Shift work has been linked to a number of health problems, including higher rates of diabetes, heart attacks, and other cardiometabolic diseases. But despite the known risks, little research has been done to identify lifestyle interventions that could help prevent these concerns. A new randomized, controlled clinical trial, published October 4 in Cell Metabolism, found that time-restricted eating (TRE) could be safely practiced in shift workers. Additionally, the researchers found that TRE provided benefits to participants who had indications of cardiometabolic disease. Called the Healthy Heroes Study, the intervention focused on San Diego firefighters.

“Shift work is much more common than many people think, affecting workers in a range of different fields as well as parents of newborn babies,” says co-corresponding author Satchidananda Panda, a professor at the Salk Institute and holder of the Rita and Richard Atkinson Chair. “Not only does shift work contribute to an increased burden of disease in our society, but it makes it hard for people with existing conditions like diabetes and cardiovascular disease to manage them.”

“Within the confines of shift work, there are many lifestyle interventions that can potentially optimize the health of shift workers,” says co-corresponding author Pam Taub, a cardiologist and professor in the University of California San Diego School of Medicine’s Division of Cardiovascular Medicine. “However, there are very few research studies on this population. Our study sheds light on one way that we can help this population.”

Panda and Taub have collaborated on research into TRE for several years. In January 2020, they published a study in Cell Metabolism that found that restricting the time of eating to 10 hours a day reduced body weight and improved blood pressure and cholesterol levels in people with metabolic syndrome. In the current study, they focused on TRE in shift workers. The trial recruited San Diego firefighters, who work 24-hour shifts. There were 137 firefighters ultimately enrolled in the study; 70 followed TRE, eating all of their meals within a 10-hour time window, and 67 were in the control group. All participants were encouraged to follow a Mediterranean diet that was rich in fruits, vegetables, whole grains, and healthy fats. The subjects were followed for 12 weeks.

One barrier to conducting research studies with shift workers has been the subjects’ inability to come to the lab during regular business hours. The researchers got around this by going to the fire stations to apply wearable devices on the participants to collect their activity, sleep, and blood glucose levels. They also customized an app that allowed the firefighters to log their food and sleep and answer study surveys; the app also enabled the researchers to send study materials and to guide the participants on following the recommended lifestyle.

The investigators found that for the firefighters, following a time-restricted eating pattern was both safe and feasible. The subjects didn’t report any problems with concentration, reaction times, or other issues. Their quality of life generally improved.

“Overall, firefighters are a pretty healthy group of people, but we found that for those who had underlying cardiometabolic risk factors like high blood pressure, high cholesterol, and hyperglycemia, there was some benefit to TRE, especially in terms of improvement in glucose levels and blood pressure,” Taub says. “Even those who were healthy with no underlying cardiomeatabolic risk factors had improvements in quality of life and in VLDL, which is a form of bad cholesterol.”

Taub and Panda say they would like to conduct similar research on other shift workers, especially healthcare workers, but it’s difficult to get funding for such studies.

“Humans have been living with circadian rhythms for at least 200,000 years, and these rhythms clearly have a profound effect on us,” Panda says. “Shift workers, whether they are astronauts or custodians, are vital to our society. It’s time to think about how we might help them improve their health.”

There’s the old saying in dieting that one must “breakfast like a king, lunch like a prince, and dine like a pauper,” based on the belief that consuming the bulk of daily calories in the morning optimizes weight loss by burning calories more efficiently and quickly. But according to a new study publishing September 9 in Cell Metabolism, whether a person eats their largest meal early or late in the day does not affect the way their body metabolizes calories. However, people who ate their largest meal in the morning did report feeling less hungry later in the day, which could foster easier weight loss in the real world.

“There are a lot of myths surrounding the timing of eating and how it might influence either body weight or health,” says senior author Professor Alexandra Johnstone, a researcher in the field of appetite control at the Rowett Institute, University of Aberdeen, Scotland. “This has been driven largely by the circadian rhythm field. But we in the nutrition field have wondered how this could be possible. Where would the energy go? We decided to take a closer look at how time of day interacts with metabolism.”

In this study, the investigators recruited healthy subjects who were overweight or obese to have their diets controlled and their metabolisms measured over a period of time; 16 men and 14 women completed the study. Each participant was randomly assigned to eat either a morning-loaded or an evening-loaded diet for four weeks. The diets were isocaloric, with a balance of 30% protein, 35% carbohydrate, and 35% fat. After a washout period of one week in which calories were balanced throughout the day, each participant crossed over to the opposite diet for four weeks. In that way, each participant acted as their own study control.

