Circadian Rhythm: Timing as a Therapeutic Variable

In 2017, the Nobel Prize in Physiology or Medicine was awarded for the discovery of the molecular mechanisms controlling circadian rhythm: a set of genes and proteins that oscillate in a roughly 24 hour cycle in almost every cell. That discovery transformed circadian biology from a curiosity into a central part of physiology. For practitioners, its most useful implication is simple: when things happen matters, not only what happens. Timing of light, meals, sleep and activity can be adjusted to improve health.

How the clock works

The master clock

The suprachiasmatic nucleus in the hypothalamus acts as the body’s master clock. It receives light information directly from specialised cells in the retina, which are particularly sensitive to blue enriched light. Light in the morning advances the clock; light in the evening and at night delays it and suppresses melatonin, the hormone of biological night.

Peripheral clocks

Organs including the liver, pancreas, muscle, fat tissue and gut have their own clocks. They are coordinated by the master clock but also respond to other signals, particularly the timing of food intake, physical activity and body temperature. When meals are eaten at the wrong biological time, peripheral clocks can become misaligned with the master clock.

Daily rhythms in physiology

Many functions follow daily patterns: cortisol peaks in the early morning; melatonin rises in the evening; body temperature falls at night; insulin sensitivity and glucose tolerance are generally better in the morning than the evening; blood pressure dips during sleep; alertness and physical performance vary predictably across the day.

Chronotypes and social jetlag

People differ in their natural timing, their chronotype, from early larks to late owls, partly for genetic reasons and partly with age; adolescents and young adults tend to be later. When work or school schedules conflict with a person’s chronotype, they sleep at the wrong biological time during the week and shift their sleep at weekends. This mismatch, called social jetlag, is common and has been associated in population studies with higher body weight and metabolic risk.

When the clock is disrupted

Shift work

Night shift work forces people to be awake, active and eating during their biological night. Shift workers have higher rates of obesity, type 2 diabetes, cardiovascular disease, gastrointestinal problems and mood disorders. The International Agency for Research on Cancer has classified night shift work as probably carcinogenic to humans. Experimental studies that simulate shift work show impaired glucose tolerance and reduced energy expenditure within days.

Evening light

Exposure to bright light in the evening, including from screens, delays the clock and suppresses melatonin. In one study, reading on a light emitting e reader before bed, compared with a printed book, delayed melatonin release, lengthened the time taken to fall asleep and reduced next morning alertness.

Late eating

Because glucose tolerance declines through the day, the same meal eaten late at night produces a higher glucose response than in the morning. Studies have associated late eating with higher body weight and poorer metabolic markers, and a trial in women with overweight found that eating a larger share of daily energy at breakfast rather than dinner produced greater weight loss and better glucose and lipid markers.

Irregular sleep

Variability in sleep timing from night to night has been associated with poorer metabolic health, independent of average sleep duration.

Timing as intervention

Supporting shift workers

For people who must work at night, practical strategies can reduce harm:

• keep shift patterns as stable as possible, and prefer forward rotating schedules where there is a choice;
• avoid large meals during the night shift, favouring lighter meals and eating the main meal before the shift;
• use bright light during the early part of a night shift and wear dark glasses on the way home in the morning;
• protect daytime sleep with a dark, quiet, cool room;
• be cautious with caffeine late in the shift;
• monitor metabolic health more closely.

Melatonin

Melatonin supplements act mainly as a timing signal rather than a sedative. They have evidence for reducing jet lag and for shifting sleep timing in delayed sleep wake phase disorder, where low doses taken several hours before the desired bedtime are used. Effects on general insomnia are modest. Product quality and dose vary, and regulations differ between countries: melatonin is prescription only in some and sold as a supplement in others.

Timing of medicines

Chronotherapy, timing medicines to biological rhythms, is an appealing idea. For some medicines, timing matters for practical or pharmacological reasons. For others, evidence is mixed. A large pragmatic trial comparing morning with evening dosing of antihypertensive medicines found no difference in major cardiovascular outcomes, contrary to an earlier trial that had reported large benefits of evening dosing. Changes to medication timing should be made with the prescriber.

An illustrative case

A 24 year old graduate student with insomnia, low mood and weight gain goes to bed at 3 am and wakes at noon on free days, but must wake at 7 am on 3 days a week for classes. She uses her phone in bed and eats her largest meal after midnight. Her pattern suggests delayed sleep timing with social jetlag.

Her plan uses timing as the main intervention: a gradual advance of her wake time with bright light exposure outdoors soon after waking, dimmed lights and no phone in the last hour before bed, her main meal moved to the early evening and a consistent schedule across the week. Her doctor suggests a low dose of melatonin in the early evening for a limited period. Over 6 weeks her sleep onset moves earlier, her mood improves and her late night eating stops.

When as well as what

Circadian biology adds a dimension to nearly every lifestyle intervention. The same meal, light exposure or activity can have different effects depending on when it happens. Aligning daily routines with the body’s clock is simple, inexpensive and often overlooked, and it can make other changes more effective.