Time-restricted eating suggest an improvement to this article

Time-restricted eating is a form of daily fasting wherein the time of the day during which a person eats is limited, or compressed. People who practice time-restricted eating typically eat during an 8- to 12-hour daytime window and fast during the remaining 12 to 16 hours. Unlike intermittent fasting, which involves caloric restriction, time-restricted eating permits a person to eat as much as they want during the eating window. Time-restricted eating aligns the eating and fasting cycles to the body’s innate 24-hour circadian system.[1] Within the scientific literature, time-restricted eating primarily refers to human trials, while time-restricted feeding primarily refers to animal studies; however, both terms are occasionally used interchangeably.

The circadian system is composed of multiple cellular clocks found in all cells throughout the body. These clocks orchestrate the regulation of gene expression that coordinates metabolic programs needed to support bodily functions. Of the entire human genome, approximately 15 percent of the genes display daily oscillations, or fluctuations, in their activity. Many of these genes participate in carbohydrate, lipid, and cholesterol metabolism.[2] In both animal studies and human trials, time-restricted feeding and eating have elicited beneficial health effects, including weight loss, reduced fat mass, improved heart function, and enhanced aerobic capacity, without altering diet quality or quantity.[3]

The circadian component of time-restricted eating

In mammals, the circadian system is organized in a hierarchical manner, with the suprachiasmatic nucleus, or SCN, a tiny region of the brain located within the hypothalamus, acting as the master "clock." The SCN, in turn, coordinates the body's peripheral clocks, such as those found in the liver, pancreas, muscles, and fatty tissue.[4] Consequently, the master clock drives rhythms of rest and activity that determine eating-fasting cycles.[5] Together, the SCN and peripheral clocks comprise the core clock components. The rhythms of the core clocks are dynamic over the lifespan and change markedly with age, becoming increasingly deranged. These derangements are associated with aging and disease.

Light is the primary signal that entrains the master clock to set the body's 24-hour circadian cycle, synchronizing the SCN to external light-dark cycles. Other external cues, such as body temperature, oxygen delivery to tissues, and food intake also have the capacity to permanently alter the circadian system. These cues are commonly referred to as zeitgeber (a combination of two German terms, meaning "time giver") signals. The zeitgeber signals elicit alterations in the SCN and peripheral clocks' activities, which can subsequently alter the expression of genes involved in metabolism.

Food intake is the dominant zeitgeber signal in the peripheral clocks.[6] Circulating nutrients from the diet, such as glucose, amino acids, and fatty acids, and their relative quantities possess zeitgeber capacity[7] [8] [9] and can desynchronize the peripheral clocks from the SCN. For example, specific nutritional challenges in mice, such as high dietary fat intake, elicit systemic changes in circadian regulation even after just three days of the challenge.[10] [11]

Timing of food intake also determines the body's physiological response to food, especially the peripheral circadian rhythms, as seen with time-dependent alterations in glucose metabolism. For example, a trial that monitored the glycemic response to the same meal at different times of the day demonstrated that the postprandial (after a meal) glucose increase was lowest in the morning and highest in the evening.[12] Given the zeitgeber signaling capacity of food, time-restricted eating has emerged as a key intervention to maintain synchronized circadian rhythms between the master and peripheral clocks as a means to improve health.

Time-restricted eating and metabolic health

The circadian system is profoundly intertwined with an organism's metabolism to optimize performance over a 24-hour cycle. Metabolic processes such as appetite, insulin responsiveness, and energy expenditure (the number of calories needed for normal bodily function), occur in rhythmic fashion throughout the cycle.[13] Disruption of the circadian system, whether by shift work, overeating, or aging, likely contributes to the derangement of metabolic and neurological systems.

Human trials are now demonstrating the potential of time-restricted eating as a novel means to prevent or reverse metabolic diseases. A recent study implemented both "early" eating (starting at 8 a.m.) and time-restricted eating strategies to investigate whether meal timing influences energy expenditure. When the study participants ate three standardized meals in a 6-hour window per day, they experienced decreased appetite and increased fat metabolism, compared to when they ate three standardized meals that were similar in calories and composition during a 12-hour window per day. These combined strategies may serve as a means to facilitate weight loss in overweight adults.[13]

