Health Sense

Way too tired?

Resting may hurt, not help, say those unraveling the mystery of fatigue

By Judy Foreman
October 13, 2008
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Fatigue has long been one of the most common, yet least understood, of medical problems. It drives millions to their doctors every year, and doctors typically have had little to offer except the usual bromides - eat well and rest.

But a new understanding of everyday fatigue - the kind associated with a fundamental lack of energy, not the fatique caused by conditions such as anemia, or a lack of sleep - is emerging from labs around the country. Last month, leading physiologists gathered at the National Institute on Aging, part of the National Institutes of Health, and came up with a new paradigm of what happens in the brain and the rest of the body when a person has subjective feelings of fatigue.

The new understanding "is a fundamental jump forward in the study of fatigue," said Dr. Luigi Ferrucci, one of the conference organizers, and brings with it some good news for the tired among us.

Scientists are now convinced that fatigue has a real, molecular basis, and that at least two major biological processes are involved: An excess of natural chemicals called pro-inflammatory cytokines, which the body pumps out in response to infection. And sluggish mitochondria, the tiny organelles inside cells that make energy.

Even if these two pathways work separately - and nobody knows yet if they do - the implications are profound. For one thing, unraveling these pathways could lead to new antifatigue drugs, said Ferrucci, who is also director of the Baltimore Longitudinal Study on Aging. That's part of the good news.

For another, because both cytokine and mitochondrial problems get worse with excessive rest and improve with moderate exercise, it means exercise is an obvious, and readily available, remedy. A large body of research has already shown that exercise dampens down the "bad" cytokines and boosts the number and efficiency of mitochondria.

This doesn't mean you should go run a marathon if you've got the flu. Quite the contrary. In the acute phase of any illness, your body needs all its available energy to heal. But it does mean that, as soon as possible, you should get out and walk, even if it's just around the block for starters.

The fatigue now under the microscope - "central" or brain, fatigue - is most recognizable as a "subjective perception, the feeling that you don't have the energy to engage in any physical or intellectual challenge," said Dr. Anthony Komaroff , a fatigue specialist and professor of medicine at Harvard Medical School.

Ferrucci puts it slightly differently: "Fatigue is a physiological signal that tells the brain that you cannot keep doing what you're doing." Nobody is sure where this signal comes from, he said, though it's probably from the muscles.

While this kind of fatigue excludes the kind that stems from missing a night's sleep, or from certain illnesses such as anemia or chronic fatigue syndrome, it is relevant for people who, for example, have cancer.

A major part of the fatigue that accompanies many clinical conditions, including cancer, is triggered by "deconditioning," says William Evans, an exercise physiologist who is chair of nutritional longevity at the University of Arkansas for Medical Sciences.

"As you become less conditioned," which happens when an illness makes you lie around, "any activity becomes a higher percentage" of your capacity. The good news, he says, particularly for people with cancer fatigue, is that "every study that has been published to date" shows a positive effect for moderate exercise: "Training increases mitochondrial function to increase the capacity to use oxygen to make energy."

Doug Wallace, who directs the Center for Molecular and Mitochondrial Medicine and Genetics at the University of California, Irvine, notes that while bed rest is important at the beginning an infection, after that "it can be bad because you literally down-regulate muscle function, and with that, the number and efficiency of mitochondria also go down."

So, how do you know when to rest, when to exercise and when to see a doctor? The guiding advice is to rest at the onset of an infection, and build in exercise slowly when you start to feel better.

If, despite those steps, your fatigue lasts for weeks, call the doctor to rule out an underlying medical problem, including depression. You should also call if you've had fever plus fatigue for more than two weeks, or fatigue plus joint pain or joint swelling, which are possible signs of autoimmune disease, says Dr. Robin G. Molella, an internal and preventive medicine specialist at the Mayo Clinic in Rochester, Minn.

But so long as your doctor has ruled out major medical problems, you can find cheer in the news that feeling better, by exercising, is within your power.

It does seem paradoxical, but in many cases, lying around because you're tired by may be exactly the wrong thing to do.

Judy Foreman can be reached at

What causes fatigue

Researchers have defined a two-part cause for fundamental tiredness:

Too many pro-inflammatory cytokines, which the body produces to fight infections, and sluggish

mitochondria which produce energy in cells. Exercise reduces the cytokines and boosts the number and efficiency of mitochondria, reducing fatigue.

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