Sassone-Corsi says that it’s crucial that each and every one of the clocks in every cell in the body stay somewhat in time with one another. If the clocks become “misaligned,” it can cause a number of metabolic disorders or inflammatory responses, many of which are actually associated with aging.

By Emma Betuel, Inverse, March 2020

Photo by Karl Tapales / Getty Images.

Each of the trillions of cells in our bodies has a tiny internal clock. When all of those clocks are synchronized, they tell us when to wake up, burn calories, and go to sleep. But when they lose their beat, we become vulnerable to all sorts of aging-related diseases. Fortunately, the author of a 2018 paper in Cell Reports thinks that there’s a simple way to reset those clocks if they get off rhythm: fasting.

The circadian rhythm — that 24-hour clock that controls sleep-wake cycles — is the internal “master” clock, controlled by a big group of neurons in the brain, that most of us are familiar with. But Paolo Sassone-Corsi, Ph.D., the director of UC Irvine’s Center for Epigenetics and Metabolism and a co-author on the new paper, previously showed that the circadian clock isn’t the only clock but rather the main clock in a whole network of internal clocks in the body.

The internal clock within every cell expresses certain genes according to the master clock’s instructions. The proteins that help the cells keep those rhythms of gene expression are called “core clock proteins.” In his paper, Sassone-Corsi shows how fasting could get core clock proteins back on track if they ever lose time.

“The core clock genes and proteins are really crucial for health, as they control a large number of genes,” he tells Inverse. “These are proteins that are present in every cell of everyone’s body. They’re present in every tissue and in every single organ. They control thousands and thousands of genes. We’ve been undertaking an effort to understand how nutrition will change our circadian biology in various tissues.”

Sassone-Corsi says that it’s crucial that each and every one of the clocks in every cell in the body stay somewhat in time with one another. If the clocks become “misaligned,” it can cause a number of metabolic disorders or inflammatory responses, many of which are actually associated with aging. There are some factors that can throw a clock out of balance: For instance, high-fat and high-calorie diets have been shown to do so in turtles and mice. A well-aligned clock, explains Sassone-Corsi, is “really a signature for a healthy organism.”

“The core clock genes and proteins are really crucial for health as they control a large number of genes. They’re present in every tissue and in every single organ.

In his recent study on mice, Sassone-Corsi showed that 24 hours of fasting had some strange effects on the clock genes in liver and muscle cells of his otherwise healthy mice. When the mice fasted, he noticed that the “rhythmicity” of their core clock genes was blunted, far more so in the muscle than the liver cells. Those genes seemed to be adhering to different rhythms, expressing different genes than they normally would during a normal feeding schedule. But when he re-fed his mice, the clocks in those two tissues synced back up again.

“What fasting seems to do, at least in liver and muscle, which we studied in this particular paper, was that it was able to make [the clocks] more coordinated between the two,” he says.

This study isn’t an excuse to food-deprive yourself in order to beat your internal clock into submission. Instead, the researchers believe that strategically timed fasts might be a good way to look at treating age-related diseases that come from misaligned cellular clocks. Sassone-Corsi and his co-authors say that fasting can reorganize the way genes are expressed in each cell and “prime the genome” so when feeding starts again, the clocks in each tissue are back in sync. In short, it could hit a hard reset on an internal clock that might have gone rogue.

“Therefore, optimal fasting in a timed manner would be strategic to confer robust circadian oscillation that ultimately benefits health and protects against aging-associated diseases,” they write.

Emma Betuel is a writer based in NYC. Previously, she covered health and biology for WBUR’s Commonhealth blog and The Borgen Project Magazine.

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Brain’s Dumped DNA May Lead to Stress, Depression

Research suggests genetic material from the mitochondria can trigger an immune response throughout the body.

Scientific American| Knvul Sheikh

Photo by Pavel Chag / Getty Images.

