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]
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.[17] Furthermore, time-restricted feeding of rodents has been shown to reverse the progression of type 2 diabetes and obesity.[18]
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.[20]
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.[21]
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.[22]
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.[23] 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.[24]
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.[25] 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.[26] Lastly, polyphenols in caffeinated or decaffeinated coffee induce autophagy in the liver, muscle, and heart in mice four hours after consumption.[27]
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.[28]
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.[29] [30] [31] [32] [33]. 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.[34] [35] 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.[36] [37] [38]
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
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