Throughout the study, the subjects’ total daily energy expenditures were measured using the doubly labelled water method, an isotope-based technique that looks at the difference between the turnover rates of the hydrogen and oxygen of body water as a function of carbon dioxide production. The primary endpoint of the study was energy balance measured by body weight. Overall, the researchers found that energy expenditures and total weight loss were the same for the morning-loaded and evening-loaded diets. The subjects lost an average of just over 3 kg (about 7 pounds) during each of the four-week periods.

The secondary end points were subjective appetite control, glycemic control, and body composition. “The participants reported that their appetites were better controlled on the days they ate a bigger breakfast and that they felt satiated throughout the rest of the day,” Johnstone says. “This could be quite useful in the real-world environment, versus in the research setting that we were working in.”

One limitation of the study is that it was conducted under free-living conditions rather than in the lab. Additionally, certain metabolic measurements were available only after breakfast and not after dinner.

Johnstone notes that this type of experiment could be applied to the study of intermittent fasting (also called time-restricted eating), to help determine the best time of day for people following this type of diet to consume their calories.

The group plans to expand its research into how the time of day affects metabolism by conducting studies similar to the one described here in subjects who do shift work. It’s possible these individuals could have different metabolic responses due to the disruption of their circadian rhythms. “One thing that’s important to note is that when it comes to timing and dieting, there is not likely going to be one diet that fits all,” Johnstone concludes. “Figuring this out is going to be the future of diet studies, but it’s something that’s very difficult to measure.”

Two papers appearing April 18 in the journal Cell Metabolism confirm that the circadian clock is an important factor in how the body responds to physical exertion. The studies focused on different components of exercise, thereby complementing each other. Based on this work alone, it’s too early to say when the best time is for you to go for a jog. But at least in the lab, exercise in the evening seems to be more productive, although human lifestyles are much more complicated and so this area of research is only just beginning.

“It’s quite well known that almost every aspect of our physiology and metabolism is dictated by the circadian clock,” says Gad Asher of the Department of Biomolecular Sciences at the Weizmann Institute of Science, who is senior author of one of the studies. “This is true not only in humans but in every organism that is sensitive to light. We decided to ask whether there is a connection between the time of day and exercise performance.”

“Circadian rhythms dominate everything we do,” adds Paolo Sassone-Corsi of the Center for Epigenetics and Metabolism at the University of California, Irvine, who is senior author of the other paper. “Previous studies from our lab have suggested that at least 50% of our metabolism is circadian, and 50% of the metabolites in our body oscillate based on the circadian cycle. It makes sense that exercise would be one of the things that’s impacted.”

Both research teams looked at the association between time of day and exercise performance primarily in mice. Because mice are nocturnal, one thing they had to do was translate mouse timing to human timing, by distinguishing between the active phase and resting phase of the mice rather than using numbers on the clock.

Asher’s group started by putting mice in treadmills at different times of day within their active phase. They examined the exercise capacity of mice upon different exercise intensities and regimens and found that overall exercise performance is substantially better (about 50% on average and more in some protocols) in the “mouse evening” (toward the end of their active time) compared to the morning hours. These daily differences were diminished in mice that had mutant clocks–supporting a potential role of the clock in the observed variance in exercise performance.

To identify a potential determinant of daily variance in exercise performance, they applied high-throughput transcriptomics and metabolomics on muscle tissue. The researchers found that in response to exercise in the “mouse evening,” there were higher levels of a metabolite called ZMP (5-aminoimidazole-4-carboxamide ribonucleotide). ZMP is known to activate metabolic pathways that are related to glycolysis and fatty acid oxidation through activation of AMPK, which is a master cellular metabolic regulator. Therefore, it is likely to contribute to the increased exercise capacity in the evening. “Interestingly, ZMP is an endogenous analog of AICAR [aminoimidazole carboxamide riboside], a compound that some athletes use for doping,” Asher says.

The researchers also studied 12 humans and found similar effects. Overall, the people in the study had lower oxygen consumption while exercising in the evening compared with the morning; this translated to better exercise efficiency.

Sassone-Corsi’s team also put mice on treadmills, but they had a different approach. Using high-throughput transcriptomics and metabolomics to look at a wide range of possible factors, they characterized the changes in the mice’s muscle tissue that occur in response to exercise. This allowed them to look at processes like glycolysis (which contributes to sugar metabolism and energy production) and lipid oxidation (fat burning).

They found that a protein called hypoxia-inducible factor 1-alpha (HIF-1α) plays an important role and that it is activated by exercise in different ways depending on the time of day. HIF-1α is a transcription factor that is known to stimulate certain genes based on oxygen levels in tissue. “It makes sense that HIF-1α would be important here, but until now we didn’t know that its levels fluctuate based on the time of day,” Sassone-Corsi says. “This is a new finding.”

Based on the work from the UC Irvine team, exercise seemed to have the most beneficial impact on the metabolism at the beginning of the active phase phase (equivalent to late morning in humans) compared with the resting phase (evening).

