Biological Clocks Become Desynchronized Under Jet-Lag Conditions

The findings will be reported in the April 28 issue of the journal Science. The research was conducted at the University of Virginia, the home site of the National Science Foundation Center for Biological Timing.

"We are finding that an organism is a conglomeration of oscillators," says Michael Menaker, Commonwealth Professor of Biology at the University of Virginia. "When the primary oscillator in the brain shifts to follow an abrupt shift in the light cycle, the clocks controlling several other organs become desynchronized. It likely takes some time before these clocks adjust back to synchrony."

Menaker says the findings have health implications for air travelers who must frequently cross multiple time zones, and for shift workers who regularly rotate shift cycles.

The researchers used brain, skeletal muscle, liver and lung tissue from transgenic rats to collect their data. The rat tissue included a known clock gene indicator from a mouse that is spliced with a glowing "tag" (a fire fly enzyme). The tag is activated when the clock gene responds, or is transcribed, during changing light cycles. Menaker and his team were able to "reset" the brain and organ clocks -- the circadian rhythms -- forward by six hours or back by six hours, mimicking the effects of trans-Atlantic travel.

"Our question was, what is the physiology that explains the malaise people experience after flying across several time zones?" Menaker says. "We wanted to know how many circadian clocks there are, how the individual tissues respond when the organism is subjected to light cycle changes, and how the various biological clocks operate together as a system.

"We demonstrated clearly that both brain and peripheral tissues are rhythmic when they are removed from the animal and held in culture conditions. This is new information, but was suspected. What is surprising is that while the central oscillator in the brain keeps cycling for up to one month, the peripheral tissues rapidly lose their rhythmicity in culture. We now believe the central oscillator in the brain is the key timer that synchronizes the peripheral clock cycles. This helps us understand biologically what happens in an organism when its light cycle is suddenly shifted.

"In nature, light shifts occur slowly as the seasons change," Menaker says. "Organisms, therefore, have several months to adjust to the changes. But transmeridian flight is an unnatural event for the body. It causes very abrupt light cycle shifts. The body is not naturally prepared for this sudden change. Once the relationships between the various oscillators are disrupted, the normal function of the organs may be compromised."

Menaker says that while the symptoms of occasional jetlag may be annoying, the new findings may imply that the physiological effects of rotating shift work could be more serious.

"Twenty percent of the U.S. workforce are shift workers," Menaker says. "Our findings suggest that frequent irregular light cycle shifts may have biological repercussions. Shift workers, for example, often experience reduced alertness, fatigue, ulcers and poor digestion. We do not know yet the full extent of the health issues that may result from regular disruption of circadian rhythm synchrony."

According to Menaker, most catastrophic accidents -- such as the Exxon Valdez grounding, and the Three Mile Island and Chernoble incidents -- are the result of human error, commonly occurring among shift workers late at night.

"When people are trying to adjust to abnormal sleep and wake cycles, they tend to lose focus, become fatigued more easily, and generally don't feel as healthy as they normally would," he says. "We are showing that a physiological change is occurring. The ramifications for health and performance are real and potentially serious."

U.Va. researchers who conducted the study include Shin Yamazaki, the principal investigator, Michikazu Abe, Gene Block, and Menaker. Six researchers from the University of Tokyo and the New Technology Institute in Japan also participated.