Circadian Medicine

 https://www.nytimes.com/2022/07/06/magazine/circadian-medicine.html

The Quest by Circadian Medicine to Make the Most of Our Body Clocks

Researchers are trying to figure out the right hour of the day to do everything. Can their studies sync us up with better health?

By Kim Tingley

• July 6, 2022Updated 11:43 a.m. ET

“Time,” when we give it any thought, tends to strike us as extrinsic, a feature of our landscape: We track our passage through it as if traversing an invisible geography, our progress charted by wristwatch, clock, calendar. Humans didn’t invent time, of course, but you might reasonably argue that because we invented the units we use to keep track of it — hours, minutes, seconds — we have every right to tinker with them when we want to. This, at least, was the position the Senate took on March 15, when in a surprise, and surprisingly uncontested, vote it passed the Sunshine Protection Act. The new law would, if the House concurs and the president signs, make daylight saving time permanent, beginning on Nov. 5, 2023.

The change has long been a desire of the retail industry because it is convinced that shoppers spend more money when it stays light out later. But lawmakers also seem to have regarded the annual rolling back of the clock as a personal affront: the groggy mornings that result from turning 6 a.m. into 5 a.m., the morale killer for Boston and Billings alike when darkness abruptly descends shortly after 4 in the afternoon. When the yeas prevailed, there was bipartisan applause, as if a particularly hostile foreign adversary had been defeated.

What most of those lawmakers very likely didn’t realize was that the enemy was not just outside us — a social agreement about how to label every moment of our existence relative to the sun — it was also inside us, where our internal organs are keeping time, too. In fact, most of our physiological functions are governed by an untold number of carefully synchronized biological clocks that each complete one cycle about every 24 hours. Those cycles are known as circadian rhythms, after the Latin for “about” (circa) and “day” (dies).

Many of us are passingly familiar with circadian rhythms as a way to refer to our sleep cycle. In 1972, scientists discovered that that cycle is mediated by an area in the brain’s hypothalamus called the suprachiasmatic nucleus. This structure coordinates the release of hormones — among them dopamine — that lower body temperature and blood pressure and make us feel sleepy; in the morning, cortisol and other hormones restore our alertness, make us warmer and increase blood pressure. The a.m. surge in blood pressure is believed to be one reason heart attacks occur more often then than in the p.m.

In the past two decades, however, researchers have discovered that the clock in the brain is by no means the only one in our body. It turns out that most of our cells contain a group of genes that might be thought of as gears in a mechanical watch, keeping time everywhere internally. These “clock genes” — there are at least six that are considered integral to the watch’s operation — work together the same way in each cell. And just as they cause the release of hormones in the brain, they dictate other processes in other parts of the body. 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.”

Circadian rhythms, in other words, are relevant to more than sleep. But few realized how relevant until 2014, when a professor of pharmacology at the University of Pennsylvania named John Hogenesch published a paper 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 finding astonished circadian experts.