Tired all the time? Why fatigue isn’t just about sleep| New Scientist | 15 October 2016

October 16, 2016

From the New Scientist, 15 October 2016. Feature written by Emma Young.

You're in bed by 11, having had a busy, productive day. After a full night’s sleep you wake up naturally and feel… exhausted.

If this sounds familiar, you’re not alone. According to a recent survey of over 20,000 people by researchers at Radboud University in the Netherlands, about 30 per cent of visits to doctors involve complaints about being tired all the time. Some 20 per cent of people in the US report having experienced fatigue intense enough to interfere with living a normal life. This hits us in our pockets, too: workers who are unproductive because of fatigue cost US employers more than $100 billion a year.

It’s perhaps surprising, then, that we are only now beginning to work out what fatigue actually is. Until recently, daytime tiredness was presumed to be nothing more mysterious than simple physical exhaustion or feeling the need to sleep – the US Centers for Disease Control and Prevention estimates that 35 per cent of people are short on sleep. Combine that with the fact that tiredness is subjective and therefore difficult to measure, plus the subject falls somewhere between studies of the body and mind, and it’s small wonder fatigue has largely escaped scientific scrutiny.

Since tiredness accompanies so many common diseases, not to mention ordinary ageing, a better understanding of its causes could improve quality of life for pretty much everybody. A handful of researchers are now trying to figure out the causes, and possible fixes. Although it’s early days, a few clues are emerging.

One cause, we might think, is that life is more exhausting than it has ever been. Caught between the competing demands of work and family, not to mention the ever-present buzz of smartphone notifications, it is no surprise so many of us feel as if we are running on empty. Yet this may be a fallacy. According to Anna Katharina Schaffner, a historian at the University of Kent in Canterbury, UK, and author of Exhaustion: A history, people through the ages have consistently complained of being worn out, and harked back to the relative calm of simpler times. Over the centuries, fatigue has been blamed on the alignment of the planets, a lack of godliness and even an unconscious desire to die, says Schaffner. “Freud argued that a very strong part of ourselves longs for a state of permanent physical and mental rest,” she says.

In the 19th century, a new diagnosis appeared: neurasthenia. The American physician George M. Beard claimed that this condition, supposedly caused by exhaustion of the nervous system, was responsible for physical and mental fatigue as well as irritability, hopelessness, bad teeth, cold feet and dry hair. Beard blamed neurasthenia on the advent of steam power and newfangled inventions such as the telegraph. Women’s education was also considered to be tiring for all concerned, while the advent of the printing press brought an abundance of newspapers and magazines to keep up with.”Beard feared that the modern subject was unable to cope with such chronic sensory overload,” says Schaffner.

If modern life isn’t to blame, another possibility is that at least some fatigue is down to a lack of sleep. Researchers distinguish between the need for sleep and fatigue, however, considering them to be closely related but subtly different. The good news is that there is a fairly easy way to tell which might be wearing us out: the sleep latency test. Used widely in sleep clinics, it is based on the idea that if you lie down somewhere quiet during the day and fall asleep within a few minutes, then you are either lacking sleep or potentially suffering from a sleep disorder. If you don’t drop off within 15 minutes or so, yet still feel tired, fatigue might be the problem.

So if it’s not the same thing as sleepiness, what is fatigue? Mary Harrington, a neuroscientist at Smith College in Northampton, Massachusetts, is one of a handful of researchers looking for a telltale biological signal of fatigue. So far no single marker has emerged that tallies with how tired people say they feel, but “we do have some candidates”, she says.

One possibility Harrington is investigating is that daytime fatigue stems from a problem with the circadian clock, which regulates periods of mental alertness through the day and night. This regulation falls to the brain’s suprachiasmatic nucleus, which coordinates hormones and brain activity to ensure that we feel generally alert by day. Under normal circumstances, the SCN orchestrates a peak in alertness at the start of the day, a dip in the early afternoon, and a shift to sleepiness in the evening.

The amount of sleep you get at night has little impact on this cycle, says Harrington. Instead, how alert you feel depends on the quality of the hormonal and electrical output signals from the SCN. The SCN sets its clock by the amount of light hitting the retina, so that it keeps in line with the solar day. Too little light in the mornings, or too much at night, can disrupt SCN signals, and either can lead to a lethargic day. “I think circadian rhythm disruption is quite common in our society and is getting worse with increased use of light at night,” says Harrington.