Humans and other mammals react to stressful situations through a series of well-orchestrated evolutionary adaptations. When faced with a predator looking for its next meal, or with worry of losing a job, our bodies release a cascade of stress hormones. Our heart rate spikes, breath quickens, muscles tense up and beads of sweat appear.

This so-called “fight-or-flight” response served our ancestors well, but its continual activation in our modern-day lives comes with a cost. Scientists are starting to realize stress often exacerbates several diseases, including depression, diabetes, cardiovascular disease, HIV/AIDS and asthma. One theory is hoping to explain the link between stress and such widespread havoc by laying the blame on an unexpected source—the microscopic powerhouses inside each cell.

Each of our cells contains hundreds of small bean-shaped mitochondria — subcellular structures, or organelles, that provide the energy needed for normal functioning. Mitochondria have their own circular genome with 37 genes. We inherit this mitochondrial DNA only from our mothers, so the makeup of the DNA’s code stays relatively consistent from one generation to the next.

But our fight-or-flight response places extreme demands on the mitochondria. All of a sudden, they need to produce much more energy to fuel a faster heartbeat, expanding lungs and tensing muscles, which leaves them vulnerable to damage. Unlike DNA in the cell’s nucleus, though, mitochondria have limited repair mechanisms. And recent animal studies have shown chronic stress not only leads to mitochondrial damage in brain regions such as the hippocampus, hypothalamus and cortex, it also results in mitochondria releasing their DNA into the cell cytoplasm, and eventually into the blood.

The genetic cast-offs are not just inert cellular waste. “This circulating mitochondrial DNA acts like a hormone,” says Martin Picard, a psychobiologist at Columbia University, who has been studying mitochondrial behavior and the cell-free mitochondrial DNA for the better part of the last decade. Ejection of mitochondrial DNA from the cell mimics somewhat adrenal glands’ release of cortisol in response to stress, he says. Certain cells produce the circulating mitochondrial DNA and, as with the adrenal glands, its release is also triggered by stress.

To demonstrate psychological stress can cause mitochondrial DNA to be released by cells, Picard and his team devised a quick stress test. They asked 50 otherwise healthy men and women to deliver a quick speech defending themselves against a false accusation on camera. Afterward the researchers took blood samples from the participants and compared them with blood taken immediately before they were stressed. Even though the stressful task only lasted a total of five minutes, the scientists found participants’ serum circulating mitochondrial DNA levels more than doubled 30 minutes after the test. These results, currently under review, provide the first direct evidence for how bits of mitochondrial DNA floating in our blood may relay stress to other parts of the body, like dominoes tumbling one after another.

Previous studies have provided several clues that suggest circulating mitochondrial DNA is a hallmark of stress. In 2016 Swedish researchers published findings in Translational Psychiatry demonstrating elevated levels of mitochondrial DNA outside the cell in 37 people who had recently attempted suicide. Earlier this year the same group of scientists published another paper in Neuropsychopharmacology showing people with major depression had high levels of circulating mitochondrial DNA, and these levels kept increasing in patients who did not respond well to antidepressant medication.

These studies are all part of an emerging field of research on mitochondrial DNA, where scientists are recognizing that the tiny organelles have effects across a wide range of diseases. “Mitochondrial DNA is probably the most sensitive thing in your body,” says Douglas Wallace, director of the Center for Mitochondrial and Epigenomic Medicine at The Children’s Hospital of Philadelphia. “If your mitochondria are sensing a problem, then all the rest of you is in trouble, too.” wallacedl@email.chop.edu

In his own research Wallace has shown mitochondrial DNA mutations are more common in people with autism spectrum disorders than in neurotypical adults. Other studies in the past few years have linked mitochondrial dysfunction to schizophrenia, Alzheimer’s, arthritis and cancer—all problems where inflammation is also known to occur, Picard notes.