Another study, which involved obese people who followed an 8-hour time-restricted eating regimen for 12 weeks, found that participants experienced a 3 percent weight loss, compared to the control group, whose weight remained stable.[14] In addition, men at risk for type 2 diabetes who adhered to either a 9-hour "early" time-restricted eating window (8 a.m. to 5 p.m.) or a "delayed" window (12 p.m. to 9 p.m.) experienced a 36 percent reduction in their glycemic response to a meal as well as reduced fasting triglycerides. These findings suggest that there is likely some flexibility in determining the window during which a person eats when practicing time-restricted eating.[15]

Studies also show that time-restricted eating improves circulating insulin and blood pressure independent of weight loss. For example, in a small study involving eight overweight men with prediabetes who were randomized to early time-restricted eating (a 6-hour eating period, with dinner before 3 p.m.) or a control schedule (a 12-hour eating period) for five weeks, the morning systolic and diastolic blood pressure readings of the participants in the 6-hour time-restricted eating window decreased by 11mm and 10mm, respectively, which is comparable to the improvements commonly observed with anti-hypertensive medications such as angiotensin-converting enzyme, or ACE, inhibitors. In addition, the fasting insulin levels of participants in the 6-hour window decreased by 3.4mU/L, and plasma levels of 8-isoprostane, a marker for lipid oxidative stress, decreased by 14 percent.[16]

A very recent study looked at whether the weight loss benefits associated with TRE arise from changes in how the body metabolizes food or whether they're simply an artifact of eating less during the restricted period. The study involved 11 overweight adults who ate on an early time-restricted eating schedule (8 a.m. to 2 p.m.) and a control schedule (8 a.m. to 8 p.m.) for four days each. On the fourth day, the participants' energy expenditure and metabolic measures were assessed. When the participants followed the early TRE schedule, their hunger levels were diminished, they felt fuller, and their levels of ghrelin, an appetite-stimulating hormone, were lower, compared to eating on the control schedule. The authors of the study concluded that TRE could facilitate weight loss by decreasing appetite.[13]

A separate group of researchers gathered data from the same participants to investigate the effects of early time-restricted eating on 24-hour glucose levels and markers of circadian rhythms, aging, and autophagy. They found that when the participants followed the early schedule of eating, they had lower 24-hour blood glucose, lower evening cortisol, and higher BDNF levels. The participants also had increased levels of the ketone beta-hydroxybutyrate, demonstrating that short-term daily fasting can modestly increase circulating ketones. In addition, their gene-expression changed: levels of an autophagy-related gene increased by 22 percent, suggesting that some degree of autophagy occurred during the fasting window, and levels of SIRT1, an aging gene, increased by as much as 13 percent.[17]

In patients with metabolic syndrome, a 10-hour time-restricted eating window and 14-hour fasting window for 12 weeks reduced weight, blood pressure, and atherogenic lipids. The study included 13 men and 6 women, a majority who were considered to be obese, with an average age of 59 years; 12 of the patients had elevated fasting glucose and HbA1c (a biomarker of circulating glucose), at a level considered pre-diabetic. Additionally, 16 of the patients were taking statins or anti-hypertensive medications. The participants chose their 10-hour eating window between 8 a.m. and 10 a.m. and ended the eating window between 6 p.m. and 8 p.m. A cell phone app was used to log calorie intake and monitor adherence to the 12 week time-restricted eating regime. The average adherence to the 12 week regime was 85.61 percent. After 12 weeks, time-restricted eating resulted in a significant decrease of 3.3 kilograms (7.26 pounds) in body weight and approximately a 3 percent decrease in body fat compared to baseline. The average decrease in body weight by week was approximately 275 grams, which is considered within the safe range for weight loss. The researchers noted that there was an average 8.62 percent decrease in daily calorie intake despite no recommendations to change dietary quantity or quality and a trend of decreased physical activity over the 12 week period.

Within the same study, the patients also had significant reductions in circulating lipids that are associated with cardiovascular disease. Total cholesterol was significantly reduced by 7 percent and low-density lipoprotein cholesterol was significantly reduced by 11 percent compared to baseline levels. Further, systolic blood pressure was significantly reduced by 4 percent and diastolic blood pressure was significantly reduced by 8 percent compared to baseline. The researchers noted that time-restricted eating may be an effective therapy in conjunction with statins and anti-hypertensive medication. Statins are recommended in high-risk patients to reduce low-density lipoprotein cholesterol below 100 milligrams per deciliter of plasma. Time-restricted eating reduced low-density lipoprotein cholesterol from a baseline value of 104 milligrams per deciliter to 92 milligrams per deciliter. Time-restricted eating also decreased blood pressure in light of 63 percent of the patients actively taking anti-hypertensive medication. The 12 patients who had elevated fasting blood glucose levels at baseline had a significant 3.7 percent decrease in HbA1c levels after 12 weeks. A statistical analysis found an absence of a significant correlation between changes in weight and the metabolic parameters measured, which could indicate that the metabolic improvements may not entirely be driven by weight reduction but by other mechanisms of time-restricted eating.[18]