The researchers note that even though circadian clocks have been conserved throughout evolution, translating the findings to humans is not so straightforward. One reason is that humans have more variation in their chronotypes than mice living in a lab. “You may be a morning person, or you may be a night person, and those things have to be taken into account,” Sassone-Corsi says.

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Cell Metabolism, Ezagouri, Zwighaft, and Sobel et al.: “Physiological and Molecular Dissection of Daily Variance in Exercise Capacity” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30141-X DOI: 10.1016/j.cmet.2019.03.012

This study was supported by the European Research Council and an EMBO Young Investigator Award. It was also supported by Fonds de Dotation AGIR pour les Maladies Chroniques and a fellowship from the Placid Nicod Foundation.

Cell Metabolism, Sato et al.: “Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30183-4 DOI: 10.1016/j.cmet.2019.03.013

This study was supported by the Novo Nordisk Foundation, the Swedish Diabetes Foundation, the Swedish Research Council, the National Institutes of Health, INSERM, and the Della Martin Foundation.

In recent years there has been a surge in studies looking at the biologic effects of different kinds of fasting diets in both animal models and humans. These diets include continuous calorie restriction, intermittent fasting, and alternate-day fasting (ADF). Now the largest study of its kind to look at the effects of strict ADF in healthy people has shown a number of health benefits. The participants alternated 36 hours of zero-calorie intake with 12 hours of unlimited eating. The findings are reported August 27 in the journal Cell Metabolism.

“Strict ADF is one of the most extreme diet interventions, and it has not been sufficiently investigated within randomized controlled trials,” says Frank Madeo, a professor of the Institute of Molecular Biosciences at Karl-Franzens University of Graz in Austria. “In this study, we aimed to explore a broad range of parameters, from physiological to molecular measures. If ADF and other dietary interventions differ in their physiological and molecular effects, complex studies are needed in humans that compare different diets.”

In this randomized controlled trial, 60 participants were enrolled for four weeks and randomized to either an ADF or an ad libitum control group, the latter of which could eat as much as they wanted. Participants in both groups were all of normal weight and were healthy. To ensure that the people in the ADF group did not take in any calories during fast days, they underwent continuous glucose monitoring. They were also asked to fill in diaries documenting their fasting days. Periodically, the participants had to go to a research facility, where they were instructed on whether to follow ADF or their usual diet, but other than that they lived their normal, everyday lives.

Additionally, the researchers studied a group of 30 people who had already practiced more than six months of strict ADF previous to the study enrollment. They compared them to normal, healthy controls who had no fasting experience. For this ADF cohort, the main focus was to examine the long-term safety of the intervention.

“We found that on average, during the 12 hours when they could eat normally, the participants in the ADF group compensated for some of the calories lost from the fasting, but not all,” says Harald Sourij, a professor at the Medical University of Graz. “Overall, they reached a mean calorie restriction of about 35% and lost an average of 3.5 kg [7.7 lb] during four weeks of ADF.”

The investigators found several biological effects in the ADF group:

* The participants had fluctuating downregulation of amino acids, in particular the amino acid methionine. Amino acid restriction has been shown to cause lifespan extension in rodents.

• They had continuous upregulation of ketone bodies, even on nonfasting days. This has been shown to promote health in various contexts.
• They had reduced levels of sICAM-1, a marker linked to age-associated disease and inflammation.
• They had lowered levels of triiodothyronine without impaired thyroid gland function. Previously, lowered levels of this hormone have been linked to longevity in humans.
• They had lowered levels of cholesterol.
• They had a reduction of lipotoxic android trunk fat mass–commonly known as belly fat.

“Why exactly calorie restriction and fasting induce so many beneficial effects is not fully clear yet,” says Thomas Pieber, head of endocrinology at the Medical University of Graz. “The elegant thing about strict ADF is that it doesn’t require participants to count their meals and calories: they just don’t eat anything for one day.”

The investigators point to other benefits that ADF may have, compared with continuous calorie restriction. Previous studies have suggested calorie-restrictive diets can result in malnutrition and a decrease in immune function. In contrast, even after six months of ADF, the immune function in the participants appeared to be stable.

“The reason might be due to evolutionary biology,” Madeo explains. “Our physiology is familiar with periods of starvation followed by food excesses. It might also be that continuous low-calorie intake hinders the induction of the age-protective autophagy program, which is switched on during fasting breaks.”

Despite the benefits, the researchers say they do not recommend ADF as a general nutrition scheme for everybody. “We feel that it is a good regime for some months for obese people to cut weight, or it might even be a useful clinical intervention in diseases driven by inflammation,” Madeo says. “However, further research is needed before it can be applied in daily practice. Additionally, we advise people not to fast if they have a viral infection, because the immune system probably requires immediate energy to fight viruses. Hence, it is important to consult a doctor before any harsh dietary regime is undertaken.”

