Circadian Rhythms: The Timekeepers Within
In another study, Young considered the synthesis of triglycerides. In people who are obese or who have diabetes, these fatty acids can accumulate in the heart and cause dysfunctional contractions. Young fed two groups of mice an identical diet but at different times of day. One group ate a high-fat breakfast at the beginning of its active period, the other a high-fat meal at the end of the active period. The mice that ate the high-fat dinner developed metabolic syndrome, gaining more weight and developing fat and insulin resistance—precursors of diabetes—and high cholesterol. The highest rate of triglyceride synthesis—which promotes storage of calories as fat—was at the end of the active period for the rodents. That could help explain why people who skip breakfast tend to weigh more—because they tend to eat more calories later in the day.
In his work with healthy human subjects, Steven Shea uses changes in schedule to force a desynchronization of behavior from circadian systems. Volunteers live in Shea’s lab for as long as two weeks, changing the time they go to bed and get up so they’re following either a 20-hour or a 28-hour day. For the 20-hour schedule, the volunteers typically go to bed at midnight the first day, 8 p.m. the second, 4 p.m. the third, noon the fourth and so on. By the time they’re turning in at noon, all their normal waking activities are happening during “biological night”—what would be nighttime on a normal schedule. Then Shea and his associates measure the subjects’ physiological responses to exercising, eating and sleeping, which now occur at different circadian phases than they normally would.
“We’re finding considerable differences in the magnitude of physiological responses based on circadian phases,” Shea says. For example, blood tests showed that subjects’ platelets became more likely to clot between 8 a.m. and 9 a.m. Platelet activation followed its own circadian cycle independent of when subjects slept or woke, and that timing corresponded to the vulnerable morning period when most heart attacks, strokes and sudden cardiac death occur. Platelets form blood clots, a process that goes awry in cardiovascular disease, the frequent cause of a heart attack.
As research leads to a greater appreciation of the circadian system’s role in developing disease, scientists are considering how they might use the body’s clocks to improve clinical treatments and to minimize side effects. “It would be especially useful in the case of such chronic diseases as diabetes and obesity to reduce the toxicity of drugs that have to be taken for decades,” Lazar says. Or instead of giving people the highest dose of a drug that they can tolerate in treating a heart condition, for example, it could be better to have them take less but have the drugs arrive at just the time of day that platelets tend to aggregate, Shea says.
Physicians have known for decades that cancer chemotherapy is most effective during particular times of day, and in a mouse experiment, Takahashi and Marina Antoch of the Roswell Park Cancer Institute in Buffalo found that the agent cyclophosphamide was minimally toxic to healthy tissues when given at dusk, but that mice died if they got it at dawn. Clinical trials in Europe are attempting to optimize timing so that patients receive treatments when they’re least sensitive to toxic side effects and cancer cells are most vulnerable.
Meanwhile, after 25 years of investigating circadian rhythms, Till Roenneberg has abandoned his alarm clock, except when he has to catch an early flight. “For the past 500 million years, organisms have gone to the trouble of inventing a system in which every reaction in the cell and every communication between cells creates a harmonic biochemical orchestration,” he says. “This ancient system is not something we can override with discipline or learning. And if we do mess with it, we’ll develop more illnesses than we would normally have.”