A larger study of 116 participants with obesity, between the ages of 18 to 64 years, found that a delayed 8-hour time-restricted eating window and 16-hour fasting window had minimal effects on body weight; a sub-analysis that included 46 of the participants found that the metabolic parameters including fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, HbA1C, triglycerides, total cholesterol, low-density lipoprotein levels and high-density lipoprotein levels were unchanged with time-restricted eating. The participants were randomized to follow a 8-hour eating period (12 p.m to 8 p.m.) with water, zero-calorie drinks, and coffee with calorie-free sweetener permitted during the fasting cycle. The control group followed a consistent eating pattern of 3 meals per day with snacks permitted. Compared to pre intervention the control group lost approximately 1.5 pounds while the time-restricted eating group lost approximately 2.1 pounds after 12 weeks. No statistically significant difference in body weight between groups was observed. The self-reported adherence to the diet of the control group was 92.1 percent and 83.5 percent for the time-restricted eating group, although these adherence estimates may be inaccurate since the researchers did not directly monitor daily adherence to the eating regimens. Additionally, there was no monitoring of diet, recommendations for calorie and macronutrient intake or physical activity.

A subgroup of 46 participants, 24 individuals who followed the control regime and 22 who followed the time-restricted eating regime, completed in-person metabolic testing. There were no significant differences between the groups in fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, HbA1C, triglycerides, total cholesterol, low-density lipoprotein levels and high-density lipoprotein levels. Further, there was no observed change in fat mass in either group, but the researchers attributed the decrease in body weight to an observed reduction in lean mass only in the individuals who followed the time-restricted eating regime. The researchers reported that the loss of lean mass far exceeds the normal 20 to 30 percent typically observed with weight loss. Since a daily food log was not recorded, it is possible that the individuals who followed the time-restricted eating regime were consuming inadequate amounts of protein and therefore lost muscle mass. In fact, a separate study found that when calorie and protein intake during time-restricted eating was matched to baseline intake, no reductions in lean mass was observed.[19] Additionally, lean mass was calculated as fat-free mass minus bone mineral content, however the decrease in lean mass could have been attributed to water weight and not muscle. It is possible that the negligible effects seen with time-restricted eating were due to a lack of adherence to the 16-hour fasting window.[20] Future data from ongoing clinical trials will further elucidate the effects of time-restricted eating on metabolic diseases.

Recent animal studies have revealed that time-restricted eating can improve metabolic health. Mice that were fed a variety of obesogenic diets while following an 8- to 10-hour time-restricted weekday eating regimen experienced an attenuation of metabolic syndrome through improvements in glucose tolerance and insulin resistance, protection against hypercholesterolemia, and reductions in whole-body fat accumulation. These effects were maintained even when the time-restricted feeding was temporarily disrupted by unrestricted eating on the weekends.[21] Furthermore, time-restricted feeding of rodents has been shown to reverse the progression of type 2 diabetes and obesity.[22]

Time-restricted eating and muscle mass and exercise performance

In addition to the metabolic improvements observed in obese and overweight individuals, time-restricted eating has demonstrated beneficial effects in healthy adults. In conjunction with resistance training, an 8-hour time-restricted eating window in healthy males resulted in a decrease in blood glucose, blood insulin, and fat mass, while maintaining muscle mass.[19] Furthermore, resistance-trained females who followed an 8-hour time-restricted eating window and fasted for 16 hours per day did not experience skeletal muscle atrophy. Rather, they experienced muscle hypertrophy and performance similar to women in a control diet group who ate all their food within a 13-hour per day period. Notably, the two groups' dietary intake were similar in energy and protein content.[23]

Time-restricted feeding also appears to enhance the aerobic capacity of mice. Mice that ate during a 9-hour time-restricted feeding window ran approximately one hour longer than mice of similar weight that had unrestricted access to food.[24]