If you spend the day feeling as if you have never quite woken up properly but are not sleepy at bedtime, a poorly calibrated SCN might be to blame, says Harrington. She suggests trying to spend at least 20 minutes outside every morning and turning off screens by 10 pm to avoid tricking the SCN into staying in daytime mode.

Another way to reset the SCN is to exercise, Harrington suggests. Several studies have linked exercise – whether a single bout or regular physical exertion – to reduced fatigue. “People with fatigue hate to hear this, but exercise can make a big difference,” she says. This may explain why people who start exercising regularly often report sleeping better, when some studies show they don’t actually sleep for any longer. Quality of sleep may be more important than quantity.

As well as resetting the SCN, exercise fights the flab, and there are good reasons to think that reducing fat levels could help tackle fatigue. Body fat not only takes more energy to carry around, but releases leptin, a hormone that signals to the brain that the body has adequate energy stores. Studies have linked higher leptin levels to greater perceived fatigue, a finding that makes perfect sense from an evolutionary perspective: if you aren’t short of food, you don’t need the motivation to go out and find some. Interestingly, people who fast regularly often report feeling more energetic than when they ate frequently.

With obesity on the rise, leptin signalling might well be a common reason for feeling tired all the time. But there could be something else at play. People who carry excess fat also show higher levels of inflammation, a part of the body’s immune response that rouses other parts into action by releasing proteins called cytokines into the bloodstream. Body fat stores large quantities of cytokines, which may mean that more end up circulating, too. As well as stimulating the immune system, cytokines also make you feel drained of energy, as anyone who has ever had a common cold can attest. In 1998, Benjamin Hart at the University of California, Davis, argued that this feeling is an evolved strategy to help fight a bacterial or viral attack: when you need time to rest and recuperate, fatigue is your friend.

Animal studies have shown this effect in action. In one, Harrington gave mice a drug that causes low-level inflammation. She found that while they still moved around their cages and ate as normal, they avoided the running wheels. Contrast that with healthy mice, which seem to seek out the wheels for kicks. “It is like wanting to go out and be active, and have fun and do something that is not necessary for just staying alive.” If low-grade inflammation robs mice of their zest for life, there’s no reason, she thinks, to suspect something similar shouldn’t hold for people.

Robert Dantzer at the University of Texas M. D. Anderson Cancer Center, Houston, and colleagues have found changes in a few key brain areas that might account for a lack of motivation. They describe how inflammation alters activity in motivation-linked brain areas such as the fronto-striatal networks involved in reward-based decision-making, and the insula, which processes the bodily sensation of fatigue. These changes could explain aspects of fatigue such as a lack of motivation, uncertainty about what to do, and simply being aware of feeling sapped.

Even if you’re not overweight or sick, inflammation could still be running you down. A sedentary lifestyle, regular stress and poor diet – one high in sugar and low in fruits and vegetables – have all been linked to chronic, lower-level inflammation. There is also preliminary evidence that disruption of circadian rhythms can increase inflammation in the brain. So could lifestyle-related inflammation help to explain why so many of us feel so tired so much of the time? “The answer is yes,” says Dantzer. Epidemiological surveys do point to a relationship between fatigue and elevated levels of IL-6, an inflammatory marker, he says.

It’s early days, but inflammation is emerging as potentially a common pathway linking fatigue to everything from poor-quality sleep and physical inactivity to a bad diet. If that’s correct, then a handful of potential lifestyle changes could go a long way to fighting everyday fatigue: more exercise, and eating more fruits and vegetables that contain high levels of polyphenols (such as resveratrol in grapes or curcumin in turmeric), which some studies suggest can reduce inflammation.

Inflammation probably isn’t the whole answer, though, says Anna Kuppuswamy, a neuroscientist at the Institute of Neurology at University College London. Kuppuswamy studies people who suffer debilitating fatigue in the aftermath of a stroke, a time when their brains are highly inflamed. “Inflammation is definitely a trigger for fatigue. But what is frustrating is that we find fatigue in people long after inflammatory markers normalise,” she says.

Another factor muddying the waters is that biological signals that might lead to a feeling of overwhelming exhaustion in one person won’t necessarily trigger it in another. Some people are able to push through it, says Kuppuswamy.

That requires motivation, low levels of which are clearly an important aspect of fatigue. So some researchers have been looking at the role of dopamine – a neurotransmitter that drives us to seek out pleasure. When dopamine is lost, as happens in Parkinson’s disease, for example, the accompanying depression and apathy that comes with it can be crushing.

