In Sync: How to take control of your many body clocks

You have not one, but thousands or even millions of body clocks. Learn to control them, and you can tackle problems from jet lag to weight loss

New Scientist, 13 April 2016

GERDA POT’S grandmother was a stickler for timekeeping. “She always had breakfast at the same time, lunch and dinner at the same time, but even in between she had tea and coffee breaks every day at the same time,” says Pot. She also aged robustly, living independently well into her 90s. That got Pot wondering: was there something in the regularity of her grandmother’s habits that held the key to her rude health?

A nutrition researcher at King’s College London, Pot was better placed than most to investigate – and she soon found she wasn’t the first to ask such questions. She had stumbled into the field of chrononutrition, and is now one of a growing number shedding light on the misunderstood role of time in human biology.

We have known for a long time that messing with our body clocks can take a severe toll on our health. For decades, however, we thought that the body clock was one central timepiece housed in our brain. No longer. We now know our bodies contain thousands, if not millions, of disparate clocks that carefully orchestrate the functioning of our tissues and organs from the heart to the lungs to the liver.

These clocks mean not only that there are benefits to eating regularly, as Pot and others are discovering, but that different parts of the body are tuned to work optimally at certain times of the day. When these clocks fall out of sync it can have serious consequences. Conversely, learn how to take advantage of these rhythms and we could be on a fast track to everything from slimmer waistlines to more effective treatments for cancer.

The first written report of circadian rhythms – the idea that living things operate according to a regular daily cycle – came about 300 years ago when a French astrophysicist, Jean-Jacques d’Ortous de Mairan, showed that, when placed in darkness, some plants continued to open and close their leaves with a rhythm of about 24 hours.

 Credit: Jonny Wan

Credit: Jonny Wan

But it wasn’t until the 1970s that researchers looking for the seat of biological rhythms in mammals struck gold. When they disrupted different areas of rodent brains to see whether any of them affected the animals’ day-to-day activity, they discovered that two small areas, collectively now called the suprachiasmatic nucleus and located in the hypothalamus directly behind the eyes, track light and dark signals coming in from the eye to keep the body in time with day and night. These areas send signals around the brain and body to control things such as hormone release, the regulation of body temperature and appetite.

Only years later did gene studies reveal the startling fact that this clock isn’t the only one. In fact, the activity of almost half of mammalian genes varies regularly with time, says John Hogenesch of the University of Pennsylvania, Philadelphia. In 2014, he published an atlas of these circadian genes across 12 organs in mice, showing how the heart, lungs, liver, pancreas, skin and fat cells, among others, function over the course of a day (PNAS, vol 111, p 16219).

These clocks work in a similar way to the brain’s timepiece. In response to an outside signal, two core genes activate a cascade of other genes, causing a burst of cellular activity. Eventually, a few of the activated genes act to switch off the core genes, dampening down the tissue’s cellular activity once more.

Perhaps the biggest surprise was that the outside signals controlling the timing of this frenetic genetic activity didn’t necessarily come from the brain. “Put a liver cell in a petri dish and it very happily ticks along at its rhythm of about 24 hours,” says neuroscientist Frank Scheer of Harvard Medical School in Boston, Massachusetts. The idea of “the body clock” had clearly had its day. “You went from it being a single clock that drove every rhythmical process of the body to a complex network of thousands or millions of clocks all over the body, all doing their own thing and all of which have to talk to each other and synchronise to each other,” says Jonathan Johnston at the University of Surrey in Guildford, UK. “That totally changed how people thought about circadian rhythms.”

Then, in 2000, a seminal paper revealed that, in mice, you could uncouple the peripheral clocks from the central pacemaker simply by changing the time at which they ate. If the mice could only eat during the day, when they are usually asleep, their peripheral clocks shifted by 12 hours, but the central, light-activated brain clock remained the same. The liver was the fastest to adapt, taking three to four days, but after a week the heart, kidney and pancreas had shifted too (Genes and Development, vol 14, p 2950).

There was more. Further research revealed how mice that had their eating patterns disturbed, or their core clock genes disabled, were more likely to gain weight and acquire fatty livers. “They are eating the same thing and it’s having a different effect,” says Hogenesch.

Equally, restrict the time windows in which mice could eat, and they responded similarly to mice on a calorie-controlled diet, regardless of how much they ate. It seems that external cues such as food can reset a body’s peripheral clocks, such as those in the liver and pancreas involved in controlling blood sugar levels, leaving them running out of sync with signals sent out by the brain’s master controller. Eat at an unusual time, and confused clock signalling means the relevant organs aren’t prepared to deal with food.

Time for a smackerel

These findings echoed Pot’s suspicions about the role of food timing in human health. But teasing out such effects is hard because you can’t take regular samples of human organs to monitor their daily activity, or disable genes in specific tissues. Pot instead used data from the UK National Survey of Health and Development, in which, starting in 1946, over 5000 people kept detailed records of when and what they ate over much of their lives.

It provided good evidence for her grandmother hypothesis, showing that adults who ate their meals at irregular times had a greatly increased risk of metabolic syndrome – which includes cardiovascular problems and diabetes – decades later (International Journal of Obesity, vol 38, p 1518). “Even though it’s individual, I think consuming regular meals is beneficial for everyone,” she says. In other words, it’s not just about what you eat and how much you eat – but when you eat it, too.

And it’s not just about metabolism. We are starting to build a timeline of activity around the body. For instance, the heart experiences a burst of activity first thing as our bodies prepare for the rigours of the day, as do other organs. We are also privy to a surge of the stress hormone cortisol in this pre-dawn rush hour, which may explain why things like heart attacks are so common in the morning.

Similarly our lungs work to a circadian rhythm that appears to make them more efficient and have a better immune function when we need them most during our most active hours. There are even hints that neurodegenerative diseases such as Alzheimer’s and Parkinson’s could be tied to changes in circadian rhythms, explaining why symptoms are often worse in the afternoon and evening. Disrupted circadian clocks are also increasingly being linked to psychiatric disorders including depression and schizophrenia.