should occur. It communicates that information to the rest of the body by stimulating, for example, melatonin secretion at night and cortisol – a stress hormone – in the early hours of the morning.

“So the way in which light affects your body clock is quite well understood,” says Dr O’Neill.

“It has also been known for decades that meal timing is just as important, if not more so, for setting the timing of these cellular clock mechanisms throughout the body, but it’s not really been understood how it works. That is what we believe we have found out.”

Working with cultured human cells, and with mice, the team learned that the hormone insulin, which is released when we eat, affects the circadian rhythms in our cells and tissues individually by stimulating the production of PERIOD proteins.

“What we noticed, almost serendipitously, is that when we added insulin into the cell culture medium, it completely reset the cellular clock in all the different cell types we were working with,” says Dr O’Neill.

John O'Neill, at the MRC Laboratory of Molecular Biology in Cambridge. Picture: Keith Heppell
John O'Neill, at the MRC Laboratory of Molecular Biology in Cambridge. Picture: Keith Heppell

“That immediately proposed a mechanism by which cells might sense and synchronise with feeding times, because every cell in the body is sensitive to insulin.

“People have heard of insulin because it’s so important in controlling blood sugar levels, but what we found is an additional function.

“An increase in insulin in the blood seems to be sufficient to tell the cells throughout the body that this is feeding time by making more of these PERIOD proteins.”

Working with a team at the University of Manchester, the researchers found that mice given insulin at a time when they would normally be resting led to disrupted circadian rhythms, blurring the distinction between night and day.

In a normal, healthy circadian rhythm, the body’s signals should be in sync.

“Before you wake up, you would normally expect a cortisol surge. Then a few hours later when you have your first meal of the day, you get an increase in insulin,” says Dr O’Neill.

“Those two signals should agree with each other and be in that sequence.

“If you have them the wrong way around, which is what happens if you eat in the middle of the night, it sends a completely confused signal to your body clock.

“That means your circadian clocks become less robust and start to desynchronise.

“That’s what we think happens during shift work and jet lag. But of course, with jet lag, it’s short term and over a few days you settle into a new environment and rhythm.

“But with shift work, people are usually skipping forward and backward between the day and night shift because whenever they have time off, they want to spend it with family and friends.

Sticking to a regular routine is beneficial (11613255)
Sticking to a regular routine is beneficial (11613255)

“That’s why we think shift work is so bad for you – you’re getting timing cues, such as when you see light and when you eat, in the wrong order.

“We know that if you have disrupted circadian rhythms that there is a strong relationship with a number of chronic, age-related diseases, such as type II diabetes, various cancers and neurodegenerative disorders. We think we can explain that link.”

The study could help shift workers mitigate the risk.

“Our study suggests strategies that people doing shift work could employ in order to reset as quickly as possible,” says John. “The findings agree with what people have thought anecdotally for a long time – you need to pay attention to the timings when you see light and when you eat.

“That could mean wearing sunglasses on your walk home from your shift, and not necessarily eating when you are hungry but eating at the correct time for your biological clock.

“So if I’m about to start a job on the night shift, I’d want to avoid seeing bright light during the day and fast until it gets to the beginning of my shift. That’s when I’d want to expose myself to bright light and have a decent meal. If I do that for two or three days, it should allow me to adjust to the night shift more quickly.

“The easier way of thinking about it is that it’s not so much about feeding and light, as the timing of dark and fasting.

“You need to have a prolonged period of dark every 24 hours and a prolonged period of fast and they need to occur at the same time.

“When you see light and eat should occur at the same time – that sends the right message.”

The study supports the old adage, then, that breakfast is the most important meal of the day.

And for those who have disrupted sleeping and eating patterns, it underscores the work of other researchers who advise sticking to a regular routine, and avoiding the blue wavelength light of mobile phones and TV just before bedtime.

“If you can’t sleep, you would be exacerbating the problem if you get up, turn the lights on, watch TV or go and make yourself a big sandwich,” says Dr O’Neill.

“In order to stay healthy, you need to follow a fairly stable routine for when you see light and when you eat.

Using devices like phones and tablets late at night can lead to difficulty sleeping (11613246)
Using devices like phones and tablets late at night can lead to difficulty sleeping (11613246)

“The comparison epidemiologists make is that lifelong disrupted circadian rhythm – if you’re swapping between day and shifts for example – is equivalent to having a packet of cigarettes a day.”

Dr Priya Crosby, a researcher at the MRC LMB and lead author on the study, published in Cell, adds: “Even for those who work more traditional hours, being careful about when we eat is an important way to help maintain healthy body clocks, especially as we age.”

For those with diabetes, who have difficulties with their supply of insulin, another hormone called IGF1 – insulin-like growth factor – compensates to some extent.

“If you don’t have insulin, there is usually an increase in IGF1. So we’re not sure that people with diabetes would not have the same mechanism in place, but we’d expect it to be weaker in people with type II diabetes,” says Dr O’Neill.

We do know that not everyone’s body clock is identical – and nor is it static through our lives: it has a degree of ‘plasticity’ or flexibility.

“Our genetic make-up is hard-wired in. That is where we see changes in chronotype between individuals, such as whether you are an early morning lark or an owl and prefer to get up later in the day,” says Dr O’Neill.

While children naturally rise early, teenagers – as parents of them will know too well – prefer to lie in. But as we get older, our natural waking time generally becomes earlier once more.

“That seems to be part of normal healthy ageing and that tells us there is give and take in the system,” suggests Dr O’Neill.

“But when you look at people of any given age, there is quite a wide distribution. Some of that is down to genetics. But some is down to the lifestyle we choose to live.

“A lot of these mechanisms are encoded in the brain and we know the brain is quite flexible – if you give it a new routine, we can adjust to it.

“We could cope with living on Mars, where a day length is 24.7 hours, which is close enough to Earth’s for a human biological clock to cope.

“But we couldn’t live on a planet with a 28-hour day. We don’t have that much flexibility...”

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