Low dopamine is also implicated in depression, as is reduced availability of another neurotransmitter, serotonin. Since the vast majority of people with major depression report severe fatigue, and about one in five people become depressed at some point in their lives, it’s no wonder that depression is also a potential common factor in fatigue.

Ranjana Mehta, director of the NeuroErgonomics Lab at the Texas A&M Institute for Neuroscience, is one researcher who points to widespread depression as an explanation for why so many of us feel so drained. As her team has recently shown, the kind of mental exhaustion that accompanies depression can lead to a real sense of physical fatigue. In experiments, people who were asked to lift weights while doing mental arithmetic had 25 per cent less endurance than those who simply lifted weights. Subsequent imaging studies showed why: thinking hard lowers activity in frontal brain regions, which are involved in directing movements as well as having a hand in concentration. When the brain is challenged, it can make muscles tired, too.

With so many emerging causes for fatigue, interest in trying to crack the problem is growing. The US National Institutes of Health is in the planning stages of a programme aimed at finding the elusive physical signatures of fatigue. Harrington says that better animal models are needed, along with a concerted effort from many more researchers to rescue fatigue once and for all from medical obscurity. “I’ve done a lot of work on this because I think we can crack it,” she says. “But I do feel pretty alone out there.”

In the meantime, Harrington’s advice is not to let fatigue stop you doing something you enjoy. In fact, it is worth forcing yourself to keep at it because a potent reward could trigger the release of dopamine in brain areas linked to motivation and alertness. Alternatively, do something stressful: the release of adrenaline could help you overcome lethargy. Ideally, put stress and enjoyment together. As Harrington says, “who feels fatigued when they’re on a roller coaster?”


Pharmacy shelves are groaning with supplements claimed to “fight fatigue” and help you “re-energise”. So is there any evidence that boosting some magic ingredient will endow us with greater vitality?

Too little iron certainly can lead to fatigue. And while only 3 per cent of men and 8 per cent of women are diagnosed with clinical iron-deficient anaemia, there is some evidence that iron supplements may still provide an energy boost for the rest. One group of non-anaemic women who experienced “considerable fatigue” had their fatigue score nearly halve after 12 weeks on iron tablets. Those on a placebo reported a 29 per cent drop, however, so the true effect is hard to gauge. Nevertheless, we need to understand the importance of iron deficiency in fatigue – even where there is no anaemia, according to Jill Waalen, an epidemiologist at the Scripps Research Institute in La Jolla, California.

B vitamins
B vitamins are also commonly touted as a magic bullet to boost energy, but there is little evidence that supplements will make any difference unless you are deficient. David Kennedy, who researches the impacts of nutrients on brain function at Northumbria University in Newcastle Upon Tyne, UK, says that while most people who eat a healthy diet shouldn’t expect any benefit from the standard B6, B9 or B12 supplements, we don’t fully understand how all eight B vitamins interact in the body, and that people who are obese or eat a poor diet could well be deficient in at least one of them. So, he suggests, there may be an argument for taking B-vitamin supplements, but only if you take them all rather than a select few.

There is some evidence that flavonols, found in dark chocolate, wine and tea, can mildly enhance blood flow to the brain, says Kennedy. So consuming them may boost brain functioning and alertness, although he points out that exercise is more effective than supplements at boosting brain blood flow.

Dehydration is often cited online as an explanation of why so many of us feel tired. There is some evidence to support the idea. One study at the University of Connecticut, for example, found that “mild dehydration” – a 1.5 per cent dip below the body’s normal water volume, which the team says can occur in the course of routine activities – can cause fatigue and difficulty concentrating, particularly in younger women. On the other hand, a 2 per cent drop in hydration is enough to make us feel thirsty, so if we drink normally we shouldn’t get dehydrated very often and it probably isn’t necessary to force down gallons of the stuff.

Also much trotted out in cyberspace is the notion that long-term stress drains the adrenal glands, leading to tiredness and weakness. Adrenal fatigue is not a diagnosis recognised by the medical establishment – it was James Wilson, a chiropractor and naturopath, who came up with it in 1998. “No scientific proof exists to support adrenal fatigue as a true medical condition,” says Katherine Chubinskaya, an endocrinologist in Vancouver, Canada. Adrenal insufficiency, however, a condition in which the adrenal cortex does not produce enough hormones – is real enough but also rare, so is unlikely to be the cause of most common fatigue.

Emma Young is a science writer based in Sheffield, UK

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