Excerpt – In the early 2000s, advances in the ability to detect the activity of genes in various tissues revealed that the cell clocks are organized into separate organ-level clocks representing every physiological system: There’s a skin clock and a liver clock and an immune-system clock; there’s a clock for the kidney, heart, lungs, muscles and reproductive system. Each of those clocks syncs itself to the central clock in the brain like an orchestra section following its conductor. But those sections also adjust how and when they perform based on guidance they receive both from the environment and from one another, and their timing can provide feedback to the central clock and cause it to adjust the time it keeps too. The liver, for instance, determines when to rev up your metabolism based on when you eat; if you do that in the middle of the night, the liver will be receiving contradictory cues from the brain, which is telling it to rest. As a result, when the liver starts processing the midnight food, it will do so less efficiently than it would have done after a daytime meal — and it sends conflicting signals back to the brain and other organ systems.
Such internal misalignment, or dysregulation, can throw our physiology out of whack. Perhaps the most familiar way we experience this sort of internal chaos is when traveling across multiple time zones: As we eat, sleep or engage in other activities based on the local time, our central and peripheral clocks reset themselves at different rates to match the new environment. The symptoms of jet lag — insomnia, exhaustion and stomach problems, sluggishness and distractedness — are examples of the sort of overall malaise caused by circadian confusion. Staying up hours later on the weekend than you do during the week has the same effect: This has been dubbed “social jet lag.” [..]
[..] a professor of pharmacology at the University of Pennsylvania named John Hogenesch published a paper [in 2014] with his colleagues showing that almost half of the genes in mice produce proteins on a 24-hour schedule. This means that as the clock genes cycle through their functions, their work is activating or deactivating thousands of other, nonclock genes in consistent daily patterns. [..]
The fact that the genes oscillated — became active or inactive in a predictable pattern — meant that those drugs might be very effective at certain times of the day and less so at others. And they might trigger side effects at certain times but not others, depending on the phase of the clocks in affected tissues. Hogenesch has since found that 50 percent of our genes are controlled by the clock. That amounts to about 10,000 of the roughly 20,000 genes we have. [..]
Western medicine has long been skeptical of studies that tout the health benefits of synchronizing treatments with biological cycles — as traditional Chinese medicine does — in large part because there was no scientific explanation for the results. The relatively recent revelation of the genetic underpinnings of circadian rhythms has sparked a re-evaluation of many decades-old ideas. Previously, those ideas were tested by seeing whether people who received a particular health intervention had different outcomes depending on when they received it, or by observing associations between the timing of certain behaviors, like sleep, and people’s risk of disease. [..]
Eating at night increases the risk of glucose intolerance, which causes diabetes, because the kidney, pancreas and liver are primed to be resting then. But a 2021 study in Science Advances demonstrated that when subjects were kept up at night, as shift workers are, but were awakened during the day to eat, they did not experience glucose intolerance. [..]
Research has repeatedly shown [..] that premature infants who receive 12 hours of light followed by 12 hours of darkness are discharged an average of two weeks earlier than those who are exposed to near constant darkness or near constant light. The new system will allow the hospital to go a step further and investigate for the first time the optimal lighting conditions for premature infants. This fall, doctors plan to test the effect of both various spectra and light-dark cycles on the metabolism and growth of newborns with gastrointestinal disorders. It’s easy to imagine similar experiments revolutionizing the best practices for illuminating nursing homes, schools and office buildings. Oftentimes, as is true in the NICU, there is a presumption that drawn curtains and darkness bring tranquillity to the elderly and those suffering from pain or illness — when in fact the absence of light most likely results in worse moods, sleep and health.
Now scientists possess the technology to see how circadian rhythms oscillate at a molecular level based on behavior and time of day in both mice and people. [..]
Phyllis Zee, the neurologist who in 2014 founded the Center for Circadian and Sleep Medicine at the Feinberg School of Medicine, the first place in the United States to consider circadian medicine as a separate specialty, thinks patients with lots of common chronic diseases — from diabetes to heart disease to cognitive decline — might see improvement by changing their behaviors to improve the synchronization of their internal clocks. “You don’t need to do the fancy stuff,” she says. Keeping a log of when you sleep and wake, eat and take medications — as well as how the night goes and how you feel — could give you and your primary care doctor plenty of information to act on.
Indeed, one of the great promises of circadian medicine is its D.I.Y. appeal: If we could figure out the optimal time to eat or exercise, for example, we could change our behavior immediately — free of charge — not only to minimize the harm but also to maximize the health benefits of given activities. Professional athletes and their trainers, for instance, know that physical performance peaks in the late afternoon or early evening. (Most world records are broken in the evening.) In February, Cell Metabolism published an “atlas of exercise metabolism” that showed how, for mice, the metabolic effects of running on mini-treadmills changed over 24 hours. [..]
Studies involving mice have found that when the animals’ caloric input is restricted to 30 percent below what they typically consume, they live 30 percent longer than usual. Looking at those experiments, Joseph Takahashi, the Texas Southwestern neuroscientist, who is also an investigator at the Howard Hughes Medical Institute, wondered how much influence circadian rhythms, as opposed to caloric restriction and the fasting period, had on the mice’s longevity. In a study published in Science last month, he and his colleagues managed to tease apart this correlation. When the restricted diet was meted out to mice around the clock, their life spans were only 10 percent longer than those of mice in a control group that ate as much as they wanted whenever they wanted. Mice on the restricted diet that got their food all at once ate all their calories within a two-hour window — and lived an additional 10 percent longer. Finally, when the mice ate during their active phase, rather than during their rest phase, they lived another 15 percent longer yet.
This suggests that the time of day when the mice ate was just as important to their longevity as any other factor. [..]
Hogenesch thinks that we could take advantage of our biological clocks to improve the efficacy and reduce the side effects of the drugs we already have. In August 2019, he and his colleagues published a paper in Science noting that the circadian half of our genome includes many targets of the roughly 2,000 prescription drugs available in the United States. Very few of those medicines have been tested clinically at multiple times of day. Only four of the top 50 most-prescribed drugs come with F.D.A.-approved recommendations for when they should be taken. [..]
“Clinical decisions should be made around the clock,” he [Hogenesch] and his co-authors wrote in a 2019 PNAS publication. “Pain, infection, hypertensive crisis and other conditions do not occur selectively in the morning.” In person, he is blunter: “No matter how dumb it is,” he says, referring to conventional hospital practices involving lighting, for example, or drug delivery, “they don’t want to change it.” [..]
Circadian medicine may enhance our well-being, in other words, but most of us should not expect it to transform our lives anytime soon. There are, though, exceptions to that rule whose unusual circumstances may point toward broader applications later. As Hogenesch put it to me, “You learn from the edge cases.”
Full article, K Tingley, New York Times Magazine, 2022.7.6
Hogenesch was the senior author of a meta-analysis about factors associated with medicine timing effects published on medRxiv (a pre-print server) on October 26, 2021. The authors saw the largest effect with the timing of aspirin administration and were skeptical of claims that antihypertensives were more effective if taken at night (one study with larger-than-expected effect size).