Time-restricted eating and longevity

There is some animal evidence that time-restricted feeding also elicits long term health benefits, as evidenced by increased lifespan. Mice that were fed one meal per day lived approximately 11 to 14 percent longer when fed the same caloric content as mice that ate freely, suggesting that time-restricted feeding not only improves metabolic health but may be a contributor to longevity even in the absence of caloric restriction.[25]

Coffee and time-restricted eating

As described above, nutrients such as glucose, amino acids, and fatty acids possess zeitgeber capacity and can activate peripheral clocks such as those in the liver.[7] [8] [9] It is unclear whether caffeine, such as that found in black coffee, can act as a zeitgeber to activate peripheral clocks. Since time-restricted eating has a circadian component to it, and caffeine disrupts circadian rhythms through its stimulating effects, some argue that it could affect peripheral clocks. For example, caffeine consumption at night induced a 40-minute shift in the body's internal clock, about half the shift that occurred after three hours of night-time bright light exposure.[26] Additionally, caffeine is taken up in the gut and metabolized in the liver, activating metabolic processes in those tissues and potentially starting the circadian clocks.[27]

However, some time-restricted eating studies demonstrating health benefits have included black coffee in their protocols. For example, when women who were in remission for breast cancer practiced a time-restricted eating protocol that included an 11-hour window of eating and a 13-hour period of fasting in which black coffee consumption was permitted, the women experienced a 36 percent reduction in breast cancer recurrence.[28] In a pilot study in which people with diabetes practiced time-restricted eating within a 4- to 8-hour window but were allowed to drink coffee and tea during the fasting period, the participants showed improvements in glucose regulation and weight loss. Notably, they also had an 18 percent reduction in caloric intake, a potential confounder for their findings.[29] Lastly, polyphenols in caffeinated or decaffeinated coffee induce autophagy in the liver, muscle, and heart in mice four hours after consumption.[30]

Genetic mechanisms

The circadian system in most cells relies primarily on two feedback loops in which the translation of core clock genes is regulated by their own protein products. These interlocking feedback loops generate rhythmic transcription cycles to control sleep-wake and eating-fasting cycles by driving the expression of thousands of target genes.

Many of these genes that follow rhythmic patterns are involved in metabolism and can directly interact with the core clock genes to coordinate metabolic programs. For example, the peroxisome proliferator-activated receptors family (PPARs) follow circadian oscillations, and their various isoforms can regulate adipocyte differentiation and fatty acid synthesis (PPAR𝛾), modulate the fatty acid oxidation and amino acid catabolism in the liver (PPARα), and regulate the inflammatory process as well as increase muscle fatty acid oxidation (PPARẟ). The two isoforms PPARα and PPAR𝛾 have been shown to interact with other clock genes, leading to time-dependent alterations of lipid metabolism.[9] Genes involved in glucose uptake and metabolism, such as the hepatic glucose transporter and the enzyme glucokinase, also show daily rhythms, which likely coincide with alterations in glucose and insulin sensitivity at various times of the day.[31]

Further linking the circadian clock and metabolism, animal studies, clinical studies, and observational studies have demonstrated that frequent disruptions in light-dark and eating-fasting cycles can lead to circadian dysregulation and metabolic dysfunction. Mice whose core clock genes have been knocked out develop metabolic syndrome and become obese, indicating a link between circadian regulation and metabolism.[32] [33] [34] [35] [36]. Furthermore, shift workers and healthy people who intentionally disrupt their circadian rhythms exhibit signs of metabolic dysfunction and higher incidence of several chronic diseases, including cancer.[37] [38] Genome-wide association studies, or GWAS, have also uncovered human gene polymorphisms in the principal circadian clock gene, CLOCK, that are associated with overweight or obesity.[39] [40] [41]

Disruptions in the body's innate 24-hour clocks due to irregular light-dark cycles and unrestricted eating have been implicated in the pathogenesis of several metabolic and neurological diseases, as well as cancer. Time-restricted eating, however, is emerging as a potential strategy for avoiding major dietary changes while improving overall metabolic health. Further research likely will elucidate many of the mechanisms that elicit these beneficial effects while also uncovering the therapeutic potential of time-restricted eating to prevent or improve the prognosis of age-related diseases.

Learn more about time-restricted eating in this episode with Dr. Satchin Panda

A COMPREHENSIVE OVERVIEW OF TIME-RESTRICTED EATING

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