Body Clock Shift May Cause Sickness-Linked Fatigue

Targeting this change could lead to new therapies, researchers say

THURSDAY, July 19, 2007 (HealthDay News) -- As anyone who has battled the flu knows, "sick and tired" often go hand-in-hand.

Now, research suggests that illness-linked biochemistry may interfere with the body's "clock" to bring on the low-energy blahs.

Especially for patients battling chronic fatigue, the new findings "could pave the way for further exploration of the interaction between the immune system and the circadian system, hopefully leading to a better understanding of how daytime fatigue could be treated," said study co-lead researcher Thomas Birchler, of the University Hospital Zurich, in Switzerland.

His team published its findings in this week's online edition of the Proceedings of the National Academy of Sciences.

A sudden, profound loss of daytime energy is one of those "uh-oh" symptoms that signals the onset of acute illness, such as colds or influenza. Fatigue of a more chronic kind is also one of the most common and debilitating hallmarks of a wide variety of disorders, from cancer to autoimmune disease to Chronic Fatigue Syndrome.

Up until now, however, scientists knew little as to why fatigue so often accompanies illness.

In the new study, Birchler's team sought to determine how TNF-alpha -- an immune system inflammatory protein or "cytokine" -- might induce daytime tiredness.

A jump in TNF-alpha activity "is found in most of the acute and chronic infectious diseases and is also part of the inflammatory response in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease," Birchler explained.

TNF-alpha helps spur immune-fighting cells that then seek out and destroy the agent causing the illness.

However, the Swiss group's work with both cell cultures and mice found that TNF-alpha has other physiological effects.

"Besides the known functions of TNF-alpha to eliminate infectious agents, we provide evidence that TNF-alpha interferes with clock gene expression," Birchler said.

In other words, the cytokine may affect genes that, in turn, upset the body's normal sleep/wake rhythms -- the "biological clock." This circadian clock guides the daily cycle of alertness and fatigue that people typically feel when healthy, but TNF-alpha appears to help put this cycle into disarray.

According to the study, TNF-alpha activity also "impairs locomotor activity and induces increased rest periods in mice," Birchler noted.

From an evolutionary and survival standpoint, feeling listless and sleepy during short-term illness probably isn't such a bad thing, the Swiss expert said.

"There's evidence that sleep is a helper for the fight against infections, and sleep deprivation leads to worsened immune response," Birchler explained. "From an evolutionary standpoint, fatigue -- by preventing the affected individual from joining social life -- may thereby hinder spread of infectious agents in the population," he added. "Fatigue in animals may be a mechanism which puts pressure on the affected animal to hide and thereby be protected from enemies."

Unfortunately, many patients can suffer from a chronic, unending form of fatigue, usually linked to long-term illness. That kind of tiredness is not useful, Birchler said, and is often the leading complaint of people battling disease.

"So, in the short term, illness-linked fatigue is an advantageous adaptation, but in the long term not necessarily so," said Wilfred Pigeon, an assistant professor of psychiatry at the University of Rochester, N.Y., and the director of the university's Sleep & Neurophysiology Research Laboratory.

Pigeon said the Swiss findings are intriguing and "point the way to some potential therapeutic targets" to help patients ease chronic fatigue. "We probably don't want to tinker with it in flu, for instance, but we may want to tinker with those targets for people who have some chronic illness or autoimmune diseases," he said.

And that "tinkering" might not always come in the form of a pill, Pigeon said.

In numerous studies, exercise "has successfully alleviated fatigue symptoms," Pigeon noted. "Of course, people with Chronic Fatigue Syndrome or cancer-related fatigue really don't want to go to the gym, but, in fact, when they do go, it does alleviate [fatigue] symptoms," he said. The reasons for the effect remain unclear, he added, but "it would be interesting to look at exercise or other behavioral interventions to see if we actually change [clock] gene function."

More information

There's more on Chronic Fatigue Syndrome at the U.S. Centers for Disease Control and Prevention.

SOURCES: Wilfred Pigeon, Ph.D., assistant professor, psychiatry and director, Sleep & Neurophysiology Research Laboratory, University of Rochester, N.Y.; Thomas Birchler, Ph.D., University Hospital Zurich, Switzerland; July 16-20, 2007, Proceedings of the National Academy of Sciences
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