In the future, the researchers plan to study the effects of strict ADF in different groups of people including people with obesity and diabetes. They also plan to compare ADF to other dietary interventions and to further explore the molecular mechanisms in animal models.

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The research was primarily funded by the Austrian Science Fund; the Austrian Federal Ministry of Education, Science and Research; the University of Graz, and the field of excellence program BioHealth. Additional funding and declarations of interests can be found in the study.

Cell Metabolism, Stekovic, Hofer, and Tripolt et al.: “Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans.” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30429-2

Previous studies have looked at employing time-restricted eating (TRE), a form of intermittent fasting, as a way to lose weight and improve health measures such as blood sugar and blood pressure in mice and healthy people. But in a study publishing December 5 in the journal Cell Metabolism, researchers for the first time looked at the effects of TRE in people who had been diagnosed with metabolic syndrome and therefore were at a higher risk of diabetes, heart disease, and stroke. The investigators found that when participants restricted their eating to 10 hours or less over a period of 12 weeks, they lost weight and some symptoms of metabolic syndrome improved.

“There has been a lot of discussion about intermittent fasting and what time window people should eat within to get the benefits of this kind of diet,” says co-corresponding author Satchidananda Panda, a Professor at the Salk Institute. “Based on what we’ve observed in mice, a 10-hour time window seems to convey these benefits. At the same time, it’s not so restrictive that people can’t follow it long-term.”

Metabolic syndrome is characterized by having three or more of five specific risk factors: high fasting blood sugar, high blood pressure, high triglyceride levels, low HDL (“good”) cholesterol, and abdominal obesity. People with metabolic syndrome are at greatly increased risk of developing more severe health problems, including diabetes, heart disease, and stroke.

“As a preventive cardiologist, I try to work with my patients and encourage them to make lifestyle changes, but it is very hard to get them to make lasting and meaningful changes,” says co-corresponding author Pam Taub, a cardiologist and Associate Professor of Medicine at the University of California San Diego School of Medicine. “When someone has been diagnosed with metabolic syndrome, this is a critical window for intervention. Once people become diabetic or are on multiple medications such as insulin, it’s very hard to reverse the disease process.”

In the study, 19 individuals with metabolic syndrome were recruited to participate in a program of TRE for three months. They were told they could decide what time to eat and how much to eat as long as all food consumption occurred within a 10-hour window. Most of the people in the study were obese and 84% were taking at least one medication, like a statin or antihypertensive.

At the end of the 12 weeks, the participants had an average of a 3% reduction in their weight and body mass index (BMI) and a 3% reduction in abdominal/visceral fat. Many also had reductions in cholesterol and blood pressure and improvements in fasting glucose.

Participants in the study used an app created by Panda called myCircadianClock (mCC) to log the times they ate and also to track their sleep. They also wore activity monitors that measured their sleeping and waking patterns and a glucose monitor that continuously tracked their glucose levels.

“We told people that they could choose when they ate their meals, as long as they remained within the 10-hour window,” Panda says. “We found that universally, they chose to eat breakfast later, about two hours after waking, and to eat dinner earlier, about three hours before going to bed.” He notes that in addition to the improvements seen in body weight and measures of metabolic syndrome, 70% of the participants also reported an increase in sleep satisfaction or in the amount they slept.

Taub says that the participants, about half of whom were already her patients, also reported generally having more energy, and some were able to have their medications lowered or stopped after completing the study. Overall, they told her that the plan was easier to follow than counting calories or embarking on an exercise program. More than two-thirds of participants continued with TRE for up to a year after the study was over, at least part of the time, she says.

Based on this pilot study, Taub and Panda have already begun a randomized, controlled clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to confirm the benefits of TRE in people with metabolic syndrome. They plan to recruit more than 100 participants–half for each arm. They also intend to conduct additional research to look at other physiological responses to TRE, including effects on the mitochondria in skeletal muscle and changes in liver function.

For anyone considering trying TRE, Taub recommends they first consult with a physician. This is especially important for anyone with metabolic syndrome who is already taking medication, she notes. “Any time someone is losing weight, they need to check with their doctor about whether their medications need to be adjusted,” she says. “For instance, if a patient is on blood pressure medications and they lose a significant amount of weight their blood pressure medication needs to be lowered.”

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This study was funded by a University of California San Diego Public Health Pilot Grant, an American College of Cardiology (ACC)/Merck Research Fellowship Award, a Larry L. Hillblom Foundation Postdoctoral Fellowship, a Salk Women in Science Fellowship, the Department of Homeland Security, the Department of Defense, the Leona M. and Harry B. Helmsley Charitable Trust, the Robert Wood Johnson Foundation, and the National Institutes of Health.

Cell Metabolism, Wilkinson et al.: “Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30611-4