But how was this inflammation triggered by mitochondrial DNA leaking out of cells? A 2010 Nature paper provided the answer: In it researchers demonstrated the way mitochondrial DNA, when released into the blood after an injury, mobilized a pro-inflammatory immune response. Because of mitochondria’s bacterial origin and its circular DNA structure, immune cells think it’s a foreign invader. When circulating mitochondrial DNA binds to a particular receptor, TLR9, on immune cells, they respond as if they were reacting to a foreign invader such as a flu virus or an infected wound. The immune cells release chemicals called cytokines telling other white blood cells they need to report for duty at sites of infection, inflammation or trauma.

Together, this growing understanding of circulating mitochondrial DNA sets a time frame for how psychological stress may lead to widespread inflammation, Picard says. “Mitochondria are the missing link between our psychological state and neurological or other disorders involving inflammation,” he says.

It is an interesting shift away from the traditional, anatomical aspects of disease, such as brain shrinkage in depressed patients. But reducing disorders like depression to brain imbalances or shrinkage simply has not explained everything, says Bruce McEwen, a neuroendocrinologist at The Rockefeller University. “If that was the case, you could take Prozac or [selective] serotonin reuptake inhibitors [SSRIs] to fix it, but everybody is now realizing that that’s not the way it works,” he says. “Otherwise, antidepressants would be more effective.”

If further evidence of the importance of healthy mitochondria continues to emerge, drugs that focus on regulating cellular energy production instead could become a new line of defense for psychiatric and biological disorders.

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• When You Eat Can Be Just As Important As What You Eat

Our bodies run on a 24-hour clock — right down to our cells. “Pretty much anything that you would get tested at the doctor’s office has a circadian rhythm. For instance, your heart rate and blood pressure naturally rise in the afternoon and are lowest while you sleep,” says Manoogian, a researcher at the Salk Institute for Biological Studies in La Jolla, California. This rhythm “helps us be alert when we wake up, it has our digestive system ready to process food when we eat, and it helps our organs rest and repair while we sleep.” In her research, Manoogian monitors the timing of daily habits in thousands of people around the world to gain insight on how these affect their health.

In our busy and highly stimulating world, our circadian rhythm could use some assistance. “The two biggest cues you can give your body to tell it the time of day [are] light and food,” says Manoogian. “Evolutionarily, those were very reliable cues to know the time of day. But in modern society, light and food are available around the clock. This can lead to circadian disruption.”

Such disruption is associated with an increased risk of heart disease and diabetes. The World Health Organization has listed it as a probable carcinogen when it becomes a regular feature of life due to shiftwork patterns. Even our treasured weekends and holidays can throw off our body’s schedule in a phenomenon known as “social jetlag,” simulating the feeling of having crossed several time zones as as result of staying up or sleeping later, or eating and drinking at odd hours.

“You need to keep your body on its schedule so it can prepare itself for what it needs to do,” says Manoogian. “This means using those external cues to support your biological clock: tell it when it’s morning and when it should be awake, and decrease simulation at night so it can get a proper rest.”

One way to help our bodies is by practicing “time-restricted eating.” What that means is this: Eat within the same 10-hour window every day. That’s it. So if the first thing that you consume is at 8 AM, your last meal should be at 6 PM.

The end of your 10-hour eating window should not coincide with your bedtime. (Water is fine, however.) “Leave at least three hours before you go to bed … so your body can get that proper rest,” says Manoogian. “[Your body] needs at least 12 hours of fasting every day to function properly.”

If you decide to try time-restricted eating, this does not mean you can never go to a party again or have a midnight snack. When you do exceed your 10-hour window, just get on track the next day. But you may find the benefits of this practice outweigh the inconvenience. “Time-restricted eating … can improve glucose tolerance and insulin sensitivity, can lead to about a 5 percent weight loss, improves endurance and decreases blood pressure,” says Manoogian.

If you’re interested in participating in Manoogian’s research and in tracking your own rhythms, check out the free tracking app MyCircadianClock (which was co-created by Manoogian).

Watch her TEDxSanDiegoSalon talk here: